Rozprawy doktorskie: „Neurodegenerative disease”

1

Biro, Andrew J. "Specific aspects of neurodegenerative disease". Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/28919.

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This thesis is broken into four chapters. The first two chapters summarize two separate lines of investigation into the role of a putative neurotoxin in the pathogenesis of Huntington's Disease (HD). The third chapter outlines an investigation of the putative role of beta-N-methylamino-L-alanine (BMAA) in the pathogenesis of amyotrophic lateral sclerosis (ALS), while the final chapter details a post-mortem investigation of the contents of biogenic amines and amino acids in the brain of a man who died of a familial form of parkinsonism. Chapter I is a description of a chromatographic technique developed to isolate quinolinic acid (QA), an endogenous compound implicated in the pathogenesis of HD, from deproteinized human sera. A cation exchange column was used to selectively isolate QA, which was eluted with 10 mM HCl. The eluted fractions were analyzed by UV spectrometry to isolate and quantify QA. Once the fractions corresponding the elution of authentic QA were isolated, concentrated and the excess HCl removed, the fractions were added to growing fetal rat striatal explant cultures as an assay of neurotoxicity. Since HD involves the selective degeneration of GABAergic neurons in the striatum, the activity of glutamic acid decarboxylase, the final enzyme in the synthesis of GABA, was used to determine the viability of the cultures. Unfortunately, the method was confounded by the contamination of all effluents by compounds originating from the cation exchange resin, which were discovered to be neurotoxic to the striatal cultures, and as a result the investigation had to be abandoned. Chapter II describes an investigation designed to further characterize the nature of neurotoxicity observed in the sera obtained from patients with HD (Perry et al. 1987). Compounds with the capacity to selectively stimulate neurons at the N-methyl-D-aspartate (NMDA) receptor have been implicated in a variety of neurodegenerative disorders, including HD. Selective antagonists at the NMDA receptor have been shown to protect neurons from the degenerative effects of such "excitotoxins". The investigation described used MK-801, a potent noncompetitive NMDA antagonist, in an attempt to protect fetal rat striatal cultures from the neurodegenerative effects of the sera obtained from HD patients. The results obtained were equivocal. No evidence was obtained to support a role of the NMDA receptor in the mediation of the neurotoxicity, and in addition the neurodegenerative effects of HD sera were not reproduced in the present investigation. A variety of possible explanations for the apparent discrepancy are suggested. Chapter III describes an experiment intended to produce an animal model of ALS based on the observations by Spencer et al. 1987 that chronic oral administration of BMAA in monkeys produced the histological and behavioural characteristics of this disease. In the present investigation synthetic D,L-BMAA was given by gavage to mice over an eleven week period. Since BMAA is known to act at the NMDA receptor, a subset of the mice were also given MK-801 in an effort to protect them from any deleterious effects based on the action of BMAA at this receptor. The animals were sacrificed at the end of the experiment, and biochemical analyses were performed on the striata and cortices of the animals. In addition, neuropathological studies were performed on the spinal cords, basal ganglia and related structures. The results indicated no biochemical or neuropathological abnormality as a result of BMAA administration. Chapter IV describes a post-mortem investigation of a man who was a member of a well described pedigree which carries an autosomal dominant form of parkinsonism. The object of the investigation was to determine post-mortem levels of dopamine, noradrenaline, serotonin and their metabolites, in addition to amino acids in various regions of brain. Although conflicting evidence was obtained during life, neuropathological findings and the present neurochemical analyses confirm the degeneration of the nigrostriatal dopaminergic tract, characteristic of parkinsonism, in this man.
Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
Graduate

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2

Sleven, Hannah. "Models of neurodegenerative mitochondrial disease". Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598048.

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Mitochondrial diseases affect the core energy generating pathways and can result in significant cognitive impairment and neurodegeneration. The mechanisms underlying the neurological and pathological consequences of mitochondrial disease are not understood and current treatment of mitochondrial diseases is limited in scope and efficacy. pyruvate dehydrogenase (PDH) and Complex I are key mitochondrial enzymes pivotal for cellular energy metabolism, and mutations in genes coding for PDH and Complex I proteins are common causes of mitochondrial disease. This thesis describes the use oftwo techniques, gene targeting, and RNA interference, to generate in vitro models of Complex I and PDH deficiency in pluripotent cell lines. Gene targeting of the ndufal gene was unsuccessful, however, a number of cell lines were isolated with significant reductions in PDH activity mediated by RNAi targeted against the Pdhal transcript. These cells lines were neurodifferentiated in vitro and used to characterise the developmental and degenerative consequences of PDH deficiency on neural cultures. The cultures were found to successfully differentiate into neural cells, but were developmentally abnormal with defective neuronal migration and neurite extension, and neuritic varicosities, an indication of neuritic degeneration in many neurological disease models. These features were activity-dependent with the most severe phenotype found in the cell line with the least residual PDH activity. These cultures were used to explore the nature of energy metabolism in PDH deficient neurons, and therapeutic strategies were successfully tested. This research has successfully established a reproducible and practical model to assess neurodegeneration in PDH deficiency, to test t reatments and to model theories of disease mechanisms. As such it provides promise for the improvement of the understanding of and treatment of disorders of brain energy metabolism in the future.

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3

Radakovic, Ratko. "Multidimensional apathy in neurodegenerative disease". Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25959.

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Apathy is characterised by a lack of motivation towards goal directed behaviour and is a symptom of various neurodegenerative diseases. There are various tools that can be used to assess apathy but a caveat of these is that they usually assess it as a unidimensional concept. Apathy has been recognised to have a multidimensional substructure. The Dimensional Apathy Scale is the only comprehensive measure designed to quantify neurobiologically-based subtypes, called Executive, Emotional and Initiation apathy. The first aim of this study was to explore multidimensional apathy, and its associations with demographic variables, in healthy, community dwelling adults. Secondly, multidimensional apathy was explored in neurodegenerative diseases, specifically Amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD). For each disease group, the validity and reliability of both the self rated and carer rated DAS were also determined. Finally, the association between specific apathy subtype impairments and executive dysfunction was explored in ALS patients. Four hundred healthy community dwelling adults, eighty-three ALS patients (seventy-five carers), thirty-four PD patients (thirty carers) and forty-nine AD patients (eighty-nine carers) were recruited for the questionnaire study. In the healthy community dwelling adults, Executive apathy decreased with age, whereas Emotional increased with age. Gender differences were also shown with higher apathy in males on Emotional apathy. There were also employment differences, in that Executive apathy was higher in unemployed individuals compared to those who were employed. Emotional apathy showed difference in type of employment, where full time employed individuals were significantly more apathetic than those employed part time. These findings were taken into account in selecting the appropriate control samples to match our patient groups. In the patient groups, ALS patients were found to be significantly more impaired on the Initiation subscale when compared to controls. Furthermore, Initiation apathy was found to be the most frequent impairment above abnormality cut-off on the carer rated DAS. PD patients were significantly more impaired on Executive and Initiation apathy when compared to controls. These two subscales were most frequently above abnormality cut-off in the carer rated DAS. Finally, AD patients were significantly more impaired on all subscales when compared to controls and, on the carer rated DAS, global impairment over all subscales was most often reported as above abnormality cut-off. Additionally in AD, there was a significant disparity between carer and patient ratings on Executive and Initiation apathy, indicating patients’ impaired awareness. When comparing patient groups, there was a significant difference between carer rated apathy subtype impairments for each patient group. Validity and reliability of the DAS was found to be robust when compared to standard measures of apathy and depression. In the experimental study, a sample of ALS patients (and their carers) and healthy controls (and their informants) were recruited to complete a battery of neuropsychological tests, the DAS, other apathy and depression measures. ALS patients were impaired on tasks of executive functioning when compared to controls. Furthermore, apathy subtype deficits were associated with executive dysfunction in ALS. In conclusion, apathy is a multidimensional concept that manifests in different subtype profiles dependent on neurodegenerative disease. This has further implications for understanding and assessment of cognitive dysfunction and neuropsychiatric symptoms, such as apathy, in ALS and other neurodegenerative disease patient groups.

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Dury, R. J. "Understanding haemodynamics in neurodegenerative disease". Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/50380/.

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In this thesis, the haemodynamic, functional and structural changes in Alzheimer's Disease, Huntington's Disease and Multiple Sclerosis are assessed at 7T. Across all chapters, there is a focus on the use of Arterial Spin Labelling (ASL) to provide haemodynamic measures of perfusion (or cerebral blood flow) and transit time (TT) to provide a useful marker of disease. Arterial Spin Labelling (ASL) has the advantage that it is a non-invasive method to measure perfusion using magnetic resonance imaging (MRI). Clinically, perfusion is assessed using contrast-enhanced techniques which requires the intravenous administration of an exogenous gadolinium-based contrast agent, such as Prohance-TM and Gadovist-TM. Contrast-enhanced techniques typically provide higher SNR than ASL methods, however the non-invasive nature of ASL makes it a safe method suited for repeated measures in any subjects, including those with poor renal clearance. Additionally, gadolinium contrast agents have been shown to accumulate in neuronal tissue, and until the clinical significance of this is determined, contrast-enhanced scans should be performed with caution. In Chapter 5, arterial spin labelling is used to assess cerebral perfusion in a patient group with Alzheimer's Disease (AD) and compared with an age-matched healthy control group (HC). Functional MRI (fMRI) is used to assess functional connectivity within the default mode network (DMN) and measures compared between the AD and HC group. In addition, high resolution structural data is acquired to assess the effects of atrophy in AD. Results demonstrate a significant decrease in grey matter perfusion and a significant increase in grey matter transit time in the AD group compared the HC group. A trend showing a decrease in functional connectivity in the DMN was found in the AD group as compared to the HC group. As expected, significant grey matter loss and cortical thinning were observed in the AD group compared to the HC group. Secondly, haemodynamic and vascular changes in a Huntington's Disease (HD) patient group are assessed and compared with healthy age matched controls (HC). Phase contrast angiography is used to assess vessel density and vessel radius distributions between the two groups. Structural data was also acquired to assess grey matter volume and cortical thickness differences between the two groups. A significant reduction in perfusion was found in grey matter, putamen and the caudate in the HD group compared to the HC group. The ASL transit time was found to be significantly increased in the caudate and putamen in the HD group compared to the HC group. Phase contrast angiography data showed an increase in the frequency of smaller vessels (0.15-0.35mm) in the HD group compared to the HC group, whereas larger vessels appeared more frequently in the HC group. A significant reduction in grey matter volume was also observed in the HD group compared to the HC group, which manifested as thinning of the cortical ribbon. In the final study of this thesis, high spatial resolution arterial spin labelling is used to assess perfusion inside cortical lesions and compare with perfusion in surrounding normal appearing grey matter in a Multiple Sclerosis (MS) patient group. Grey matter perfusion as a function of distance from the cortical lesions was also assessed. It was found that cortical lesions have reduced perfusion compared to surrounding normal appearing grey matter. Perfusion increased and stabilised immediately outside of the cortical lesion itself, suggesting that the perfusion deficit observed is highly spatially localised.

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Vadnal, Jonathan. "Epigenetic Mechanisms in Neurodegenerative Disease". Kent State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=kent1353955013.

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Gu, Mei. "Mitochondrial function in Parkinson's disease and other neurodegenerative diseases". Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322371.

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Franco, Iborra Sandra. "Mitochondrial quality control in neurodegenerative diseases: focus on Parkinson’s disease and Huntington’s disease". Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/565668.

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Darrerament s’han produït avanços importants que han contribuït al coneixement dels mecanismes de disfunció cel·lular i mort en la malaltia de Parkinson (MP) i en la malaltia de Huntington (MH). Ambdues malalties són trastorns del moviment que es caracteritzen per la pèrdua específica de neurones dels ganglis basals, les neurones dopaminèrgiques de la substància nigra (SN), en el cas de la MP i les neurones espinoses de l’estriat, en el cas de la MH. Malgrat les diferències, ambdues comparteixen processos patològics comuns com la presència de proteïnes malplegades, l’estrés oxidatiu i disfunció mitocondrial. La mitocòndria és la font d’energia principal en les cèl·lules eucariotes, però també és un orgànul dinàmic relacionat amb una gran quantitat de processos cel·lulars. La disrupció de la homeòstasis mitocondrial i la subseqüent disfunció mitocondrial juguen un paper important en la patofisiologia de les malalties neurodegeneratives. El manteniment de la integritat mitocondrial a través de diferents mecanismes de control és crític per a la superviviència neuronal. Aquesta tesi es centra en l’estudi dels mecanismes de control de qualitat mitocondrial en la MP i la MH, per tal d’entendre millor els mecanismes que duen a la mort cel·lular. En el primer capítol, he estudiat el transport de proteïnes a la mitocòndria en models in vitro i in vivo de la MP. In vitro, la inhibició del complexe I produeix una alteració del transport de proteïnes a la mitocòndria així com una disminució dels nivells de proteïnes OXPHOS, acumulació de proteïnes agregades i disminució dels nivells de chaperones mitocondrials. Per tal de restablir el transport de proteïnes mitocondrials es van sobreexpressar dos components clau del sistema de translocases: la translocasa de la membrana externa 20 (TOM20) i la translocasa de la membrana interna 23 (TIM23). La sobreexpressió in vitro de TOM20 i TIM23 va restaurar el transport de proteïnes mitocondrials i va alleugerar la disfunció mitocondrial i la mort cel·lular. La inhibició del complexe I en ratolins també dóna lloc a una alteració del transport de proteïnes mitocondrials i produeix neurodegeneració del sistema dopaminèrgic. La sobreexpressió de TIM23 va restaurar parcialment el transport de proteïnes i va protegir lleugerament les neurones dopaminèrgiques de la SN. En canvi, la sobreexpressió de TOM20 va ser incapaç de millorar el transport de proteïnes mitocondrials i, fins i tot, va exacerbar la mort cel·lular. Aquests resultats posen de relleu el paper de la disfunció del transport de proteïnes mitocondrials, en particular de dos dels seus components, en la patogènesis de la MP i suggereixen la necessitat de futurs estudis es centrin en altres elements d’aquest sistema. En el segon capítol, he estudiat el paper de la proteïna huntingtina en la mitofàgia i com la seva mutació, que dóna lloc a una expansió de glutamines, pot afectar a aquesta funció. Per a tal fi, he treballat en un model in vitro de cèl·lules estriatals ST-Q7 (control) i ST-Q111 (mutant). En condicions fisiològiques, la mitofàgia induïda no es troba mitjançada pel reclutament de parkin als mitocondris despolaritzats. La huntingtina mutada afecta la mitofàgia induïda a través de l’alteració de la seva funció de scaffold en diferents passos del procés de mitofàgia: (i) activació d’ULK1 a través de l’alliberament de mTORC1, (ii) formació del complexe Beclin 1-Vps15,(iii) interacció dels adaptadors de mitofàgia OPTN i NDP52 amb huntingtina i, (iv) amb LC3. Com a resultat, els mitocondris de les cèl·lules ST-Q111 estan més danyats i tenen una respiració mitocondrial deficient. Aquests resultats demostren la presència d’una alteració en la mitofàgia com un mecanisme lligat a la MH. En conclusió, el descobriment de noves dianes mitocondrials en la MP i MH emfatitza el paper important que juga el control de qualitat mitocondrial en la neurodegeneració.
In the past years, several important advances have expanded our understanding of the pathways that lead to cell dysfunction and death in Parkinson’s disease (PD) and Huntington’s disease (HD). Both diseases are movement disorders characterized by the loss of a specific subset of neurons within the basal ganglia, dopaminergic neurons in the substantia nigra pars compacta (SNpc), in the case of PD, and medium spiny neurons in the striatum, in the case of HD,. Despite distinct clinical and pathological features, these two neurodegenerative disorders share critical underlying pathogenic mechanisms such as the presence of misfolded and/or aggregated proteins, oxidative stress and mitochondrial anomalies. Mitochondria are the prime energy source in most eukaryotic cells, but these highly dynamic organelles are also involved in a multitude of cellular events. Disruption of mitochondrial homeostasis and the subsequent mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative diseases. Therefore, maintenance of mitochondrial integrity through different surveillance mechanisms is critical for neuronal survival. In this thesis I have studied in depth some mitochondrial quality control mechanisms in the context of PD and HD, in order to broaden the knowledge about the pathomechanisms leading to cell death. In the first chapter I have studied mitochondrial protein import in in vitro and in vivo models of PD. In vitro, complex I inhibition, a characteristic pathological hallmark in PD, impaired mitochondrial protein import. This was associated with OXPHOS protein downregulation, accumulation of aggregated proteins inside mitochondria and downregulation of mitochondrial chaperones. Therefore, we aimed to reestablish the mitochondrial protein import by overexpressing two key components of the system: translocase of the outer membrane 20 (TOM20) and translocase of the inner membrane 23 (TIM23). Overexpression of TOM20 and TIM23 in vitro restored protein import into mitochondria and ameliorated mitochondrial dysfunction and cell death. Complex I inhibition also impaired mitochondrial protein import and led to dopaminergic neurodegeneration in vivo. Overexpression of TIM23 partially rescued protein import into mitochondria and slightly protected dopaminergic neurons in the SNpc. On the contrary, TOM20 overexpression did not rescue protein import into mitochondria and exacerbated neurodegeneration in both SNpc and striatum. These results highlight mitochondrial protein import dysfunction and the distinct role of two of their components in the pathogenesis of PD and suggest the need for future studies to target other elements in the system. In the second chapter, I have studied the role of huntingtin in mitophagy and how the polyglutamine expansion present in mutant huntingtin can affect its function. For such, I worked with differentiated striatal ST-Q7 (as control) and ST-Q111 (as mutant) cells, expressing full length huntingtin. In these conditions, induced mitophagy was not mediated by Parkin recruitment into depolarized mitochondria. Mutant huntingtin impaired induced mitophagy by altering wildtype huntingtin scaffolding activity at different steps of mitophagy process: (i) ULK1 activation through its release from the mTORC1, (ii) Beclin1-Vps15 complex formation, (iii) interaction of the mitophagy adapters OPTN and NDP52 with huntingtin and (iv) with LC3. As a result, mitochondria from ST-Q111 cells exhibited increased damage and altered mitochondrial respiration. These results uncover impaired mitophagy as a potential pathological mechanism linked with HD. In conclusion, we have discovered new mitochondrial targets for PD and HD emphasizing the important role that mitochondrial quality control plays in neurodegeneration

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Ryan, Philip. "An Investigation Into Novel Molecular Strategies Targeting Neurodegenerative Diseases". Thesis, Griffith University, 2020. http://hdl.handle.net/10072/395102.

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Neurodegenerative diseases are characterised by the progressive loss of neuron function and structure. The most prevalent neurodegenerative diseases are hypothesized to be due to the misfolding and accumulation of specific proteins in the brain. Alzheimer’s disease (AD) is suspected to result from the aggregation of amyloid-β (Aβ) or tau proteins, Parkinson’s disease (PD) from the aggregation of α-synuclein (α-syn), and so on for numerous other diseases including Huntington’s disease, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. There are no curative therapies for any of these fatal diseases, only palliative care is available in some cases currently. Research is currently focussed on modulating the aggregation processes common amongst the diseases. Various projects are dedicated to targeting the protein monomers, or small oligomeric assemblies, present at the early stages toward therapy. Modern strategies to target these proteins involve the use of peptide-based agents, effective at selectively binding the proteins through engaging with multiple sites along the protein sequences; and multitarget directed ligands (MTDL), which engage with multiple pathological factors to produce an overall beneficial effect. Here we set out to investigate various novel chemical scaffolds that we envisaged may prove effective at inhibiting protein aggregation mechanisms in the hopes of identifying new strategies and promising leads. Following review of the literature, compound scaffolds were designed based on existing data and then synthetic chemistry was employed to construct panels of candidate inhibitors. The compounds synthesised were then screened against protein aggregation including Aβ, α-syn and prion formation. Chapter 2 describes the development of a novel strategy to construct selective glycopeptide-based inhibitors of protein aggregation. This strategy employs the peptide sequences that are reported to recognise the target proteins in their monomeric or oligomeric state and then hinder their aggregation via a disruptive glycoside unit. This component of the project led to the identification of an inhibitor of α-syn aggregation and provided proof-of-concept for the design. The rationale was also used for the construction of Aβ and tau-targeted inhibitors, however evaluation of their effectiveness is ongoing. Chapter 3 describes the use of the quinazoline scaffold to construct MTDLs designed to be capable of modulating the aggregation of α-syn and the formation of prion proteins. This component of the project led to the identification of a panel of highly potent inhibitors of prion formation in yeast, which are undergoing further evaluation currently, as well as a number of leads that are effective α-syn aggregation inhibitors. Chapter 4 describes investigation into α-syn oligomerisation modulating analogues of anle138b, a promising candidate undergoing preclinical development. The compounds designed and synthesised were found to be as effective as inhibiting α-syn aggregation in vitro as the preclinical candidate. Chapter 5 describes attempts at investigating the thiazolone scaffold for use in the design of MTDLs targeting protein aggregation. Unfortunately, this objective of the project was hampered by challenging syntheses and unfavourable solubility profiles, discouraging further commitment to the component of the project. In summary, a number of novel molecular scaffolds were designed, synthesised and found to be effective modulators of protein aggregation implicated in multiple neurodegenerative diseases. This project has culminated in the identification of promising leads against pathological targets for PD, prionopathy, and AD therapy, as well as contributing to the knowledgebase to stimulate future research efforts.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Pharmacy and Pharmac
Griffith Health
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Blundell, James Michael. "Cognitive assessment of paediatric neurodegenerative disease". Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6042/.

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Inherited metabolic diseases (IMD’s) are a large class of heterogeneous genetic disorders caused by dysfunction within a single pathway of intermediary metabolism. In many of these diseases, the dysfunction of metabolic enzymes leads to the accumulation of toxic metabolites which disrupts the normal development of the central nervous system. With the advent of treatments that positively influence neuropsychological outcomes, there is a need for sensitive and objective neuropsychological measures that allow patients to be systematically tracked in order to understand the efficacy of existing treatments. In this thesis, a neuropsychological test battery consisting of attention, language and oculomotor measures was developed to accurately describe individual and developmental differences between IMD patients and healthy developing controls. The functioning of five diseases was examined: Morquio syndrome (\(N\) = 12), Hurler syndrome (\(N\) = 3), Maroteux-Lamy syndrome (\(N\) = 2), Tyrosinemia type I (\(N\) = 13) and Tyrosinemia type III (\(N\) = 5). Findings indicated that disease effects were not homogeneous across tasks, and that performance on the same tasks was not uniform across diseases. The obtained data offers a promising basis for understanding how biological factors influence the severity and timecourse of developmental effects in future research.

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STOCCORO, ANDREA. "Mitoepigenetics investigations in neurodegenerative diseases". Doctoral thesis, Università di Siena, 2019. http://hdl.handle.net/11365/1072183.

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Neurodegenerative diseases (NDs) represent a group of disorders characterized by the progressive neuronal loss in specific areas of the central nervous system. NDs are incurable and often fatal shortly after diagnosis. The global prevalence of these disorders is dramatically increasing worldwide as populations age and life expectancies increase. The identification of valuable biomarkers for an early diagnosis is of outmost importance as it would promote early interventions able to prevent or delay as much as possible the onset of the disease. Despite their high heterogeneity and the differences in their primary etiologies, NDs share many common aspects in relation to their clinical, biochemical, and pathological features and multiple lines of evidence suggest that mitochondrial dysfunction is involved in the pathogenesis of many NDs, especially Alzheimer´s disease (AD), Parkinson´s disease (PD) and amyotrophic lateral sclerosis (ALS). To date, several papers showed that aberrant epigenetic mechanisms in the nuclear DNA may be involved in the onset and development of NDs, and several studies have found altered gene methylation levels in both post-mortem brain specimens and peripheral tissues from patients with these diseases. In recent years growing evidence for a potential role of altered mitochondrial DNA (mtDNA) methylation and hydroxymethylation in several diseases has emerged. Although mitochondrial impairment is a classical feature of neurodegeneration, little attention has been given until now to the role of the mitochondrial epigenome itself in NDs. Particularly, studies performed so far have investigated mtDNA methylation in animal models of ALS, and in brain tissue of patients with AD, PD and ALS. However, potential mtDNA methylation alterations in peripheral tissues of NDs patients have not been investigated in those studies. The main aim of the work presented in the current thesis was to investigate the presence of mitoepigenetic signatures in peripheral blood of patients with AD (Study 1), ALS (Study 2) and PD (Study 3). DNA methylation analysis of the mitochondrial D-loop region, which regulates mitochondrial transcription and replication, was performed by means of Methylation Sensitive-High Resolution Melting and Pyrosequencing techniques. In study 1 D-loop methylation levels were analyzed in people affected by AD with different clinical dementia impairment degrees and results suggest that mtDNA methylation could vary with the stage of the disease. In study 2 D-loop methylation levels were analyzed in ALS patients with mutations in SOD1, TARDBP, FUS or C9ORF72 genes, and in their relatives, and results showed that mtDNA methylation levels were decreased in ALS tissues, partcularly in carriers of SOD1 mutations. In study 3 higher Dloop methylation levels, although not statistically significant, were detected in peripheral blood from PD patients. Results presented in the current thesis indicate a potential involvement for impaired mtDNA methylation in NDs, which is detectable in peripheral blood suggesting that this field of research deserves to be further studied. Moreover, current results suggest that mtDNA methylation could be sensitive to different disease stages and dementia levels, thus adding a new layer of interest in the search for peripheral mitoepigenetic biomarkers for neurodegeneration. Given the pivotal role of mitochondrial dysfunction and of epigenetic mechanisms in neurodegeneration, the field of mitoepigenetics in neurodegenerative diseases is a timely and attractive recent area of investigation, where preliminary results really seem encouraging, but more research is warranted to clarify the connections between epigenetic changes occurring in the mitochondrial genome, mitochondrial DNA dynamics, and the neurodegenerative process.

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Wiberg, Henning. "Analytical Approaches to Neurodegenerative Disease Protein Aggregation". Licentiate thesis, KTH, Analytisk kemi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-34027.

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Guest, William Clay. "Template-directed protein misfolding in neurodegenerative disease". Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/41990.

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Protein misfolding diseases represent a large burden to human health for which only symptomatic treatment is generally available. These diseases, such as Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, and the systemic amyloidoses, are characterized by conversion of globular, nativelyfolded proteins into pathologic β-sheet rich protein aggregates deposited in affected tissues. Understanding the thermodynamic and kinetic details of protein misfolding on a molecular level depends on accurately appraising the free energies of the folded, partially unfolded intermediate, and misfolded protein conformers. There are multiple energetic and entropic contributions to the total free energy, including nonpolar, electrostatic, solvation, and configurational terms. To accurately assess the electrostatic contribution, a method to calculate the spatially-varying dielectric constant in a protein/water system was developed using a generalization of Kirkwood Frohlich theory along with brief all-atom molecular dynamics simulations. This method was combined with previously validated models for nonpolar solvation and configurational entropy in an algorithm to calculate the free energy change on partial unfolding of contiguous protein subsequences. Results were compared with those from a minimal, topologically-based Gō model and direct calculation of free energies by steered all-atom molecular dynamics simulations. This algorithm was applied to understand the early steps in the misfolding mechanism for β₂-microglobulin, prion protein, and superoxide dismutase 1 (SOD1). It was hypothesized that SOD1 misfolding may follow a template-directed mechanism like that discovered previously for prion protein, so misfolding of SOD1 was induced in cell culture by transfection with mutant SOD1 constructs and observed to stably propagate intracellularly and intercellularly much like an infectious prion. A defined minimal assay with recombinant SOD protein demonstrated the sufficiency of mutant SOD1 alone to trigger wtSOD1 misfolding, reminiscent of the “protein-only” hypothesis of prion spread. Finally, protein misfolding as a feature of disease may extend beyond neurodegeneration and amyloid formation to cancer, in which derangement of protein folding quality control may lead to antibodyrecognizable misfolded protein present selectively on cancer cell surfaces. The evidence for this hypothesis and possible therapeutic targets are discussed as a future direction.

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Yates, Alexandra Caroline. "Stress-activated protein kinases and neurodegenerative disease". Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287325.

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PATERGNANI, Simone. "Mitochondrial dysfunctions in cancer and neurodegenerative disease". Doctoral thesis, Università degli studi di Ferrara, 2013. http://hdl.handle.net/11392/2388846.

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Mitochondria are dynamic, semi-autonomous organelles surrounded by a double membrane that have their own genome and protein synthesis machinery. In addition to being the major source of ATP in eukaryotes, they are the site of many important metabolic reactions such as the urea cycle, lipid metabolism, steroid hormone and porphyrin synthesis and interconversion of amino acids. Moreover, mitochondria play a central role in complex physiological processes including cellular proliferation, differentiation, apoptosis and in cellular processes like glucose sensing/insulin regulation and cellular Ca2+ homeostasis. It is therefore not surprising that mitochondrial dysfunctions have been found to be associated with several diseases such as neurodegenerative diseases, aging and cancer. In this work, we investigate on the relationship between mitochondrial dynamics and two of the main research priorities in the world: cancer and neurodegenerative disease. In particular, we have addressed: - i) The role of the PKCβ and mitochondrial physiology in the modulation of autophagy, a major phenomenon of cell biology, which acts as a pro-survival or pro-death mechanism and takes part in different biological events. - ii) The identification of a microRNA (miR-25), highly expressed in cancer cells, that by targeting the newly discovered calcium channel of mitochondria (Mitochondrial Calcium Uniporter) reduces the sensitivity of cancer cells to apoptotic agents. - iii) How, one of the most important cytokines for the aetiology of Multiple Sclerosis, TNFα, lead to alteration of the mitochondrial bioenergetics, with a consequent impairment of oligodendrocytes differentiation In conclusion, these findings reveal new relations between mitochondria, calcium signalling and cell physiology, shedding new light on the role for this fascinating organelle.

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Sassi, Mohammed M. "Apolipoprotein-E genotype in major neurodegenerative diseases". Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339716.

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Chandrasekaran, Sreedevi. "A Network View on Neurodegenerative Disorders". VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3083.

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Neurodegeneration is a chronic, progressive and debilitating condition that affects majority of the World's elderly population who are at greater risk. Numerous scientific studies suggest that there could be a common underlying molecular mechanism that promotes the degeneration and the subsequent neuronal loss, however so far the progress in this direction is rather limited. Abnormal protein misfoldings, as well as protein plaque formations in the brain, are some of the hallmark characteristic features of neurodegenerative disorders (NDDs). Genetic and environmental factors, oxidative stress, excessive reactive oxygen species formation, mitochondrial dysfunction, energy depletion and autophagy disruption etc. are some of the widely suspected mechanisms that manifest the cognitive, motor and emotional symptoms of these NDDs. Motivated by some molecular traits found in common in several NDDs, network-based systems biology tools and techniques were used in this study to identify critical molecular players and underlying biological processes that are common for Parkinson's, Alzheimer's and Huntington's disease. Utilizing multiple microarray gene expression datasets, several biomolecular networks such as direct interaction, shortest path, and microRNA regulatory networks were constructed and analyzed for each of the disease conditions. The network-based analysis revealed 26 genes of potential interest in Parkinson's, 16 in Alzheimer's and 30 in Huntington's disease. Many new microRNA-target regulatory interactions were identified. For each disorder, several routes for possible disease initiation and protection scenarios were uncovered. A unified neurodegeneration mechanism network was constructed by utilizing the significantly differentially expressed genes found in common in Parkinson's, Alzheimer's and Huntington's microarray datasets. In this integrated network many key molecular partakers and several biological processes that were significantly affected in all three NDDs were uncovered. The integrated network also revealed complex dual-level interactions that occur between disease contributing and protecting entities. Possibilities of microRNA-target interactions were explored and many such pairs of potential interest in NDDs were suggested. Investigating the integrated network mechanism, we have identified several routes for disease initiating, as well as alleviating ones that could be utilized in common for Parkinson's, Alzheimer's and Huntington's disease. Finding such crucial and universal molecular players in addition to maintaining a delicate balance between neurodegeneration promoters and protectors is vital for restoring the homeostasis in the three NDDs.

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Last, Victoria. "A role for phospholipase A2 in neurodegenerative disease". Thesis, Royal Veterinary College (University of London), 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558969.

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Hesse, William R. (William Reichard). "Quantitative analysis of proteotoxicity associated with neurodegenerative disease". Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/112510.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2017.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 125-147).
Neurodegenerative diseases are a costly burden, both economically and in terms of human suffering. A common feature of neurodegenerative diseases is that they stem from problems with protein folding, but the underlying biology that leads to neuron death is not well understood. Due to this lack of mechanistic information there are currently no therapeutics that treat underlying mechanisms that lead to cell loss. This thesis explores the link between complications in protein folding and cell death. In the first part of this thesis, I combined modeling of the proteotoxicity of polyglutamine (as exemplified in Huntington's Disease) in Saccharomyces cerevisiae with microfluidics and automated microscopy. From these studies, I have found that glutamine-rich proteins suppress the toxicity of poly-glutamine expanded Huntingtin by physically interacting and sequestering the protein at the IPOD (insoluble protein deposit) quality control compartment. These studies have provided new insight into possible therapeutic strategies and how the proteomes of different cell types may protect or sensitize sells to specific proteotoxic stresses. In the second part of this thesis, I quantitatively and systematically studied the toxicity of a-synuclein, which is implicated in the synucleinopathy family of diseases, including Parkinson's Disease. To systematically study the effect of toxic levels of a-synuclein expression on cellular homeostasis, I constructed a library of fluorescent reporters and utilized automated, high-throughput microscopy to image changes in reporter localization and abundance in response to a-synuclein toxicity. The results from this study have illuminated a number of pathways that were not previously studied for a-synuclein toxicity and have tied together disparate findings from many other studies. Additionally, I have shown that our experimental strategy is generalizable and can be applied other yeast models of neurodegenerative toxicity, such as poly-glutamine and AO 1-42. In summary, the quantitative studies presented in this thesis have expanded our understanding of the mechanisms underlying a variety of toxicities related to neurodegeneration. The biological insights gained from these studies have helped illuminate new areas of inquiry that may be used to combat these diseases.
by William R. Hesse.
Ph. D.

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19

Mok, K. Y. B. "Genetics of neurodegenerative disease : a genome-wide approach". Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1398391/.

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Neuro-degenerative diseases present an increasingly heavy burden in our ageing population. Genetic factors play an important role in the aetiology of the neuro-degenerative diseases. Dissecting the underlying genetic mechanism gives us vital clues to the pathophysiology, and ultimately helps us develop novel therapeutic interventions. Recent technological advances in genotyping genetic variants and bioinformatics have revolutionized the approach to the study of genetic diseases. The initial major advance was the accurate genotyping and data processing for hundreds of thousands single nucleotide polymorphisms simultaneously. Studies on the association between these polymorphisms, mostly common variants, and complex diseases became feasible. The association can shed light to the pathophysiology. My thesis rides on these developments, applying them to the study of genetics in neurodegenerative diseases. The first part of the thesis is a pilot study on genetics of cervical dystonia, using a genome-wide association approach. Given the small sample size, no statistically significant results were identified. A few potential loci were suggested after imputation. The second part is a study on amyotrophic lateral sclerosis. Meta-analysis was performed on five recently published genome-wide association studies. A follow-up haplotype analysis was carried out on these cohorts, comparing this with data available from familial studies. A single founding haplotype leading to amyotrophic lateral sclerosis was proposed. Subsequent identification of the causal gene, C9orf72, within the haplotype region by our collaborators led to further phenotyping studies. The third part describes a copy number variant analysis of idiopathic Parkinson’s disease. The study was based on the genome-wide association data in the UK cohort in comparison to other cohorts. Chromosome 22q11.2 heterozygous deletion was found to play an important role in the aetiology of Parkinson’s disease. This thesis demonstrates that utilization of emerging genetic technology has advanced our understanding of some of the genetic factors predisposing to these neurodegenerative diseases.

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Mroczkowska, Stephanie. "Ocular and systemic vascular dysfunction in neurodegenerative disease". Thesis, Aston University, 2012. http://publications.aston.ac.uk/16525/.

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The important role played by vascular factors in the pathogenesis of neurodegenerative disease has been increasingly realised over recent years. The nature and impact of ocular and systemic vascular dysfunction in the pathogenesis of comparable neurodegenerative diseases such as glaucoma and Alzheimer’s disease (AD) has however never been fully explored. The aim of this thesis was therefore to investigate the presence of macro- and micro-vascular alterations in both glaucoma and AD and to explore the relationships between these two chronic, slowly progressive neurodegenerative diseases. The principle sections and findings of this work were: 1. Is the eye a window to the brain? Retinal vascular dysfunction in Alzheimer’s disease · Mild newly diagnosed AD patients demonstrated ocular vascular dysfunction, in the form of an altered retinal vascular response to flicker light, which correlated with their degree of cognitive impairment. 2. Ocular and systemic vascular abnormalities in newly diagnosed normal tension glaucoma (NTG) patients · NTG patients demonstrated an altered retinal arterial constriction response to flicker light along with an increased systemic arterial stiffness and carotid artery intima-media thickness (IMT). These findings were not replicated by healthy age matched controls. 3. Ocular vascular dysregulation in AD compares to both POAG and NTG · AD patients demonstrated altered retinal arterial reactivity to flicker light which was comparable to that of POAG patients and altered baseline venous reactivity which was comparable to that of NTG patients. Neither alteration was replicated by healthy controls. 4. POAG and NTG: two separate diseases or one continuous entity? The vascular perspective · POAG and NTG patients demonstrated comparable alterations in nocturnal systolic blood pressure (SBP) variability, ocular perfusion pressure, retinal vascular reactivity, systemic arterial stiffness and carotid IMT. · Nocturnal SBP variability was found to correlate with both retinal artery baseline diameter fluctuation and carotid IMT across the glaucoma groups.

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Keller, Margaux Finn. "HERITABILITY AND SEX-EFFECT ANALYSES OF NEURODEGENERATIVE DISEASE". Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/288134.

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Anthropology
Ph.D.
This work analyzes the genetic basis of three neurodegenerative diseases using several thousands of individuals of European descent to determine a range of phenotypic heritability outside of what has been identified by prior methods. By measuring additive genetic variance genome-wide, measures of its contribution to the phenotypic variance of these diseases were substantially increased, in some instances by a factor of 10 or more. Additionally, regional-mapping methods identified segments of the genome exhibiting significantly high heritability estimates associated with one of the neurodegenerative diseases, Amyotrophic lateral sclerosis. This resulted in the detection of novel candidate regions and provided conclusive evidence for the polygenic architecture of this disease. Lastly, novel risk variants associated with Parkinson's disease were identified on the X chromosome, a previously ignored genomic region. Overall, the employment of new analytic methods produced robust and novel results, adding substantial information to the neurodegenerative disease literature and connecting the anthropological perspective with growing informatics-based methods.
Temple University--Theses

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22

Hosp, Fabian. "A quantitative interaction screen for neurodegenerative disease proteins". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2013. http://dx.doi.org/10.18452/16669.

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Der erste Teil dieser Arbeit beschreibt die Durchführung eines quantitativen Ansatzes zur Detektion von Protein-Protein-Interaktionen (PPI) mit einem Schwerpunkt für Proteine, die in vier häufigen neurodegenerativen Krankheiten eine Rolle spielen: die Alzheimer-, Parkinson- und Huntington-Krankheit, sowie die spinozerebelläre Ataxie Typ 1 (SCA1). Die Interaktionsstudie kombiniert die stabile Isotopen-Markierung von Aminosäuren in der Zellkultur mit der Affinitätsaufreinigung von Proteinen und hochauflösender Massenspektrometrie. Dieser Ansatz zielt darauf ab, systematisch die Interaktionspartner von gesunden und krankheitsassoziierten Proteinvarianten zu identifizieren und zu quantifizieren. Darüber hinaus wurde das quantitative Interaktionsverfahren genutzt, um zu prüfen ob PPI durch krankheitsassoziierte Mutationen beeinträchtigt werden. Neben der Validierung möglicher Nebeneffekte, sowie dem Vergleich mit Informationen über PPI aus der Literatur, wurde ein Teil der identifizierten Interaktoren durch zusätzliche Koimmunopräzipitations-Experimente in zwei verschiedenen Zelllinien bestätigt. Mit Hilfe von Drosophila SCA1-Krankheitsmodellen und in Kombination mit RNAi-basierter Stummschaltung identifizierter Interaktoren wurde festgestellt, dass ein großer Teil der Kandidaten Neurodegeneration in vivo beeinflusst. Zusätzlich wurden die Alzheimer-spezifischen PPI-Daten auf genomweite Assoziationsstudien übertragen. Bemerkenswerterweise waren Polymorphismen in einzelnen Nukleotiden in den Genen zugehöriger Interaktoren wahrscheinlicher mit solchen Genen assoziiert, die eine Prädisposition für die Alzheimer-Krankheit haben, als mit zufällig ausgewählten Genen. Schlussendlich konnten Folgeexperimente für zwei ausgewählte Interaktionspartner den Nachweis für eine bislang unbekannte Rolle der N-Glykosylierung und einen neuen Zusammenhang zwischen dem RNA-bindenden Protein LRPPRC und mitochondrialer Dysfunktion in der Alzheimer-Krankheit vorlegen.
The first part of the present thesis describes the establishment of a quantitative protein-protein interaction (PPI) screen with a focus on proteins involved in four common neurodegenerative diseases (NDDs): Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and spinocerebellar ataxia type 1 (SCA1). The interaction screen combines stable-isotope labeling by amino acids in cell culture (SILAC) with protein affinity purification and high-resolution mass spectrometry. This approach aims to systematically identify and quantify interaction partners of normal and known disease-associated variants of proteins involved in NDDs. Moreover, the quantitative interaction screen was employed to study how PPIs are affected by disease-associated mutations. Along with validation of possible off-target effects and comparison of the data with literature-reported PPIs, a subset of identified interactors was validated by additional co-immunoprecipitation experiments in two different cell lines. Utilizing Drosophila models for SCA1 in combination with RNAi-mediated silencing of identified interactors, a large fraction of candidates was observed to also affect neurodegeneration in vivo. In addition, AD-specific PPI data was mapped to patient cohort data obtained from genome-wide associations studies. Notably, single-nucleotide polymorphisms in the genes of interactors of the disease-associated protein variants were more likely associated with susceptibility to AD than randomly selected genes. Finally, functional follow-ups for two selected interaction partners provided evidence for a yet unreported role of N-linked glycosylation in AD, and a novel link to mitochondrial dysfunction in AD by means of the RNA-binding protein LRPPRC.

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Pruccoli, Letizia <1989&gt. "Neuroprotective effects of coumarins in neurodegenerative disease models". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2019. http://amsdottorato.unibo.it/8975/1/Pruccoli_Letizia_tesi.pdf.

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Coumarins represent promising scaffolds for the design and development of novel polyfunctional drugs for the treatment and/or prevention of chronic neurodegenerative disorders including Alzheimer’s (AD), Parkinson’s and Huntington’s (HD) diseases. The aim of our research was to evaluate the potential antioxidant and neuroprotective effects of various natural coumarins such as esculetin (ESC), scopoletin, fraxetin and daphnetin in several experimental models of AD and HD. We used: i) human neuronal SH-SY5Y cells treated with tert-butyl hydroperoxide (t-BuOOH) and amyloid-β protein oligomers (OAβ), a specific neurotoxin for AD; ii) an inducible cell model (PC12 HD-Q74) and a transgenic Drosophila melanogaster model (HTT93Q, pan-neuronal expression), both of which express mutant huntingtin (HTT) exon 1 fragments, a typical feature of HD. The treatment with ESC prevented or counteracted the oxidative stress elicited by t-BuOOH in SH-SY5Y cells. ESC effectively increased intracellular glutathione levels and activated the translocation of Nrf2 into nucleus via Erk and Akt/GSK3β signalling pathways. ESC prevented both the oxidative damage and necrosis induced by OAβ. Further, ESC counteracted the early and late neurotoxic events, in terms of formazan exocytosis and necrosis, respectively, evoked by OAβ. The treatment with ESC partially modulated the aggregation of mutant HTT protein in PC12 HD-Q74 cells induced by doxycycline. ESC ameliorated the cell proliferation and counteracted the necrosis elicited by HTT74Q expression in PC12 HD-Q74 cells. ESC showed to counteract the oxidative stress as well as to increase the intracellular glutathione levels and restore the nuclear Nrf2 levels. In addition, ESC significantly decreased photoreceptor neurodegeneration in HTT93Q flies and enhanced in a dose-dependent manner the emergence of adult HD flies from the pupal case. ESC feeding also improved the shortening of median life span in HD flies. Our results encourage further research to better investigate the potential therapeutic profile of ESC as a neuroprotective agent.

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Nourse, Jamie. "An Examination into the Molecular Associations Between Cholesterol Homeostasis and the Neurodegenerative Disease Ataxia telangiectasia". Thesis, Griffith University, 2008. http://hdl.handle.net/10072/365866.

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The Ataxia telangiectasia (A-T) syndrome is a multisystem disorder exhibiting a complex array of clinical features for which there is no effective therapy. The earliest and most debilitating aspect of this disease is progressive ataxia resulting from neurodegeneration of the cerebellum. Several lines of evidence suggest a potential function for ATM in the maintenance of cellular homeostasis, and disruptions in functional ATM appear to result in alterations cholesterol homeostasis. This association may provide some insight into the neurodegenerative aspect of this disease. Cholesterol homeostasis is particularly significant in the central nervous system (CNS) with several neurodegenerative disorders involving disturbances in cholesterol homeostasis. The goal of this thesis was to attempt to establish a potential relationship between ATM and cholesterol homeostasis. As well it was hoped the establishment of a mechanism for such a relationship may help contribute to the establishment of therapies for this debilitating aspect of A-T...
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Science, Environment, Engineering and Technology
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Messmer, Kirsten. "Studies relating to inflammatory neurotoxicity in neurodegenerative diseases". Thesis, University of Sheffield, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340182.

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Hansson, Sara. "Proteomic strategies for analysis of cerebrospinal fluid in neurodegenerative disorders /". Göteborg : Institute of Neuroscience and Physiology, Dept. of Psychiatry and Neurochemistry at Sahlgrenska Academy University of Gothenburgh, 2008. http://hdl.handle.net/2077/9904.

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Vincenti, James Edward. "Role of activation of microglia in neurodegenerative prion disease". Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/15928.

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Prion diseases are a group of fatal neurodegenerative protein-misfolding diseases. Microglia, the resident myeloid cells found within the brain, have been shown to demonstrate a reactive morphology during the disease process with conflicting evidence for both a neurotoxic and neuroprotective role. The studies presented here aimed to investigate the role of microglia activation using transcriptomic and morphological analysis of prion disease in mice. Initially, the host immune response to prion disease was explored using a publically available mouse prion disease dataset. Re-analysis of this dataset was performed using BioLayout Express3D; a novel software tool that supports the visualisation and clustering of correlation networks. Disease-associated genes up-regulated during the later stages of infection were present in two main clusters. The cellular origin of these genes was explored by examining their expression in a dataset comprised of pure populations of cells. This demonstrated that the primary cluster of up-regulated transcripts encompassed genes expressed mainly by microglia and to a lesser extent astrocytes and neurons. The secondary cluster comprised almost exclusively of interferon response genes. The conclusions of these analyses were different from those of the original study that suggested disease-associated genes were primarily neuronal in origin. Mouse models of prion disease were established by infecting a novel line of BALB/cJ inbred mice, expressing EGFP under control of a myeloid specific Csf1r promoter, with the 79A prion strain. Quantification of the morphological changes of EGFP expressing microglia suggested the cells accumulated in the medulla at sites of early misfolded protein deposition with minimal change in their overall appearance. An activated microglia morphology was not observed until protein deposition was extensive. Isolation of EGFP expressing microglia was performed for transcriptome analysis. The vast majority of disease associated genes demonstrated increased expression at the onset of clinical symptoms. The gene list was found to be highly enriched for genes associated with an innate immune response regulated by the NFκB signalling cascade. Also highly enriched were processes associated with protein translation, energy production and stress response. These data suggest a high metabolic load is burdened by proliferating microglia; and as part of a response which is strikingly more pro-inflammatory in nature than has previously been attributed to the microglia phenotype within prion disease. As an active contributor to normal homeostasis, microglia are more than just innate immune surveillance and are now considered an integral component in both the healthy and diseased brain. The ramifications of activation toward the microglia phenotype shown here will have direct and potentially cytotoxic influence on neighbouring microglia and other brain cell types implying microglia as major contributors to the neurotoxic environment found within the CNS during prion disease. Furthermore the identification of genes associated with metabolism offer many intriguing possibilities for manipulating the activity of microglia in pre-clinical therapeutic intervention.

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Wang, Wenjia. "Item Response Theory in the Neurodegenerative Disease Data Analysis". Thesis, Bordeaux, 2017. http://www.theses.fr/2017BORD0624/document.

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Les maladies neurodégénératives, telles que la maladie d'Alzheimer (AD) et Charcot Marie Tooth (CMT), sont des maladies complexes. Leurs mécanismes pathologiques ne sont toujours pas bien compris et les progrès dans la recherche et le développement de nouvelles thérapies potentielles modifiant la maladie sont lents. Les données catégorielles, comme les échelles de notation et les données sur les études d'association génomique (GWAS), sont largement utilisées dans les maladies neurodégénératives dans le diagnostic, la prédiction et le suivi de la progression. Il est important de comprendre et d'interpréter ces données correctement si nous voulons améliorer la recherche sur les maladies neurodégénératives. Le but de cette thèse est d'utiliser la théorie psychométrique moderne: théorie de la réponse d’item pour analyser ces données catégoriques afin de mieux comprendre les maladies neurodégénératives et de faciliter la recherche de médicaments correspondante. Tout d'abord, nous avons appliqué l'analyse de Rasch afin d'évaluer la validité du score de neuropathie Charcot-Marie-Tooth (CMTNS), un critère important d'évaluation principal pour les essais cliniques de la maladie de CMT. Nous avons ensuite adapté le modèle Rasch à l'analyse des associations génétiques pour identifier les gènes associés à la maladie d'Alzheimer. Cette méthode résume les génotypes catégoriques de plusieurs marqueurs génétiques tels que les polymorphisme nucléotidique (SNPs) en un seul score génétique. Enfin, nous avons calculé l'information mutuelle basée sur la théorie de réponse d’item pour sélectionner les items sensibles dans ADAS-cog, une mesure de fonctionnement cognitif la plus utilisées dans les études de la maladie d'Alzheimer, afin de mieux évaluer le progrès de la maladie
Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Charcot Marie Tooth (CMT), are complex diseases. Their pathological mechanisms are still not well understood, and the progress in the research and development of new potential disease-modifying therapies is slow. Categorical data like rating scales and Genome-Wide Association Studies (GWAS) data are widely utilized in the neurodegenerative diseases in the diagnosis, prediction and progression monitor. It is important to understand and interpret these data correctly if we want to improve the disease research. The purpose of this thesis is to use the modern psychometric Item Response Theory to analyze these categorical data for better understanding the neurodegenerative diseases and facilitating the corresponding drug research. First, we applied the Rasch analysis in order to assess the validity of the Charcot-Marie-Tooth Neuropathy Score (CMTNS), a main endpoint for the CMT disease clinical trials. We then adapted the Rasch model to the analysis of genetic associations and used to identify genes associated with Alzheimer’s disease by summarizing the categorical genotypes of several genetic markers such as Single Nucleotide Polymorphisms (SNPs) into one genetic score. Finally, to select sensitive items in the most used psychometrical tests for Alzheimer’s disease, we calculated the mutual information based on the item response model to evaluate the sensitivity of each item on the ADAS-cog scale

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Workman, Victoria. "Microfluidic encapsulation of cells for transplantation in neurodegenerative disease". Thesis, Cardiff University, 2009. http://orca.cf.ac.uk/55884/.

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Polymer encapsulation is now an accepted route into cellular therapies via implantation of therapeutically active allogeneic and xenogeneic cells. Although many methods are currently used for encapsulation of cells, no single method is capable of producing large volumes of mono-disperse beads, containing cells completely covered by the polymer of choice. The overall aim of this project was to develop a microfluidic method to encapsulate dopamine releasing cells in an alginate matrix, determine their viability in vitro and investigate implantation into a rodent model of Parkinson's disease. During the course of this study a novel microfluidic method was developed. Two cell types were encapsulated a human test line and a therapeutic cell line derived from rat brain tumour cells (PC 12). Cell viability, measured using an adapted trypan blue exclusion method, was observed to be minimally affected by the encapsulation process. Confocal images of cells encapsulated within alginate beads were collected in addition to long term viability data, up to 90 days post-encapsulation. Dopamine was still detected after PC 12 cell encapsulation through use of an ELISA. Modifications to the developed microfluidic method allowed beads of an appropriate size (<250microm in diameter) to be implantated into a rodent brain via a cannula. Upon implantation of alginate beads into rats' brains there was no evidence of beads after 7 days. Attempts were made to stabilise alginate beads further by addition of barium as a cross-linking agent and polycation secondary coating. Beads were observed to be more stable and remained visible within brain tissue for 14 days. Imaging of fluorescent alginate beads revealed that beads produced using the developed microfluidic method were homogeneous in nature. The work presented here represents the first microfluidic method to be developed which is capable of encapsulating viable cells. Moreover, the viability measurements carried out were the first such experiments to be performed on cells encapsulated using microfluidic methods. Although the structure of alginate beads produced using more commonplace methods has been shown, this has not previously been reported for beads produced using a microfluidic technique.

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Witter, Daniel Philip. "Aspects of cholesterol homeostasis : Biochemical role in neurodegenerative disease". Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531800.

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Charriez, Christina Margaret. "ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR REGULATION IN EXPERIMENTAL NEURODEGENERATIVE DISEASE". UKnowledge, 2010. http://uknowledge.uky.edu/gradschool_diss/19.

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The α7 nicotinic acetylcholine receptor (nAChR) is involved in learning and memory, synaptic plasticity, neuroprotection, inflammation, and presynaptic regulation of neurotransmitter release. Alzheimer’s disease (AD), a neurodegenerative disease characterized by diminished cognitive abilities, memory loss, and neuropsychiatric disturbances, is associated with a loss of nAChRs. Similarly, traumatic brain injury (TBI) may result in long term neurobehavioral changes exemplified by cognitive dysfunction. Deficits in α7 nAChR expression have previously been shown in experimental TBI and may be related to cognitive impairment experienced in patients following TBI. The purpose of this dissertation was to investigate changes in α7 nAChR expression in models of neurodegeneration and determine if allosteric modulation of the nAChR facilitates functional recovery following experimental TBI through changes in nAChRs. Experimental models employed include a transgenic mouse model of AD that overexpresses the amyloid precursor protein (APPswe mice) and the controlled cortical impact injury model of TBI in rats. Quantitative receptor autoradiography using α-[125I]-bungarotoxin and [125I]-epibatidine and in situ hybridization were used to investigate changes in nAChR density and mRNA expression, respectively. In the first study, the effects of aging and β-amyloid on α7 nAChR expression were evaluated in APPswe mice. Hippocampal α7 nAChR density was significantly upregulated in APPswe mice compared to wild-type mice. It is postulated that elevated Aβ levels bind to the α7 nAChR resulting in upregulation. In a second study, galantamine, a medication used in the treatment of AD, was administered subchronically following experimental TBI to determine if treatment could facilitate cognitive recovery and affect nAChR expression. Interestingly, the results indicate TBI interferes with agonist mediated upregulation of nAChRs, and galantamine did not improve function in a behavioral task of learning a memory. In a third study, the regulation of TBI related deficits in α7 nAChRs was examined 48 hours following injury. α7 nAChR deficits occurred with a reduction in α7 mRNA in several hippocampal regions and non-α7 nAChR deficits occurred with a reduction in α4 mRNA in the metathalamus. The results of these studies suggest AD and TBI may involve complex but parallel processes contributing to the regulation of α7 nAChRs.

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Davison, James Edward. "Multimodal magnetic resonance investigation of childhood metabolic neurodegenerative disease". Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3612/.

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Background: The central nervous system is frequently affected in children with inherited metabolic disorders (IMD). The causes of the brain insult are incompletely understood, and novel methods are required for disease diagnosis and monitoring response to novel therapies. Aims & Methods: The study aimed to improve understanding of the pathogenesis of IMD-related neurodegeneration, and to identify potential disease biomarkers in specific IMD, by directly investigating alterations in brain tissue metabolite profiles using non-invasive in vivo magnetic resonance spectroscopy (MRS) in conjunction with conventional MRI brain scans. Results: MRI/MRS studies were performed on over 300 children. Normal brain metabolite profiles were established from a standard comparator cohort. A detailed quality analysis enabled combination of data from different scanner systems. Non-standard brain metabolites were detected in 2.3% of children. Metabolite-based methods of disease progression monitoring were evaluated in Hunter Syndrome. Mechanisms leading to strokes in patients with propionic acidaemia and to learning difficulties and epilepsy in argininosuccinic aciduria were explored using brain tissue metabolite profiling. Conclusions: Non-invasive in vivo brain tissue metabolite profiling is achievable using quantitative magnetic resonance spectroscopy in the routine clinical paediatric setting, and has utility in disease diagnostics, in monitoring disease progression and in investigating disease pathogenesis.

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Dyson, Sean Christopher. "Novel strategies for neurotrophic factor delivery in neurodegenerative disease". Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608085.

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Vigbedor, Maa Ohui Shormeh. "Structure and regulation of G-substrate in neurodegenerative disease". Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/8292.

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G-substrate is a 23 kDa protein named as a specific substrate of cGMP-dependent protein kinase and found predominantly in cerebellar Purkinje cells. As a component of the NO/cGMP/PKG pathway, G-substrate is potentially involved in several important cellular processes and has so far been associated with a number of disease conditions: a single point mutation in G-substrate has been linked to hypercholesterolaemia, while the potent inhibition of PP2A by phosphorylated Gsubstrate possibly influences Tau protein hyperphosphorylation and contributes to Alzheimer's disease pathology. Conversely, overexpression of G-substrate protein in dopaminergic neurons has been found to protect neurons from Parkinson's disease toxins, making G-substrate a possible target of interventions for mitigating the debilitating effects of Parkinson's disease on patients. A shorter splice variant, which only retains one of the phosphorylatable threonine motifs, has recently been described for G-substrate and given the importance of phosphorylation to its action as a phosphatase inhibitor, this study focuses on determining whether both variants of the protein exhibit similar levels of phosphatase inhibition and interact with the same/similar proteins in vivo. We were also interested in determining whether the 51 amino acid section absent from short G-substrate resulted in any significant differences in protein structure, which potentially has implications on functions in vivo. My results indicate the association of G-substrate with a wide range of proteins involved in processes including cell cycle regulation, endocytosis and signalling and the two variants do not always interact with the same proteins. Among these interactors is the PARK 7/ DJ-1 protease, which like G-substrate has been shown to be neuroprotective. I have found that G-substrate is proteolysed by DJ-1 in its active form and interactions between these two proteins is affected by the anti-vertigo drug Tanganil. Phosphatase inhibition studies suggest that the G-substrate variants affect phosphatase activity to different extents under similar conditions, while NMR and circular dichroism structural studies suggest that in solution, the full length Gsubstrate variant is slightly more compactly folded. Understanding the details of G-substrate action in the cell will lead to a better understanding of its roles including the protection of dopaminergic neurons from Parkinson's disease toxins and shed more light on the intricacies of the NO/cGMP/PKG signalling pathway as a whole, thus providing important information that might help improve strategies for dealing with conditions involving this pathway and help develop interventions for diseases such as Alzheimer's and Parkinson's.

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Whiteman, Ineka T. "Cytoskeletal proteins and early neurodegenerative mechanisms in Alzheimer's disease". Thesis, The University of Sydney, 2011. https://hdl.handle.net/2123/28860.

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Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder that is histopathologically characterized by several hallmark lesions, including extracellular plaques comprised of amyloid beta (AB) peptides, neuropil threads and intra-neuronal neurofibrillary tangles, both of which are comprised of hyperphosphorylated microtubule-associated (MAP) protein tau. Neuropil threads are one of the earliest lesions observed in AD brain and the extent of their presence correlates with cognitive decline and disease progression. In addition, rod-like aggregates of actin and actin depolymerizing factor (ADF)/cofilin (‘AC’ or ‘cofilin’ rods) have also been described throughout the neuropil of AD brains. Sporadic AD accounts for over 90% of all AD cases and although aging has been identified as the most significant risk factor for developing this form of the disease, the pathogenic mechanisms involved in initiation of sporadic AD remain poorly understood. Decreased mitochondrial function and increased oxidative stress are common features of the aging brain and a growing body of evidence suggests these mitochondrial changes may play a central role in the pathogenesis of sporadic AD. The key question therefore is can mitochondrial dysfunction induce histopathological features of AD and if so, by what mechanisms? Answers to these important questions may be pivotal in the development of more effective AD therapeutics. This thesis investigated the effects of mitochondrial dysfunction on the interrelationships between two AD-related cytoskeletal systems, MAP/tau and AC-actin. Employing primary neuron culture models, organotypic brain slice cultures and a range of immuno—labeling and microscopy techniques, we show that mitochondrial dysfunction rapidly induces rod-Iike aggregations of activated AC throughout neurites that subsequently recruit AD-relevant epitopes of phosphorylated MAP/tau. The resulting cytoskeletal complexes closely resemble neuropil threads observed in human AD brain. Mechanistically, the relationship between these inclusions was explored through use of actin modifying drugs, knockdown of ADF/cofilin in primary neuron culture and knockout of tau in transgenic mouse brain slices. Overall, the results suggest that during neuronal stress, AC rods form rapidly and serve as a nucleation seed for subsequent recruitment of phosphorylated MAP/tau. Moreover, this initial recruitment is specific to MAP/tau phosphorylated in the functional microtubuIe-binding domain which is of significance, since this is one of the first phosphosites identified during the early pathogenesis of AD tau pathology. Furthermore, treatments with synthetic or naturally-secreted preparations of AB peptides induced the same effects in primary neuron and brain slice cultures, thus suggesting that the major histopathologies of AD may all be reconciled in one common pathway. The studies reported here provide evidence suggesting that mitochondrial dysfunction is central to the pathogenesis of two AD-related cytoskeletal pathologies: MAP/tau neuropil threads and AC rods. Moreover, the results presented here show for the first time that these two neuritic inclusions are closely interrelated and together implicate a disrupted cytoskeletal network that may account for the widespread axonal transport deficits and axonal degeneration characteristic of this disease. To that extent, we propose that association of MAP/tau and AC-actin proteins constitutes one of the earliest events in the pathogenesis of sporadic AD.

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Grinbergs-Saull, Anna. "Patient representation and the research agenda in neurodegenerative disease". Thesis, University of Brighton, 2015. https://research.brighton.ac.uk/en/studentTheses/ab40bfb3-ce1a-4b42-9fbc-479034321619.

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Patient organisations are often characterised in sociological literature as patient representatives, speaking for people affected by an illness in medical, political and scientific spheres. Using Motor Neurone Disease and Parkinson’s organisations as case studies, I investigate the challenges faced by patient organisations attempting to fulfil this role, focusing in particular on the need to balance responsibilities associated with care and campaign functions and increasing engagement in research. The principal focus of this PhD is to examine different conceptualisations of representativeness that have been discussed overtly and implicitly by participants. I have examined the extent to which patient organisations represent their members’ needs and cultivate a sense of collective identity, the way in which the patient organisations represent their members during the setting of research agendas, and finally I have considered the extent to which representation coincides with the concept of patient involvement.

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Turnquist, Casmir. "The role of p53 and ASPP2 in neurodegenerative disease". Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:e7d4cdfb-9ebe-4716-b3ca-d50b4b278d1a.

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Two cellular processes of central importance to cancer and neurodegeneration are apoptosis and cellular senescence. Both are a means of cellular suicide that are utilized in time- and context-dependent manners and have important evolutionary purposes. However, they are also the drivers of many deleterious processes underlying cancer and neurodegeneration. Many of the cellular responses to aging and age-related diseases, including apoptosis and senescence, converge on the tumor suppressor pathway, p53. Here I examine the molecular basis for loss of cell polarity and accelerated cell death mediated by apoptosis stimulating protein of p53 2 (ASPP2) in neurodegeneration. In this study we find that ASPP2 mediates STAT1Linduced apoptosis. Lipopolysaccharide (LPS) induces ASPP2 mRNA expression in vitro. Also, LPS induces nuclear ASPP2 in vivo at the blood-cerebral spinal fluid-barrier (BCSFB), the brain's barrier to inflammation. Consistent with ASPP2's role as a gatekeeper to inflammation, ASPP2 mutant mouse brains possess enhanced neuroinflammation. Elevated ASPP2 expression is also observed in mouse models and human neuroinflammatory disease tissue in astrocytes. The identification of ASPP2 as a novel transcriptional target of STAT1 and the observed increase in ASPP2 expression in both mouse and human neuroinflammatory disorders, suggests that the identified STAT1/ASPP2 pathway may connect tumor suppression and cell polarity to neuroinflammation. Additionally, I investigate the regulation of cellular senescence by p53 isoforms as a means to enhance neuroprotection of astrocytes in chronic neurodegenerative diseases, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Here we report that p53 isoforms, Δ133p53 and p53β, are endogenous regulators of cellular senescence in the central nervous system (CNS). Δ133p53 functions as a dominant-negative regulator of full-length (FL)Lp53 and represses senescence, while p53β as a co-activator of FLLp53, promotes senescence. In neurodegenerative disease brain tissue, FLL53 and p53β are upregulated while Δ133p53 is downregulated. We demonstrate that Δ133p53 and p53β directly regulate astrocyte senescence, including the release of key neurotoxic proL inflammatory cytokines such as ILL6 and ILL1β. Also, we show that the p53 isoform switch that occurs during aging and neurodegeneration promotes neuronal toxicity using coL culture experiments with human iPSC-derived motor neurons and human astrocytes. We also demonstrate that astrocyte senescence can be rescued through overexpression of Δ133p53, revealing a promising therapeutic approach to delay or inhibit the progression of neurodegeneration.

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38

CATANIA, ALESSIA. "Characterization of disease genes and mechanisms causing neurodegenerative phenotypes". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2019. http://hdl.handle.net/10281/241335.

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Il lavoro che ho svolto durante il mio corso di dottorato è stato finalizzato a identificare e caratterizzare i geni-malattia associati a rari disturbi neurologici. In particolare ho lavorato sulla caratterizzazione fenotipica e molecolare di due pazienti affetti da una distrofia neuroassonale atipica, in cui una mutazione omozigote all'interno del gene TFG è stata identificata mediante la tecnologia WES (whole exome sequencing). Inoltre, ho anche studiato tre famiglie non correlate con individui affetti da sindrome di Leigh portatori stesse mutazioni bialleliche nel gene NDUFAF6. L'identificazione di una nuova variante intronica è stata integrata con la sua validazione funzionale attraverso l'analisi dell'mRNA. Ho anche descritto due casi con fenotipi clinici neurodegenerativi complessi. La caratterizzazione fenotipica è stata integrata con l’identificazione di due nuove mutazioni in geni-malattia già riportati, rispettivamente DNMT1 e OTX2. Nel paziente con mutazione OTX2, la presentazione molecolare e clinica non è interamente spiegata da una singola mutazione genica e sono stati identificati ulteriori possibili modificatori genetici. Questo caso rappresenta un esempio di come la raccolta dettagliata dei dati clinici e della anamnesi familiare in parallelo all'analisi dei dati NGS sia spesso utile per identificare genotipi compositi a volte associati a sindromi ereditarie complesse. Inoltre, in qualità di partner della rete internazionale europea per le malattie mitocondriali, sono stata anche coinvolto nel progetto GENOMIT; in questo contesto, ho dedicato gli ultimi mesi del mio dottorato di ricerca a studiare la praticabilità di una promettente terapia genetica xenotopica per la sindrome di Leigh e altre condizioni neurologiche associate al deficit del complesso I mitocondriale, utilizzando fibroblasti di pazienti geneticamente modificati come modello sperimentale di malattia.
The work I carried out during my PhD studies has been aimed to identify and characterize disease genes associated with rare neurological disorders. In particular I worked on phenotypic and molecular characterization of two patients with an atypical neuroaxonal dystrophy presentation, in which a homozygous mutation within the TFG gene has been identified by mean of WES (whole exome sequencing) technology. Besides, I also studied three unrelated families with individuals affected by Leigh syndrome and carrying the same biallelic mutations in the NDUFAF6 gene. The identification of a novel intronic variant has been integrated with its functional validation through mRNA analysis. I also described two cases with complex clinical neurodegenerative phenotypes. Phenotypic characterization has been integrated the identification of two novel mutations in already reported disease genes, respectively DNMT1 and OTX2. In the patient with OTX2 mutation, molecular and clinical presentation remains not entirely explained by a single gene mutation and additional possible genetic modifiers were found. This case represents an example of how detailed collection of clinical data and family history in parallel to NGS data analysis is often helpful in order to identify composite genotypes sometimes associated with complicated inherited syndromes. Additionally, as a partner of the European international network for mitochondrial disorders, I was also involved in the GENOMIT project; within this framework, I dedicated the last few months of my PhD to investigate the feasibility of a promising xenotopic genetic therapy for Leigh syndrome and other neurological conditions associated with mitochondrial complex I deficiency, using engineered patient fibroblasts as a cellular model of disease.

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Rittman, Timothy. "Connectivity biomarkers in neurodegenerative tauopathies". Thesis, University of Cambridge, 2015. https://www.repository.cam.ac.uk/handle/1810/248866.

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The primary tauopathies are a group of neurodegenerative diseases affecting movement and cognition. In this thesis I study Progressive Supranuclear Palsy (PSP) and the Corticobasal Syndrome (CBS), two parkinsonian disorders associated with accumulation of hyperphos- phorylated and abnormally folded tau protein. I contrast these two disorders with Parkinson’s disease (PD), which is associated with the accumulation of alpha-synuclein but has a genetic association with the MAPT gene encoding tau. Understanding the tauopathies to develop effective treatments will require a better grasp of the relationships between clinical syndromes and cognitive measures and how the anatomical and neurochemical networks that underlie clinical features might be altered by disease. I investigate simple clinical biomarkers, showing that a two-minute test of verbal fluency is a potential diagnostic biomarker to distinguish between PD and PSP and that the ACE-R and its subscores could play a role in monitoring cognition over time in PD, PSP and CBS. I assess the implementation of network analysis in Functional Mag- netic Resonance Imaging (fMRI) data, introduce Maybrain software for graphical network analysis and visualisation. I go on to show an overlap between graph theory network measures and I identify three main factors underlying graph network measures of: efficiency and distance, hub characteristics, network community measures. I apply these measures in PD, PSP and the CBS. All three diseases caused a loss of functional connectivity in com- parison to the control group that was concentrated in more highly connected brain regions and in longer distance connections. In ad- dition, widely localised cognitive function of verbal fluency co-varied with the connection strength in highly connected regions across PD, PSP and CBS. To take this further, I investigated specific functional covariance networks. All three disease groups showed reduced connectivity between the basal ganglia network and other networks, and between the anterior salience network and other networks. Localised areas of increased co- variance suggest a breakdown of network boundaries which correlated with motor severity in PSP and CBS, and duration of disease in CBS. I explore the link between gene expression of the tau gene MAPT and its effects on functional connectivity showing that the expression of MAPT correlated with connection strength in highly connected hub regions that were more susceptible to a loss of connection strength in PD and PSP. I conclude by discussing how tau protein aggregates and soluble tau oligomers may explain the changes in functional brain networks. The primary tauopathies are a group of neurodegenerative diseases affecting movement and cognition. In this thesis I study Progressive Supranuclear Palsy (PSP) and the Corticobasal Syndrome (CBS), two parkinsonian disorders associated with accumulation of hyperphos- phorylated and abnormally folded tau protein. I contrast these two disorders with Parkinson’s disease (PD), which is associated with the accumulation of alpha-synuclein but has a genetic association with the MAPT gene encoding tau. Understanding the tauopathies to develop effective treatments will require a better grasp of the relationships between clinical syndromes and cognitive measures and how the anatomical and neurochemical networks that underlie clinical features might be altered by disease. I investigate simple clinical biomarkers, showing that a two-minute test of verbal fluency is a potential diagnostic biomarker to distinguish between PD and PSP and that the ACE-R and its subscores could play a role in monitoring cognition over time in PD, PSP and CBS. I assess the implementation of network analysis in Functional Mag- netic Resonance Imaging (fMRI) data, introduce Maybrain software for graphical network analysis and visualisation. I go on to show an overlap between graph theory network measures and I identify three main factors underlying graph network measures of: efficiency and distance, hub characteristics, network community measures. I apply these measures in PD, PSP and the CBS. All three diseases caused a loss of functional connectivity in com- parison to the control group that was concentrated in more highly connected brain regions and in longer distance connections. In ad- dition, widely localised cognitive function of verbal fluency co-varied with the connection strength in highly connected regions across PD, PSP and CBS. To take this further, I investigated specific functional covariance networks. All three disease groups showed reduced connectivity between the basal ganglia network and other networks, and between the anterior salience network and other networks. Localised areas of increased co- variance suggest a breakdown of network boundaries which correlated with motor severity in PSP and CBS, and duration of disease in CBS. I explore the link between gene expression of the tau gene MAPT and its effects on functional connectivity showing that the expression of MAPT correlated with connection strength in highly connected hub regions that were more susceptible to a loss of connection strength in PD and PSP. I conclude by discussing how tau protein aggregates and soluble tau oligomers may explain the changes in functional brain networks.

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40

Berliocchi, Laura. "Neurodegeneration induced by clostridial neurotoxins in cerebellar granule neurons a novel in vitro model for neurodegenerative disease /". [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=961250100.

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Berliocchi, Laura. "Neurodegeneration induced by clostridial neurtoxins in cerebellar granule neurons : a novel in vitro model for neurodegenerative disease /". [S.l. : s.n.], 2000. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB9038454.

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42

Moualla, Dima. "The role of alpha synuclein in Parkinson's disease". Thesis, University of Bath, 2011. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555747.

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Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. It is characterized by the presence of intracellular inclusions termed Lewy bodies (LBs) and Lewy neuritis (LNs) in the brain, in which α-Syn aggregates constitute the main component. Therefore, α-Syn aggregation was implicated in the pathogenesis of PD. Structurally α-Syn is a disordered protein with little ordered structure under physiological conditions. However, research of α-Syn has provided substantial information about its structural properties. The precise function of α-Syn is still under investigation. Research has also shown that metals, such as copper and iron, accelerate α-Syn aggregation and fibrillation in vitro and are proposed to play an important role in vitro. In this study, isothermal titration calorimetry was used to determine iron binding properties to α-Syn revealing the presence of two binding sites for iron with an affinity of 1.06 x 105 M-1 and a dissociation constant of ~ 10μM which is physiologically relevant to iron content in the brain. In addition, α-Syn was found to reduce iron in the presence of copper. This property was demonstrated via ferrozine based assay. In vitro, thoflavin-T fluorescence assay was used to investigate the mechanism by which metals induce α-Syn aggregation and whether it is related to metal binding. Metals, mainly copper and iron, caused 2-fold increase in the aggregation rate of WT α-Syn and its metal binding mutants. Linking that to the increased metal content in the brain, α-Syn aggregation can cause changes in tissue composition, thus altering the normal functional environment in the brain. Moreover, western blotting analysis showed that copper increases the aggregate formation in mammalian dopaminergic cells over-expressing α-Syn.

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Vial, Marie-Laure. "Chemical Biology of Natural Products on Parkinson’s Disease". Thesis, Griffith University, 2016. http://hdl.handle.net/10072/367722.

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Parkinson’s disease (PD) is a chronic and slowly progressive ageing-related neurodegenerative disorder that arises from interactions between environmental risk factors and genetic predispositions. This multifactorial aspect of the disease makes it difficult to find a therapy that benefits patients. There is currently no cure for PD. Even though, their use has decreased in the last two decades, natural products (NPs) remain a rich source of lead compounds for drug discovery. Here, we developed an unbiased multidimensional profiling method to examine the activity of a set of 590 pure NPs on human olfactory neurosphere-derived (hONS) cells from a PD patient. The biological profile of NPs was examined using multiparametric analysis to investigate known cellular pathways and organelles implicated in PD such as mitochondria, lysosomes, endosomes, apoptosis and autophagy. By targeting several cell components simultaneously we increased the chance of finding a phenotypic response. The compounds were then clustered based on their biological signature. The multidimensional phenotypic screening showed that all NPs, in our screening set, showed at least one phenotypic response on our cell model. This study provides evidence that natural products occupy biological relevant space.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Resources
Science, Environment, Engineering and Technology
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44

Delic, Vedad. "Strategies for Preventing Age and Neurodegenerative Disease-associated Mitochondrial Dysfunction". Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/5676.

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Mitochondrial dysfunction plays a pivotal role in the development of aging phenotypes and aging-associated neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS). Strategies that restore mitochondrial dysfunction may rescue the deficits of central metabolism in these disorders and improve cell survival. For example, we found that modulating the mTOR signaling pathway in a tissue culture model of aging-induced mitochondrial DNA mutation enhanced mitochondrial function as evidenced by increased oxygen consumption. Our previous melatonin studies also led us to hypothesize that caloric restriction and the hormone melatonin would reverse brain mitochondrial dysfunction in animal models of AD. Although caloric restriction did not improve mitochondrial function in a transgenic P301L tau model of AD, novel insight into the regulation of F0-F1 ATP synthase activity under CR was gained that may help explain the protective effects of CR in other disease models. In addition, we determined the effects of melatonin treatment on brain mitochondrial cytochrome c oxidase (COX) activity using the transgenic APPSWE mouse model of AD bred to double melatonin receptor (MT1 and MT2) knockout mice. COX activity declined with aging in control mice, but increased with aging in AD mice, most likely as a response to mitochondrial reactive oxygen species (ROS) induced by amyloid-beta generated through APP proteolysis. Both effects were blunted by melatonin treatment. The effects of melatonin were partially dependent on the G-protein coupled melatonin receptors. We also used PD models to identify therapies that restore mitochondrial dysfunction. We showed that overexpression of wild-type alpha synuclein (α-syn) in human neuroblastoma M17 cells resulted in mitochondrial oxygen consumption deficits; similar to the levels observed when PD mutant forms (A30P α-syn, E46K α-syn, and, A53T α-syn) were overexpressed. Mitochondria from cells overexpressing α-syn were more sensitive to a high iron environment, mimicking the physiological conditions in which dopaminergic neurons are found. Diethyl oxaloacetate, succinate, and several amino acids were protective, suggesting the possibility for effective dietary interventions for PD. Lastly, we delineated the level of mitochondrial complex IV activity between gray and white matter in human cervical and lumbar spinal cord, as well as mitochondrial aggregation in the entire neurovascular units (NVU) as a consequence of ALS. At the conclusion of these projects a better understanding of the molecular mechanisms leading to mitochondrial dysfunction in AD, PD, ALS, and aging was gained and promising strategies to delay or reverse these dysfunctions were developed.

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Layfield, Robert. "Human ubiquitin pathway enzymes in normal and neurodegenerative disease brains". Thesis, University of Nottingham, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241144.

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Závodszky, Eszter. "The role of novel neurodegenerative disease genes in autophagy regulation". Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708679.

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47

Hu, Di. "Targeting mitochondria as a potential therapeutic strategy in neurodegenerative disease". Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1559999737544078.

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48

Russ, Jenny. "Systematic interaction mapping reveals novel modifiers of neurodegenerative disease processes". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16631.

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Neurodegenerative Erkrankungen (NDs) wie Alzheimer (AD), Parkinson (PD), und amyotrophe lateral Sklerose (ALS) sind Hirnerkrankungen, die durch unlösliche Proteinaggregate in Neuronen oder im Extrazellularraum charakterisiert sind. In dieser Arbeit habe ich für verschiede bekannte und vorhergesagte neurodegenerative Krankheitsproteine (NDPs) Proteininteraktionsnetzwerke erstellt, um mögliche gemeinsame Krankheitsmechanismen genauer zu studieren. Mit Hilfe eines automatisierten Hefe-Zwei-Hybrid-Systems (Y2H) konnte ich 18.663 Protein-Protein-Interaktionen (PPIs) für 449 wildtyp und 22 mutierte Proteine identifizieren. Eine genaue funktionelle Analyse der Interaktionspartner von korrespondierenden wildtyp und mutierten Proteinen ergab deutliche Unterschiede zum einen im Fall von allen untersuchten Proteinen und insbesondere im Fall vom ALS Krankheitsprotein TDP-43. Die identifizierten PPIs wurden außerdem verwendet um krankheitsspezifische Netzwerke zu erstellen und um Proteine zu identifizieren, die mit mehreren NDPs verbunden sind. Ich habe auf diese Weise vier Proteine (APP, IQSEC1, ZNF179 und ZMAT2) gefunden, die mit bekannten NDPs with Huntingtin, TDP-43, Parkin und Ataxin-1 interagieren und so fünf verschiedene NDs miteinander verbinden. Die Reduktion der mRNA Expression von IQSEC1, ZNF179 oder ZMAT2 mit Hilfe von siRNA führte zu einer Verstärkung von pathogenen Mechanismen wie der Aggregation von mutiertem Huntingtin und TDP-43 sowie der Hyperphosphorylierung des Proteins Tau. Außerdem habe ich 22 Proteine entdeckt, die die Aggregation von TDP-43 deutlich verändern und außerdem Mitglieder in sieben vorhergesagten Proteinkomplexen sind. Die Proteinkomplexe habe ich durch Kombination von Interaktionsdaten und Daten eines siRNA Screenings vorhergesagt. Zusätzlich habe ich herausgefunden, dass die Proteine eines vorhergesagten Komplexes, nämlich HDAC1, pRB, HP1, BRG1 und c-MYC, die Aggregation von TDP-43 durch Veränderung von dessen Genexpression beeinflussen.
Neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD) or amyotrophic lateral sclerosis (ALS) are progressive brain disorders characterized by the accumulation of insoluble protein aggregates in neuronal cells or the extracellular space of patient brains. To elucidate potential common pathological mechanisms in different NDs, I created comprehensive interaction networks for various known and predicted neurodegenerative disease proteins (NDPs). I identified 18,663 protein-protein interactions (PPIs) for 449 bioinformatically selected wild-type target proteins and 22 mutant variants of 11 known NDPs by using an automated yeast two-hybrid (Y2H) system. The functional analysis of the interaction partners of corresponding wild-type and mutant NDPs revealed strong differences in the case of all 11 NDPs and especially for the ALS protein TDP-43. The identified PPIs were used to generate networks for individual NDs such as AD or PD and to identify proteins that are connected to multiple NDPs. For example, I found that five neurodegenerative diseases are connected by four proteins (APP, ZMAT2, ZNF179 and IQSEC1) that link known NDPs such as huntingtin, TDP-43, parkin, ataxin-1 and SOD1. Analysis of publicly available gene expression data suggested that the mRNA expression of the four proteins is abnormally altered in brains of ND patients. Moreover, the knock-down of IQSEC1, ZNF179 or ZMAT2 aggravates pathogenic disease mechanisms such as aggregation of mutant huntingtin or TDP-43 as well as hyperphosphorylation of tau. Additionally, I identified 22 modifiers of TDP-43 aggregation, which are members in 7 protein complexes. These complexes were predicted based on combined data from PPI as well as siRNA screenings. Finally, I found that the proteins HDAC1, pRB, HP1, BRG1 and c-MYC, which form one of the predicted complexes, influence TDP-43 aggregation by altering its mRNA expression.

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Baxendale, Sarah. "Molecular analysis of the Huntingdon's disease gene region in man and pufferfish". Thesis, Open University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282510.

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Cummings, Sarah. "Investigating Oligodendrocyte Biology and Function: Insights from Neurological and Neuromuscular Diseases". Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/41489.

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Oligodendrocytes (OLs) are the cells responsible for myelin production in the central nervous system (CNS). Myelin serves to increase the efficiency of signal propagation down the axon and is essential for proper communication between the CNS and the periphery. As a result, pathologies affecting the OL, including multiple sclerosis (MS) and multiple system atrophy (MSA), present with a wide range of symptoms including impaired muscle control, loss of coordination, as well as cognitive deficits. While the biology of the OL continues to garner research interest, much remains to be understood about cell function in a healthy context, and also how the biology of these cells goes awry in disease. Our objective was to explore the effects of varying disease models on OL biology and use those findings to further our knowledge on the biology of OL development and regeneration. Here we explore OL function and dysfunction in the context of spinal muscular atrophy (SMA), MSA and MS. We have thoroughly characterized the OL response to SMN-depletion and have determined that SMN is not required for the development of OLs in the neonatal brain. Additionally, we have sought to characterize the endogenous role of MSA-disease relevant protein alpha-synuclein in OL development and have determined that this protein is not required for OL differentiation or CNS myelination. Lastly, we have explored the biology of the OL in the context of the inhibitory milieu it faces during remyelination in MS. We have investigated different pathways that may be involved in mediating signalling of one such inhibitory cue (chondroitin sulphate proteoglycans, CSPGs), and have extended this model to interrogate OL cytoskeletal dynamics in the context of CSPGs. Together, this work uses disease frameworks to investigate basic OL biology, as well as provides insights into how the OL and its interactions with the extracellular milieu should be considered in disease pathogenesis and therapeutic exploration.

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