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Gros-Louis, François. "Genetics of familial and sporadic amyotrophic lateral sclerosis." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111859.
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Diseases affecting motor neurons, such as amyotrophic lateral sclerosis (Lou Gerhig's disease), hereditary spastic paraplegia and spinal bulbar muscular atrophy (Kennedy's disease) form a heterogeneous group of chronic progressive diseases and are among the most puzzling yet untreatable illnesses. Over the last decade identification of mutations in genes predisposing to these disorders has provided the means to better understand their pathogenesis. The discovery 13 years ago of SOD1 mutations linked to ALS, which account for less than 2% of all cases, had a major impact in the field. However, despite intensive research effort, the pathways leading to the specific motor neurons degeneration in the presence of SOD1 mutations have not been fully identified. The research projects presented here aim to investigate the role of different cell types and tissues in the pathology of SOD1-linked ALS, and to identify new genetic factors involved in sporadic ALS cases. LoxP transgenic mice expressing mutated G85R SOD1, allowing transgene expression in cell and tissue specific manner, have been successfully generated. However, mice, up to 2.5 years of age, did not develop any motor neuron deficits or any developmental abnormalities. We concluded that this might be due to insufficient level of the transgene expression in our transgenic animals. Also, a number of candidate genes for ALS have been identified, such as ALS2, VEGF, PRPH, CHGA and CHGB, based on their pattern of expression and biological function. These genes have been screened for mutations in a cohort of ALS patients and, we have identified one basepair deletion in the ALS2 and in the PRPH genes, and we have also found a strong genetic association between the CHGA and CHGB genes with ALS. An in-vitro cell transfection approach has been used to investigate the biological effects of mutations within the PRPH genes and, of particular interest, this technique has revealed the first functional variants in a neurofilament associated gene ever describe in ALS.
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Abalkhail, Halah Abdullah. "Characterisation of a new familial amyotrophic lateral sclerosis." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419231.
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Gallart, Palau Xavier Ramon. "Synaptic frailty and mitochondrial dysfunction in familial amyotrophic lateral sclerosis." Doctoral thesis, Universitat de Lleida, 2016. http://hdl.handle.net/10803/386410.
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L’Esclerosi Lateral Amiotròfica (ELA) és una malaltia neurodegenerativa de la motoneurona. Totes les neurones del sistema motor es veuen afectades pel flux degeneratiu en aquesta malaltia des de l’escorça motora primària fins a la junta neuromuscular. Al 1993, la descoberta de mutacions en el gen SOD1 va obrir nous horitzons experimentals amb la creació dels primers rosegadors transgènics per aquesta malaltia. Des d’aquell moment i fins a l’actualitat la mutació més estudiada en l’ELA ha estat la SOD1-G93A a tot el món. Els models transgènics per aquesta mutació de la SOD1 han revelat mecanismes essencials de la neurodegeneració en aquesta malaltia incloent l’excitotoxicitat, la disfunció proteica i la degeneració axosinàptica entre altres. En aquest treball hem explorat els canvis moleculars que tenen lloc als terminals-C, uns terminals molt especialitzats en les α-moto neurones, dels rosegadors transgènics SOD1-G93A. A més, també hem focalitzat la nostra atenció a la relació patològica que s’estableix en l’ELA familiar (ELAF) entre la mutació SOD1-G93A i les mitocòndries de les motoneurones. En relació als terminals C en moto neurones durant la ELAF, hem trobat canvis associats a l’aparició dels símptomes com ara expressió incrementada del factor neurotròfic Neuregulina-1 localitzat també per primer cop a la cisterna subsinàptica dels terminals C aposats a les α-moto neurones. La Neuregulina-1 en aquestes estructures de reticle endoplasmàtic va ser observada a dins de vesícules extracel·lulars (VEs), suggerint que l’anàlisi de la Neuregulina-1 en VEs durant ELA és especialment prometedor com a biomarcador potencial en aquesta malaltia. Així nosaltres hem desenvolupat també un nou mètode per tal d’aïllar VEs, donat que aquest és un pas essencial previ a l’estudi de les proteïnes associades amb aquestes estructures. El nostre mètode aplicat a la purificació de VEs en teixits complexos fou capaç de facilitar la identificació de la Neuregulina-1 en VEs provinents de teixits clínics i fluids biològics. En relació a les implicacions de la mitocòndria en la ELA, hem trobat que la mutació SOD1-G93A estabilitza la proteïna PINK1 a la mitocòndria seguidament activant el factor nuclear NFκB en neurones. La interacció seqüencial entre la SOD1 mutant i NFκB crea una clara disfunció en la capacitat proteolítica del proteosoma, el qual promou coagregació de la SOD1 mutant i el PINK1 en aquestes cèl·lules. Aquests resultats afegeixen un substancial coneixement mecanístic sobre els rols de la mitocòndria en els events neurodegeneratius clàssics de l’ELA, com ara en l’agregació de proteïnes disfuncionals en moto neurones. Seguint el nostre estudi de l’afectació mitocondrial en la ELA, hem creat i caracteritzat un nou model de Drosophila que expressa la mutació humana SOD1-G93A exclusivament en fibres musculars toràciques sota el promotor 24B. Aquest model de Drosophila transgènica recapitula amb èxit el fenotip mitocondrial prèviament observat de l’ELA presentant importants avantatges sobretot en l’elecció de nous compostos terapèutics. En definitiva, els resultats generats en aquesta tesi proporcionen evidència experimental, extensa comprensió molecular i insinuen nous horitzons terapèutics sobre els mecanismes moleculars i els events neurodegeneratius associats a la disfunció sinàptica i mitocondrial en l’ELAF.La Esclerosis Lateral Amiotrófica (ELA) es una enfermedad neurodegenerativa de la motoneurona. Todas las motoneuronas se ven afectadas desde la corteza motora primaria hasta la unión neuromuscular. En 1993 la descubierta de mutaciones en el gen SOD1 abrió nuevos límites experimentales con la creación de los primeros roedores transgénicos para esta enfermedad. Desde ese momento y hasta la actualidad, la mutación más estudiada en la ELA ha sido la mutación SOD1-G93A. Los modelos transgénicos de esta mutación han revelado mecanismos esenciales de la neurodegeneración en la ELA, incluyendo la excitotoxicidad, la disfunción proteica y la degeneración axosináptica entre otras. En este trabajo hemos explorado los cambios moleculares que tienen lugar en los terminales C, unos terminales altamente especializados de las α-motoneuronas, en un modelo murino de ELA con la mutación SOD1-G93A. Además, también hemos focalizado nuestra atención sobre la relación patológica que se establece en la ELA familiar (ELAF) entre la mutación SOD1-G93A y las mitocondrias. En relación a los terminales C durante la ELAF, hemos encontrado cambios asociados con la aparición de síntomas, como por ejemplo el incremento de la expresión del factor neurotrófico Neuregulina-1, localizado por primera vez en la cisterna subsináptica de los terminales C. La Neuregulina-1 en esas estructuras de retículo endoplasmático fue observada dentro de vesículas extracelulares (VEs), sugiriendo que el análisis de la Neuregulina-1 dentro de VEs en la ELA resulta especialmente prometedor como biomarcador potencial para esta enfermedad. Así, nosotros hemos desarrollado también un nuevo método para purificar VEs, dado que este es un paso esencial previo al estudio de las proteínas asociadas con estas estructuras. Nuestro método aplicado a la purificación de VEs de tejidos complejos fue capaz de facilitar la identificación de la Neuregulina en VEs provenientes de tejidos clínicos y fluidos biológicos. En relación a las implicaciones de la mitocondria en la ELA, hemos encontrado que la mutación SOD1-G93A estabiliza la proteína PINK1 en las mitocondrias activando el factor nuclear NFκB en neuronas. La interacción secuencial entre la SOD1 mutante y el NFκB crea una clara disfunción sobre la capacidad proteolítica del proteosoma, la cual a su vez promueve co-agregación de la SOD1 mutante y PINK1 en estas células. Estos resultados suman un sustancial conocimiento mecanístico sobre los roles de la mitocondria en eventos degenerativos clásicos de la ELA, como es la agregación de proteínas disfuncionales en motoneuronas. Siguiendo nuestro estudio de la afectación mitocondrial en la ELA, hemos creado y caracterizado un nuevo modelo de Drosophila que expresa la mutación humana SOD1-G93A en fibras musculares torácicas bajo el promotor 24B. Este modelo de Drosophila transgénica recapitula con éxito en fenotipo mitocondrial característico de la ELA presentando importantes ventajas para la elección de nuevos compuestos terapéuticos. En definitiva, los resultados generados en esta tesis proporcionan evidencia experimental, extensa comprensión molecular y insinúan nuevos horizontes terapéuticos acerca de los mecanismos moleculares y eventos neurodegenerativos asociados con la disfunción sináptica y la disfunción mitocondrial en la ELAF.
Amyotrophic Lateral Sclerosis (ALS) is an orphan age-associated neurodegenerative disease. All motoneurones in ALS are affected by degenerative flow from the primary motor cortex to the neuromuscular junction. In 1993, mutations of the gene SOD1 opened new research avenues allowing for the generation of familial ALS experimental models in rodents. Since then, the FALS mutation SOD1-G93A has been extensively studied worldwide in ALS to date. Transgenic models for this SOD1 mutation have revealed essential mechanisms of neurodegeneration including excitotoxicity, proteinopathy and axosynaptic degeneration among others. In this dissertation, we explored the molecular changes that occur in C-terminals, a very specialised synapse type from α-motoneurones of SOD1-G93A rodents. Also, we focused on the pathological relationship between the FALS mutant SOD1-G93A and mitochondria in motoneurones. With regard to C-terminals in FALS motoneurones, we found changes that were symptomatically associated with the up-regulated expression of the neurotrophic factor Neuregulin-1 located for the first time in the subsurface system of C-boutons juxtaposed to α-motoneurones. Furthermore, Neuregulin-1 in these endoplasmic reticulum structures was observed inside extracellular vesicles, suggesting that analysis of Neuregulin-1 from extracellular vesicles in ALS holds promise as a potential reliable biomarker for that neurodegenerative disease. We therefore have developed a new method for isolation of extracellular vesicles, as this remains as an essential step for the study of molecules associated with these structures. Our method applied to purify extracellular vesicles from complex biological tissues was able to facilitate the identification of Neuregulin-1 in extracellular vessicles from clinical tissues and biological fluids. Regarding implications of mitochondria in ALS, we have found that the FALS mutant hSOD1-G93A stabilises PINK1 in mitochondria and subsequently activates NFκB in neuronal cells. Sequential interaction between hSOD1 and NFκB impairs the proteosome proteolitic function promoting co-aggregation of SOD1 and PINK1 in these cells. These results add substantial mechanistic insight on the roles of mitochondria in classical ALS-associated neurodegenerative events, including aggregation of dysfuntional proteins in motoneurones. Following our study of mitochondria affectation in ALS, we have created and characterised a novel Drosophila model that expresses human SOD1-G93A in thoracic muscles under the genetic muscular promoter 24B. Flies expressing human SOD1-G93A in thoracic muscles successfully recapitulate FALS mitochondrial phenotype with several advantages in front of the current available rodent models for this FALS mutation. Taken together, the results generated in this thesis provide experimental evidence, further molecular comprehension and promise novel therapeutic approaches to the molecular mechanisms and neurodegenerative events associated with synaptic frailty and mitochondrial disfunction in FALS.
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Pramatarova, Albéna. "Role of CuZn superoxide dismutase in familial amyotrophic lateral sclerosis." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=36684.
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Amyotrophic lateral sclerosis (ALS) is a late onset neuro-degenerative disorder characterized by highly selective death of large motor neurons in the cerebral cortex and spinal cord. A proportion of the familial cases (FALS) with autosomal dominant transmission was linked to chromosome 21q and the defective gene was shown to be the Cu/Zn superoxide dismutase gene (SOD1). SOD1 is a ubiquitously expressed cytoplasmic metalloenzyme catalyzing the dismutation of the superoxide free radical into hydrogen peroxide and molecular oxygen. We have screened our FALS patients for mutations in the SOD1 gene and found mutations in about 13% of the cases. All but one mutation were single base pair substitutions resulting in amino acid changes (i.e. missense mutations) predicted to produce structurally defective molecules, and some of which significantly reduced the SOD1 enzyme activity in lymphoblasts. We have also identified a two base pairs deletion, which introduces a premature stop codon at position 131 and is predicted to result in the translation of a truncated molecule.It has been hypothesized that the pathology observed in FALS cases with SOD1 mutations is due to a gain of a new deleterious function of the mutant enzyme and not to a simple loss of dismutase activity. However the exact mechanism of SOD1 toxicity is still unknown and the specificity of the degenerating cell populations remains to be addressed. In this work, we investigated whether the damage seen in ALS with SOD1 mutations results from direct motor neuron toxicity. We have generated transgenic animals carrying a human SOD1 cDNA with the G37R mutation associated with FALS, driven by the neurofilament light chain promoter in order to specifically express the mutant protein in neuronal tissues. We show that transgenic animals express high levels of the human SOD1 protein in neuronal tissues, especially in the spinal cord where the motor neurons are concentrated, but develop no apparent motor deficit at up to 2 years of age. Our animal model suggests that neuron specific expression of mutant human SOD1 might not be sufficient for the development of the disease in mice, and hints towards the involvement of additional yet unidentified cell types/mechanisms.
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Forsberg, Karin. "Misfolded superoxide dismutase-1 in sporadic and familial Amyotrophic Lateral Sclerosis." Doctoral thesis, Umeå universitet, Patologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-47550.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome of unknown etiology that most commonly affects people in middle and high age. The hallmark of ALS is a progressive and simultaneous loss of upper and lower motor neurons in the central nervous system that leads to a progressive muscle atrophy, paralysis and death usually by respiratory failure. ALS is not a pure motor neuronal syndrome; it extends beyond the motor system and affects extramotor areas of the brain as well. The majority of the patients suffer from a sporadic ALS disease (SALS) while in at least ten percent the disease appears in a familial form (FALS). Mutations in the gene encoding the antioxidant enzyme superoxide dismutase-1 (SOD1) are the most common cause of FALS. More than 165 SOD1 mutations have been described, and these confer the enzyme a cytotoxic gain of function. Evidence suggests that the toxicity results from structural instability which makes the mutated enzyme prone to misfold and form aggregates in the spinal cord and brain motor neurons. Recent studies indicate that the wild-type human SOD1 protein (wt-hSOD1) has the propensity to develop neurotoxic features. The aim of the present study was to investigate if wt-hSOD1 is involved in the pathogenesis of SALS and FALS patients lacking SOD1 mutations and to evaluate the neurotoxic effect of misfolded wt-hSOD1 protein in vivo by generating a transgenic wt-hSOD1 mice model. We produced specific SOD1-peptide-generated antibodies that could discriminate between the misfolded and native form of the enzyme and optimized a staining protocol for detection of misfolded wt-hSOD1 by immunohistochemistry and confocal microscopy of brain and spinal cord tissue. We discovered that aggregates of misfolded wt-hSOD1 were constitutively present in the cytoplasm of motor neurons in all investigated SALS patients and in FALS patients lacking SOD1 gene mutations. Interestingly, the misfolded wt-hSOD1 aggregates were also found in some motor neuron nuclei and in the nuclei of the surrounding glial cells, mainly astrocytes but also microglia and oligodendrocytes, indicating that misfolded wt-hSOD1 protein aggregates may exert intranuclear toxicity. We compared our findings to FALS with SOD1 mutations by investigating brain and spinal cord tissue from patients homozygous for the D90A SOD1 mutation, a common SOD1 mutation that encodes a stable SOD1 protein with a wild-type-like enzyme activity. We observed a similar morphology with a profound loss of motor neurons and aggregates of misfolded SOD1 in the remaining motor neuron. Interestingly, we found gliosis and microvacuolar degeneration in the superficial lamina of the frontal and temporal lobe, indicating a possible frontotemporal lobar dementia in addition to the ALS disorder. Our morphological and biochemical findings were tested in vivo by generating homozygous transgenic mice that over expressed wt-hSOD1. These mice developed a fatal ALS-like disease, mimicking the one seen in mice expressing mutated hSOD1. The wt-hSOD1 mice showed a slower weight gain compared to non-transgenic mice and developed a progressive ALS-like hind-leg paresis. Aggregates of misfolded wt-hSOD1 were found in the brain and spinal cord neurons similar to those in humans accompanied by a loss of 41 % of motor neurons compared to non-transgenic litter mates. In conclusion, we found misfolded wt-hSOD1 aggregates in the cytoplasm and nuclei of motor neurons and glial cells in all patients suffering from ALS syndrome. Notable is the fact that misfolded wt-hSOD1 aggregates were also detected in FALS patients lacking SOD1 mutations indicating a role for SOD1 even when other genetic mutations are present. The neurotoxicity of misfolded wt-hSOD1 protein was confirmed in vivo by wt-hSOD1 transgenic mice that developed a fatal ALS-like disease. Taken together, our results support the notion that misfolded wt-hSOD1 could be generally involved and play a decisive role in the pathogenesis of all forms of ALS.
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Pramatarova, Albéna. "Role of Cu/Zn superoxide dismutase in familial amyotrophic lateral sclerosis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0030/NQ64647.pdf.
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Schaldecker, Christina [Verfasser]. "Metabolism in presymptomatic mutation carriers of familial Amyotrophic Lateral Sclerosis / Christina Schaldecker." Ulm : Universität Ulm, 2019. http://d-nb.info/1189734001/34.
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Fujita, Hibiki Kawamata. "Copper, zinc superoxide dismutase and mitochondria : implications for familial amyotrophic lateral sclerosis /." Access full-text from WCMC, 2008. http://proquest.umi.com/pqdweb?did=1619236681&sid=6&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Wu, Chi-Hong. "Functional Characterization of Novel PFN1 Mutations Causative for Familial Amyotrophic Lateral Sclerosis: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/815.
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Amyotrophic lateral sclerosis (ALS) is a progressive adult neurodegenerative disease that causes death of both upper and lower motor neurons. Approximately 90 percent of ALS cases are sporadic (SALS), and 10 percent are inherited (FALS). Mutations in the PFN1 gene have been identified as causative for one percent of FALS. PFN1 is a small actin-binding protein that promotes actin polymerization, but how ALS-linked PFN1 mutations affect its cognate functions or acquire gain-of-function toxicity remains largely unknown.
To elucidate the contribution of ALS-linked PFN1 mutations to neurodegeneration, we have characterized these mutants in both mammalian cultured cells and Drosophila models. In mammalian neuronal cells, we demonstrate that ALS-linked PFN1 mutants form ubiquitinated aggregates and alter neuronal morphology. We also show that ALS-linked PFN1 mutants have partial loss-of-function effects on actin polymerization in growth cones of mouse primary motor neurons and larval neuromuscular junctions (NMJ) in Drosophila. In Drosophila, we also observe that PFN1 level influences integrity of adult motor neurons, as demonstrated by locomotion, lifespan, and leg NMJ morphology.
In sum, the work presented in this dissertation has shed light on PFN1- linked ALS pathogenesis by demonstrating a loss-of-function mechanism. We have also developed a Drosophila PFN1 model that will serve as a valuable tool to further uncover PFN1-associated cellular pathways that mediate motor neuron functions.
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Wu, Chi-Hong. "Functional Characterization of Novel PFN1 Mutations Causative for Familial Amyotrophic Lateral Sclerosis: A Dissertation." eScholarship@UMMS, 2012. http://escholarship.umassmed.edu/gsbs_diss/815.
Full textAbstract:
Amyotrophic lateral sclerosis (ALS) is a progressive adult neurodegenerative disease that causes death of both upper and lower motor neurons. Approximately 90 percent of ALS cases are sporadic (SALS), and 10 percent are inherited (FALS). Mutations in the PFN1 gene have been identified as causative for one percent of FALS. PFN1 is a small actin-binding protein that promotes actin polymerization, but how ALS-linked PFN1 mutations affect its cognate functions or acquire gain-of-function toxicity remains largely unknown.
To elucidate the contribution of ALS-linked PFN1 mutations to neurodegeneration, we have characterized these mutants in both mammalian cultured cells and Drosophila models. In mammalian neuronal cells, we demonstrate that ALS-linked PFN1 mutants form ubiquitinated aggregates and alter neuronal morphology. We also show that ALS-linked PFN1 mutants have partial loss-of-function effects on actin polymerization in growth cones of mouse primary motor neurons and larval neuromuscular junctions (NMJ) in Drosophila. In Drosophila, we also observe that PFN1 level influences integrity of adult motor neurons, as demonstrated by locomotion, lifespan, and leg NMJ morphology.
In sum, the work presented in this dissertation has shed light on PFN1- linked ALS pathogenesis by demonstrating a loss-of-function mechanism. We have also developed a Drosophila PFN1 model that will serve as a valuable tool to further uncover PFN1-associated cellular pathways that mediate motor neuron functions.
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Chen, Han-Jou. "Characterisation of novel gene mutations causing familiar amyotrophic lateral sclerosis." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/6125.
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Amyotrophic lateral sclerosis (ALS) is a complex fatal degenerative disease selectively affecting motor neurones. The cause of the disease is still uncharacterised for the sporadic cases (SALS), whereas several disease-linked genes, such as SOD1 and VAPB, have been identified in families with ALS (FALS). However, since the pathological features are indistinguishable between FALS and SALS, it is generally believed that a common ALS-causing mechanism is responsible for both forms of disease. To gain a better understanding of ALS pathogenesis, which could also provide cues for therapeutic treatment, studies on the characterisation of FALS-linked mutations have been carried out. In this study, we screened for novel FALS-linked mutations and found three TDP-43 mutations in five unrelated FALS families, that caused marked changes at evolutional conserved amino acids and were absent in previously screened control populations. In addition, functional characterisation of novel ALS linked mutations in DAO (R199W) and VAPB (T46I) were undertaken whereby both mutations were shown to disrupt the physiological properties of wild type proteins. Whereas the T46I mutation in VAPB led to a sub-cellular redistribution and shift in solubility of VAPB protein, and an impairment in the unfolded protein response (UPR) and ubiquitin-proteasome system, R199W significantly abolished DAO enzyme activity. Cell culture-based functional studies showed that the expression of both mutant proteins triggered pathological features including ubiquitin-positive aggregates and cell death. Furthermore, an association study was conducted to investigate the cause of a dramatic VAPB down-regulation seen in SALS. An intronic SNP close to exon 5 of VAPB, rs6100067, was found to be significantly linked to the expression levels of VAPB in SALS. As the down-regulation of VAPB profoundly affects the activation of IRE1/XBP1, the most characterised UPR pathway, this SNP may present as a risk factor for ALS development. From these results, we propose an ALS pathogenesis mechanism, whereby VAPB plays a central role in sustaining multiple cellular events, such as UPR. Disruption or deprivation of VAPB causes impairments in these cellular functions and leads to motor neurone death.
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Roy, Josée. "Mechanisms of preferential vulnerability of motor neurons in a familial form of amyotrophic lateral sclerosis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0022/NQ50252.pdf.
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Roy, Josée 1970. "Mechanisms of preferential vulnerability of motor neurons in a familial form of amyotrophic lateral sclerosis." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35937.
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Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper and lower motor neurons. A subset of familial ALS cases (20%; FALS-1) are linked to mutations in the Cu/Zn-superoxide dismutase (SOD-1). In order to study the mechanisms of mutant SOD-1 (mSOD-1) toxicity and preferential vulnerability of motor neurons, human wild type and seven different mSOD-1 were expressed in motor neurons or dorsal root ganglion neurons of dissociated cultures of murine spinal cord-dorsal root ganglia, or in cultured hippocampal neurons. Expression was obtained by intranuclear microinjection of plasmid expression vectors. Many features of the motor neuron disease observed in humans with ALS and in mSOD-1 transgenic mice were reproduced in this new culture model, including preferential vulnerability of motor neurons and abnormal distribution of hyperphosphorylated neurofilament proteins. A novel observation was the formation of cytoplasmic SOD-1 aggregates in motor neurons expressing mSOD-1 followed by evidence of apoptotic cell death. Both formation of aggregates and motoneuronal death were reduced by coexpression of the stress-inducible heat shock protein, HSP70, indicating that insufficiency of molecular chaperones may be involved in FALS-1. Using specific antagonists of glutamate receptor subtypes, we have demonstrated that normally nontoxic glutamatergic input, particularly via calcium-permeable AMPA/kainate receptors, is a major factor in the vulnerability of motor neurons to the toxicity of mSOD-1. Partial protection was obtained by blockade of L-type voltage-gated calcium channels, implicating Ca2+ entry through these channels in the toxicity of mSOD-1. Dramatic neuroprotection was obtained by coexpressing the calcium-binding protein calbindin-D28k indicating that the toxicity of mSOD-1 is calcium-dependent. However, increasing intracellular glutathione levels or treatment with N-tert-butyl-alpha-phenylnitrone (PBN) had no significant effect on motone
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Marino, Marianna. "Comparative analysis of protein quality control systems in two mouse models of familial amyotrophic lateral sclerosis." Thesis, Open University, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.606837.
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Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disease with considerable variability in the disease course even in familial cases associated with autosomal dominant SOD1 gene mutations. Previously, we have shown that SOD1G93A mice, the most widely used model of ALS, exhibit remarkable variability in disease onset and progression according to the mouse genetic background used (Pizzasegola et al 2009). The overall aim of this thesis was to explain the phenotype diversity between two SODIG93A mouse strains on C57BLl6J and 129S2ISv backgrounds since they carry the same number of human SODl transgene copies and express the same amount of mutant SODl mRNA and protein. We found that the levels of insoluble proteins greatly differ between the two SODIG93A mouse strains. In the lumbar spinal cord, the mice with fast disease progression (129SvG93A) exhibited an earlier and higher accumulation of ubiquitinated protein aggregates, mutant-SOD! and several chaperone proteins in comparison with the slowly progressing mice (C57G93A). In contrast, the levels of insoluble TDP43 and its phosphorylated form were higher in the slow than in the fast progressing mice. This led us to perform an in depth investigation of the protein quality control pathways during the course of the disease in these two mouse strains. In the lumbar spinal cord, the fast progressing mice showed lower expression of the chaperone αBcrystallin and an earlier reduction 0[' all the catalytic subunits of the proteasome compared to the slow progressing mice. However, a later induced expression of proteins involved in the misfolded protein recoguition complex and autophagic degradation, such as HspBS, Bag3 and the soluble Hsc70 was observed in the 129SvG93A mice. These data emphasize the involvement of impaired protein quality control mechanisms, in particular the chaperones and proteasome, in determining a more aggressive disease course in in vivo models of ALS.
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Licence, Victoria Ellen. "The role of small heat shock proteins in mutant superoxide dismutase-linked familial amyotrophic lateral sclerosis." Thesis, Durham University, 2005. http://etheses.dur.ac.uk/2725/.
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The mechanisms by which mutations in the gene encoding superoxide dismutase 1 (S0D1) lead to amyotrophic lateral sclerosis (ALS) remain incompletely understood. Mutant SODI inclusions are observed in both ALS patients and animal models of the disease. Chaperone proteins have been shown to reduce mutant S0D1 inclusion formation in both cell and animal systems and, up-regulation of heat shock proteins (HSPs) in a mouse model of ALS increases their life expectancy. The results presented in this thesis are based on an investigation into the role of small heat shock proteins (sHSPs) in mutant SODI inclusion formation, using a model HEK293 cell system. Over-expression of yellow fluorescent protein (YFP)-tagged G85R mutant SODI in HEK293 cells and subsequent treatment with proteasome inhibitor leads to mutant S0D1-inclusion formation, as shown by immunofluorescence (IMF) microscopy. Using this model of mutant S0D1- inclusion formation, we demonstrate that over-expression of sHSPs decreases the proportion of insoluble mutant SODI present within these cells. Mutations in these sHSPs prevent this function, and further increase the proportion of insoluble mutant S0D1. These mutant sHSPs also cause an increase in the insolubility of normally soluble proteins, such as wild-type SODI. Similar results were observed in Neuro 2a cells, where over-expression of sHSPs caused the phenotype of the mutant SODI inclusions to change, from dense, tight structures to more diffuse ones. We have shown that sHSPs decrease the amount of insoluble mutant SODI in HEK2S3 cells, supporting reports that chaperone proteins prevent mutant SODI-inclusion formation and are beneficial in a mouse model Gf ALS
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Kim, Soo Hyun. "Gene therapy demonstrates that muscle is not a primary target for non-cell autonomous toxicity in familial ALS." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1164829314.
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Teyssou, Elisa. "Analyses génétiques et fonctionnelles de nouveaux gènes incriminés dans la Sclérose Latérale Amyotrophique (SLA) Genetic analysis of matrin 3 gene in French amyotrophic lateral sclerosis patients and frontotemporal lobar degeneration with amyotrophic lateral sclerosis patients Genetic analysis of CHCHD10 in French familial amyotrophic lateral sclerosis patients." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066738.
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La Sclérose Latérale Amyotrophique (SLA) est une maladie neurodégénérative fatale caractérisée par la dégénérescence des motoneurones centraux et périphériques. Elle est le plus souvent sporadique (SALS, 90% des cas), tandis que les formes familiales (FALS) représentent 10% des patients. Une vingtaine de gènes liés à la SLA ont été identifiés et sont responsables de 70% des FALS et 10% des SALS. Le but de ce projet était d’étudier la contribution de 6 gènes rares dans une large cohorte de patients français atteints de SLA et d’étudier les conséquences fonctionnelles de certains variants identifiés. La première partie de ce projet a consisté à réaliser l’analyse génétique des gènes MATR3, CHCHD10, SS18L1, SQSTM1, UBQLN2 et PFN1. Aucun variant causal ne fut identifié pour les 2 premiers gènes alors que 2 nouveaux variants possiblement pathogènes ont été identifiés dans le gène SS18L1, 4 mutations pour SQSTM1, 5 dans UBQLN2 et 2 mutations déjà répertoriées dans le gène PFN1. Cette analyse génétique a permis de souligner un chevauchement génétique entre SLA et maladie de Paget pour SQSTM1 et entre SLA et Paraplégie Spastique pour UBQLN2. La deuxième partie de ce projet a consisté en l’étude de la pathogénicité de certains variants que nous avons identifiés dans les gènes SQSTM1, UBQLN2 et PFN1, par l’analyse (i) des inclusions dans les tissus post mortem de patients, (ii) de l’expression et de la dégradation protéique dans des lymphoblastes issus de patients SLA et/ou (iii) des conséquences cellulaires après surexpression in vitro et in vivo. Ces analyses ont montré, concernant SQSTM1, qui est impliquée dans la formation des autophagosomes, que les mutations perturbaient l’agrégation protéique, que les mutations dans le gène UBQLN2 altéraient la dégradation lysosomale et la liaison de la protéine avec HSP70 et que celles dans PFN1 dérégulaient la voie de l’autophagie alternative et la mitophagie. Notre travail a permis (i) d’évaluer la contribution chez les patients français atteints de SLA de plusieurs gènes incriminés dans la SLA, (i) d’élargir le spectre génétique commun à la SLA et à d’autres pathologies et (iii) de mettre en avant la pertinence de l’implication des voies de dégradation protéique, notamment l’autophagie, dans la pathogénèse de la maladieThe fatal Amyotrophic Lateral Sclerosis (ALS) motor neuron disease is characterized by the degeneration of upper and lower motor neurons. Most ALS cases are sporadic (SALS) whereas ~10% are familial (FALS). A growing number of genes has been identified in ALS and represent 70% of FALS and 10% of SALS. The aims of this project were to analyze the contribution of 6 rare genes in a large population of French ALS patients and to study the pathogenic impact of some identified variants.The first part of this work was dedicated to the genetic analysis of MATR3, CHCHD10, SS18L1, SQSTM1, UBQLN2 and PFN1 genes. No causing variants were identified for MATR3 and CHCHD10 while 2 new variants, probably pathogenic, were identified for SS18L1, as well as 4 mutations for SQSTM1, 5 for UBQLN2 and 2 already reported mutations for PFN1. These analyses also highlighted a genetic overlap between ALS and other diseases: the Paget disease of bone for SQSTM1 and spastic paraplegia for UBQLN2. The second part of this work was to study the pathogenicity of some of the mutations identified in SQSTM1, UBQLN2 and PFN1 genes using analyses of (i) inclusions in ALS patient post-mortem tissue, (ii) protein expression and degradation pathways in patient lymphoblasts and/or (iii) cellular consequences after in vitro and in vivo overexpression. Our results showed prominent aggregation of mutant SQSTM1 (involved in autophagosomes formation), impaired lysosomal degradation and disrupted protein binding to HSP70 for mutant UBQLN2 and deregulated alternative autophagy and mitophagy pathways for mutant PFN1. Our results (i) precised the contribution of several genes in French ALS patients, (i) documented the genetic overlap between ALS and other diseases and (iii) highlighted the role of protein degradation pathways, especially autophagy, in the pathogenesis of ALS
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Scarrott, Joseph. "Investigating the specificity of RNAi molecules in human gene therapy for SOD1-linked familial amyotrophic lateral sclerosis." Thesis, University of Sheffield, 2018. http://etheses.whiterose.ac.uk/22558/.
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20% of familial amyotrophic lateral sclerosis (fALS) cases are caused by mutations in the gene encoding the cytosolic protein human Cu/Zn superoxide dismutase 1 (hSOD1). RNA interference (RNAi) technology offers the therapeutic potential for the treatment of SOD-linked fALS by reducing the burden of pathogenic mutant SOD1 protein. Translation of this gene therapy strategy to the clinic requires the development of vectors that are free of significant off-target effects and with reliable biomarkers to determine treatment efficacy, successful target gene reduction, and correct dosing. Using self-complementary adeno-associated virus serotype 9 (scAAV9) to deliver RNAi against hSOD1 in the SOD1G93A mouse model, the work presented in this thesis demonstrates that intrathecal injection of the therapeutic vector via the cisterna magna delayed onset of disease, decreased motor neuron death at end stage by up to 88%, and prolonged the median survival of SOD1G93A mice by up to 42%. Using a panel of purposefully designed RNAi constructs cloned into the scAAV9 backbone this is, to our knowledge, the first study to demonstrate no significant in vitro off-target effects linked to hSOD1 silencing, providing further confidence in the specificity of this approach. This study also reports the measurement of cerebrospinal fluid (CSF) hSOD1 protein levels as a biomarker of effective dosing and efficacy of hSOD1 knockdown. Together, this data provides further confidence in the safety of the clinical therapeutic vector.
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Oeda, Tomoko. "Oxidative stress causes abnormal accumulation of familial amyotrophic lateral sclerosis-related mutant SOD1 in transgenic Caenorhabditis elegans." Kyoto University, 2003. http://hdl.handle.net/2433/148674.
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Darbyson, Angie L. "ORP-3 Rescues ER Membrane Expansions Caused by the VAPB-P56S Mutation in Familial ALS." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/29054.
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A mutation in ER membrane protein VAPB is responsible for causing a familial form of ALS (ALS8). The VAPB-P56S mutation causes protein aggregation and a nuclear envelope defect, where retrograde transport is disrupted. Over-expression of a FFAT peptide from OSBP1 reduces the size of VAPB-P56S aggregates and restores retrograde transport. A screen was performed on FFAT-motif containing ORPs to determine if any could rescue the mutant phenotype. ORP3 successfully reduced aggregate size and restored transport to the nuclear envelope. ER membrane protein Sac1, a PI4P phosphatase cycles between the ER and Golgi and becomes trapped in expanded ERGIC compartments with VAPB-P56S. Loss of Sac1 in the ER leads to an increase in intracellular PI4P. ORP3 may increase Sac1 phosphatase activity by acting as a lipid sensor. We propose that VAPB, Sac1 and ORP3 are interacting partners that together modulate levels of PI4P. Disruptions in the gradient of PI4P may result in the vesicle trafficking defects observed in VAPB-P56S cells.
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Workinger, Paul M., and Paul M. Workinger. "Familial Amyotrophic Lateral Sclerosis with a focus on C9orf72 Hexanucleotide GGGGCC Repeat Expansion Associated ALS with Frontotemporal Dementia." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/625350.
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Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disorder resulting in the loss of motor neurons from the spinal cord and frontal cortex. The patterns of neurodegeneration, affected regions, age of onset, and time course of disease progression are all highly variable between and within variants of the disease. Familial ALS (fALS), inherited versions of ALS due to genetic changes, accounts for between 5-20% of all ALS cases, while the rest are sporadic, with either no causative mutation identified or no familial history of ALS. Recently, the discovery of C9orf72 hexanucleotide repeat expansions have been identified as one of the most common causes of familial ALS, with some patients presenting with dual phenotypes of ALS and frontotemporal dementia, leading to new hypotheses about the nature of neurodegenerative diseases. Despite the continued discovery of new ALS causative genes, little is known about the pathogenesis of the disease. While almost all variants include the presence of intracellular protein inclusions, the site of the protein plaques and involved proteins varies between genetic and phenotypic variants of this disease. Due to the lack of clear pathogenic mechanisms, several hypotheses have been developed to explain the process of neurodegeneration. Autophagy, the process of self-eating, leading to destruction of damaged or excess proteins and organelles, has been implicated as being altered in ALS. Multiple variants have demonstrated altered mitochondrial morphology and cellular energetic dynamics, which could explain previous observations that implicate the process of apoptosis in cellular death. Many of the involved proteins in ALS have functional roles for intracellular, nucleocytoplasmic, and axonal transport of various proteins or RNA. These three competing hypotheses are currently the most prominent hypotheses in the pathogenesis of ALS, and have largely been considered as separate and competing in past research. Is there a chance that the true pathogenesis leading to neuronal destruction via apoptosis involve all three hypotheses? Altered protein and RNA transport dynamics could lead to changes in cellular stress responses or overload autophagy pathways, leading to exacerbated cellular stress responses, leading to alterations in mitochondrial morphology and eventually cell death via apoptosis.
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Anagnostou, Georgia. "Characterisation of a new familial amyotrophic lateral sclerosis (FALS) locus and the analysis of the expression of FALS genes." Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435435.
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Hall, Jennifer Rejeanne. "Vector design for transgenic and allele replacement mouse models of Cu,Zn superoxide dismutase 1-associated familial amyotrophic lateral sclerosis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ32483.pdf.
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Kyllo, Hannah Marie, and Hannah Marie Kyllo. "Multifactorial Gene Therapy as a Novel Approach for the Treatment of Mutant Superoxide Dismutase-1 Linked Familial Amyotrophic Lateral Sclerosis." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/625029.
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Amyotrophic lateral sclerosis is a rapidly progressing disease characterized by the
degeneration and death of upper and lower motor neurons, and it is associated with a
lifetime risk of 1 in 1000. The disease not only involves damage to the motor neurons
themselves but also to neighboring glial cells. Since the characterization of the disease
roughly a century and a half ago, few successes have been seen in the development of a
treatment plan that yields viable results and prevents neurodegeneration. The
shortcomings of past therapies have been attributed to the narrow focus of treatment plans,
targeting a single aspect of the disease pathology. The pathophysiology is complex and
multifactorial, integrating aspects such as aberrant reactive oxygen species formation,
excitotoxicty, a reduced antioxidant response, and dysfunction of the endoplasmic
reticulum and mitochondria. Recent research employing a multifactorial approach to
treatment has yielded success in mice engineered with the mutant SOD1 gene, a mutation
which mimics the disease progression and pathophysiology seen in ALS patients. Current
clinical research for ALS has focused on using gene therapy techniques to introduce
therapeutic genes coding functional proteins into affected cells in the hopes of addressing
several of the pathological aspects of the neurodegenerative disease.
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Alves, Aleandro Geraldo. "MUTAÇÕES DO GENE SOD-1 (SUPERÓXIDO DISMUTASE 1) NA FORMA FAMILIAR DA ESCLEROSE AMIOTRÓFICA LATERAL: REVISÃO SISTEMÁTICA." Pontifícia Universidade Católica de Goiás, 2011. http://localhost:8080/tede/handle/tede/2361.
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Previous issue date: 2011-08-11Amyotrophic lateral sclerosis (ALS) is a multifactorial disease that affects motor neurons. In most cases, the disease is sporadic, however, 5 to 10% of patients have a familial history (FALS). Among patients with FALS, 12 to 23% present with mutations in the SOD1 gene. Objectives: To present a systematic review about the mutations described in SOD1 gene in patients with FALS. Methods: The databases used in this study included PubMed, ISI Web of Science and Cochrane Library Virtual Health. After reading the abstracts, 71 articles were selected and systematically reviewed on this study. Results: The largest number of publications was found in 1997, and Japan was the country with the majority of published studies on the subject, with 23 articles. The majority of the mutations were described in éxons four and five of SOD1 gene, and A4V, I113T, I144F, D90A and L38V were the most commonly mutation described. More than 156 mutations in the SOD1 gene have been cataloged in patients with ALS-F and these data are deposited in ALS GENETICS ONLINE DATABASE, a database that contains specific information on mutations associated with amyotrophic lateral sclerosis. However, the articles reviewed in this study described 103 mutations. Conclusions: Several mutations in the SOD1 gene have been described in patients with ALS-F, however, the relationship between such mutations and the pathogenesis of ALS-F remains unclear, as well as the relationship between mutations and disease progression. Further studies are necessary in order to better explain such relationship.
A esclerose amiotrófica lateral (EAL) é uma doença multifatorial que afeta os neurônios motores. Na maioria dos casos, a doença é esporádica, entretanto, 5 a 10% dos pacientes apresentam história familiar (EAL-F). Dentre os pacientes com EAL-F, 12 a 23% apresentam mutações no gene SOD1. O objetivo deste trabalho foi realizar uma revisão sistemática acerca das mutações descritas no gene SOD1 em pacientes com EAL-F. As bases de dados consultadas incluíram Pubmed, ISI Web of Science e Cochrane Biblioteca Virtual em Saúde. Após a revisão dos resumos, 71 artigos foram selecionados descrevendo mutações no gene SOD1 em pacientes com EAL-F. O ano que apresentou o maior número de publicações foi 1997 e o Japão foi o país que mais publicou sobre o assunto, aparecendo em 23 artigos. O maior número de mutações foi descrito nos éxons 4 e 5 do gene SOD1 e as mutações A4V, I113T, I144F, D90A e L38V foram as mais comumente citadas. Até o momento 156 mutações no gene SOD1 já foram catalogadas em pacientes com EAL-F e esses dados encontram-se depositados no ALS ONLINE GENETICS DATABASE, um banco de dados que contém informações específicas sobre mutações associadas à esclerose amiotrófica lateral. Entretanto, os artigos revisados neste estudo descrevem 103 destas mutações. As causas relacionadas às mutações no gene SOD1 permanecem incertas, assim como a relação entre tais mutações e a evolução da doença, portanto, muito ainda deve ser estudado acerca desse tema.
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Jackson, Mandy. "Screening of familial and sporadic amyotrophic lateral sclerosis patients for mutations in CuZn superoxide dismutase (SOD-1) and other candidate genes." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363787.
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Cheroni, Cristina. "The role of proteasome dysfunction in the mechanisms of motor neuron degeneration in a mouse model of familial amyotrophic lateral sclerosis." Thesis, Open University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446112.
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Hoshino, Tomonori. "6-Deoxyjacareubin, a natural compound preventing hypoxia-induced cell death, ameliorates neurodegeneration in a mouse model of familial amyotrophic lateral sclerosis." Kyoto University, 2020. http://hdl.handle.net/2433/253490.
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Cooper, Laura. "Mitochondrial heat shock protein 60: evaluation of its role as a neuroprotectant in familial amyotrophic lateral sclerosis and its mutation as a cause of hereditary spastic paraplegia." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104556.
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In the fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS), protein misfolding and aggregation are involved in motor neuron death. Heat shock proteins (Hsp), which help refold misfolded proteins or target them to the proteasome for degradation, have been studied as a therapeutic target in ALS, with some success. At the same time, it has been shown that mitochondrial dysfunction is one of the earliest pathogenic events leading to motor neuron death in ALS. The mitochondria have their own Hsps, for protein folding in the matrix, an important example of which is Hsp60. Given the finding that increased expression of another mitochondrial Hsp, Hsp22, preserved motor function, reduced motor neuron death and increased resistance to oxidative stress in a Drosophila model of aging, it is possible that the upregulation of mitochondrial Hsp60 might have similar neuroprotective effects in ALS. The current study examined Hsp60 upregulation in a primary dissociated spinal cord culture model of familial ALS (fALS) due to mutation in the SOD1 gene. Increasing Hsp60 expression failed to improve motor neuron viability, to ameliorate SOD1 protein misfolding/aggregation, and to prevent mitochondrial rounding in motor neurons. Therefore, the upregulation of mitochondrial Hsp60 would not be an effective therapy for ALS.Meanwhile, dominantly-inherited mutations in the gene encoding for Hsp60 have been linked to hereditary spastic paraplegia SPG13 (HSPG13), a disease in which the axons of motor neurons degenerate. Disease mechanisms are not known; however, given the importance of mitochondria to axonal integrity, and the mitochondrial localization of Hsp60, mitochondrial dysfunction seems a likely candidate. Hsp60V72I, a mutation found in HSPG13 patients, was expressed in motor neurons in primary dissociated spinal cord culture to model potential mitochondrial abnormalities. Hsp60V72I expression did not reduce motor neuron viability, alter mitochondrial morphology, or impair mitochondria on functional measures, including membrane potential (ΔΨ), resistance to oxidative stress, or axonal transport. It is possible that Hsp60V72I causes no, or a weak, mitochondrial phenotype. However, the expression of a severe, ATPase-deficient mutant, Hsp60D423A, also failed to induce mitochondrial dysfunction in this culture model. Thus, these phenotypes might not manifest because of culture conditions or because they are masked by the high level of endogenous Hsp60.Lors de la maladie neurodégénérative de la sclérose latérale amyotrophique (SLA), le mauvais repliement et l'agrégation des protéines ont une incidence sur la mort des motoneurones. Les protéines du choc thermique (Hsp), lesquelles aident les protéines au mauvais repliement à se replier de nouveau ou encore ciblent ces dernières au niveau du protéasome pour leur dégradation, ont été étudiées comme source de traitement possible pour la SLA, non sans réussite. Parallèlement, il a été démontré que le dysfonctionnement mitochondrial est un des événements pathogènes menant à la mort des motoneurones, les anomalies mitochondriales apparaissant avant qu'une agrégation ou un mauvais repliement des protéines significatif ne soit observé. Les mitochondries ont leurs propres Hsp pour les protéines se repliant dans la matrice, les Hsp60 étant l'exemple par excellence. Si on considère que l'expression intensifiée d'autres mitochondries comme les Hsp22 peut préserver la fonction motrice, empêcher la mort de motoneurones et augmenter la résistance au stress oxydatif dans un modèle vieillissant de Drosophila, il semble que la régulation positive des Hsp60 mitochondriales pourrait possiblement protéger les neurones contre la SLA. La présente étude avait pour but d'examiner la régulation positive des Hsp60 dans un modèle de moelle épinière dissociée atteinte de SLA familiale causée par une mutation du gène SOD1. L'intensification de l'expression des Hsp60 n'a pas contribué à préserver la viabilité des motoneurones, ni à rectifier le mauvais repliement ou l'agrégation des protéines SOD1, ni à prévenir l'arrondissement mitochondrial dans les motoneurones. Par conséquent, la régulation positive des Hsp60 mitochondriales n'est pas recommandée pour le traitement de la SLA.Entretemps, les mutations de l'encodage du gène pour les Hsp60 transmises selon le mode dominant ont été associées à la paraplégie spasmodique héréditaire SPG13 (HSPG13), une maladie au cours de laquelle la dégénérescence axonique cause la mort des motoneurones. On ne connait aucun autre mécanisme de mort cellulaire plus précis. Toutefois, étant donné la présence des anomalies mitochondriales dans grand nombre de maladies neurodégénératives, l'importance des mitochondries pour l'intégrité des axones et la localisation mitochondriale des Hsp60, le dysfonctionnement mitochondrial pourrait très bien constituer un tel mécanisme. Les Hsp60V72I, une mutation observée chez les patients atteints de HSPG13, ont pu être exprimées dans les motoneurones provenant de cultures de moelle épinière dissociée afin de servir de modèle pour de potentielles anomalies mitochondriales. L'expression des Hsp60V72I n'a pas mené à une baisse de viabilité chez les motoneurones, ni à une modification de la morphologie mitochondriale, ni à une détérioration des mesures fonctionnelles des mitochondries, incluant le potentiel de membrane (ΔΨ), la résistance au stress oxydatif et le transport axonal. Il se peut que les Hsp60V72I ne causent qu'un faible phénotype mitochondrial, ou encore qu'elles n'en causent aucun du tout. Cependant, l'expression d'un mutant à grave déficience en ATP-ase, soit les Hsp60D423A, n'est pas non plus parvenue à causer un dysfonctionnement mitochondrial dans ce modèle de culture. On ne sait toujours pas si l'absence de phénotype est révélatrice du rôle des Hsp60 dans les maladies touchant les motoneurones, ou si les résultats négatifs sont un artefact du modèle de culture, lequel était caractérisé par un niveau élevé d'expression endogène des Hsp60 de phénotype sauvage qui pourrait potentiellement masquer les effets de l'expression du mutant exogène Hsp60. Les études à venir devraient se pencher sur les effets mitochondriaux de l'expression des Hsp60V72I dans un contexte où le phénotype sauvage Hsp60 endogène est réduit, en utilisant par exemple les Hsp60 shRNA particulières aux souris.
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Peviani, Marco. "Development of lentiviral vectors targeted to p38MAPK inhibition and Akt activation in motor neurons of a mouse model of familial amyotrophic laterial sclerosis." Thesis, Open University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522240.
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Malaspina, Andrea. "Amyotrophic lateral sclerosis (ALS) : analysis of differential gene expression in spinal cord and study of the Cu/Zn superoxide dismutase gene (SOD1) in familial ALS cases (FALS) of Italian origins." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248425.
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Praline, Julien. "Génétique des formes sporadiques de sclérose latérale amyotrophique." Thesis, Tours, 2009. http://www.theses.fr/2009TOUR3139/document.
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La sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative d’évolution toujours fatale. Dans les formes sporadiques (SLAS), l’étiologie demeure inconnue et l’hypothèse d’une participation génétique dans le cadre d’un modèle de maladie complexe est envisagée. Notre travail porte sur deux gènes de susceptibilité dans la SLAS : le gène de l’Apolipoprotéine E (APOE) et le gène impliqué dans l’hémochromatose familiale de type 1 (HFE). Notre première étude confirme sur une population de 1482 patients atteints de SLA sporadique le lien entre allèle ε4 et la forme bulbaire de la maladie mais uniquement chez les hommes. Nous proposons une explication physiopathologique faisant intervenir le récepteur aux androgènes, particulièrement exprimé au niveau des motoneurones bulbaires. Notre deuxième étude sur 244 patients et 302 contrôles ne retrouve pas l’association entre le polymorphisme H63D et le risque de SLA sporadique notée dans d’autres populations. En revanche, l’allèle Y du polymorphisme C282Y semble exercer un effet protecteur vis-à-vis de la SLA. Ces données sont discutées dans le contexte de l’hypothèse physiopathologique du stress oxydantAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. The cause of sporadic cases (SALS) remains unknown but a genetic participation in a model of complex disease is suspected. Our work concerns two susceptibility genes for SALS: Apolipoprotein E gene (APOE) and the gene involved in familial hemochromatosis (HFE). Our first study including 1482 patients with SALS confirms a link between ε4 allele and bulbar-onset of the disease, only in men. We suggest a pathophysiological explanation with a role for the androgen receptor which is particularly abundant in motor neurons of the brainstem. Our second study about 244 patients and 302 controls did not find any association between the H63D polymorphism and SLAS, which has previously been showed. However, the Y allele of the C282Y polymorphism seems to exert a protective effect against SALS. We discuss these data within the pathophysiological hypothesis of oxidative stress in ALS
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Flowers, Joanna Mary. "Molecular studies in amyotrophic lateral sclerosis." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397027.
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Schymick, Jennifer. "The genetics of amyotrophic lateral sclerosis." Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:f68f15c2-2875-46ba-bf25-8324c1dead91.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. There is no cure for ALS and no definitive explanation for the onset and rapid progression of motor neuron degeneration. Genetics is a known risk factor for a portion of familial cases. However, the role of genetics in the commoner sporadic form of the disease is poorly understood, although numerous genes have been implicated. The primary aim of this thesis project is to uncover the genetic causes that underlie ALS. To accomplish this goal, the main focus of this thesis is to perform genome-wide association analysis of sporadic ALS using high density SNP arrays. This thesis describes the first and the largest genome-wide association studies of ALS to date. Results demonstrate that there is no single large effect susceptibility variant underlying a large proportion of ALS, such as ApoE in Alzheimer’s disease. However, the genotyping data has been made publically available and the digital nature of this data means that it is a resource that can grow with future studies. Beyond genome-wide association, this thesis describes work using linkage, haplotype and sequence analysis to investigate the genetic overlap between ALS and frontotemporal dementia. Lastly, this thesis presents a novel method for linkage analysis using high throughput SNP arrays. Ultimately, it is hoped that by uncovering the genes that cause ALS, such knowledge will shed light on the pathogenic mechanisms underlying motor neuron degeneration and potentially lead to new rational therapies effective in slowing or even halting disease progression.
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Tjust, Anton. "Extraocular Muscles in Amyotrophic Lateral Sclerosis." Doctoral thesis, Umeå universitet, Anatomi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-129638.
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Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease of motor neurons characterized by muscle paralysis and death within 3-5 years of onset. However, due to unknown mechanisms, the extraocular muscles (EOMs) remain remarkably unaffected. The EOMs are highly specialized muscles that differ from other muscles in many respects, including innervation and satellite cells (SCs). Understanding whether these factors play a role in the relative sparing of EOMs in ALS could provide useful clues on how to slow down the progression of ALS in other muscles. The EOMs and limb muscles from terminal ALS patients and age-matched controls as well as the commonly used SOD1G93A ALS mouse model were studied with immunofluorescence. Antibodies against neurofilament and synaptophysin were used to identify nerves and neuromuscular junctions (NMJs); against Pax7, NCAM, MyoD, myogenin, Ki-67, dystrophin and laminin, to identify SCs and their progeny in EOMs and limb muscles. The proportion and fiber size of myofibers containing myosin heavy chain (MyHC) slow tonic and MyHC slow twitch were also determined in human EOMs. The abundance of SCs differed extensively along the length of control human EOMs, being twice as abundant in the anterior portion. Pax7-positive cells were also detected in non-traditional SC positions. EOMs from terminal ALS patients showed similar numbers of resting and activated SCs as the controls. In limb muscles of ALS patients, the number of resting and activated SCs ranged from low (similar to normal aged, sedentary individuals) to high numbers, especially in muscles with long duration of disease and varied between the upper and lower limbs. The EOMs maintained a high degree of innervation compared to hindlimb muscles of symptomatic SOD1G93A mice. MyHC slow tonic fibers were less abundant in ALS patients than in controls. The change seemed more pronounced in bulbar onset patients, and in this group of subjects only, there was a strong association between decline in MyHC slow tonic fibers and age of death. Notably, the decline in MyHC slow tonic fibers was unrelated to disease duration. Our data suggested that SCs play a minor role in the progression of ALS in general and in the sparing of the EOMs in particular. The generally preserved innervation in the EOMs of G93A mice may reflect distinct intrinsic properties relevant for sparing of the oculomotor system. Even though the EOMs are relatively spared in ALS, MyHC slow tonic myofibers were selectively affected and this may reflect differences in innervation, as these fibers are multiply innervated.Amyotrofisk lateralskleros (ALS) är en obotlig neurodegenerativ sjukdom som främst påverkar kroppens viljestyrda motoriska nervceller. ALS leder till förlamning, muskelförtvining och slutligen döden genom andningssvikt, vanligen inom tre till fem år efter sjukdomsdebuten. Av okända anledningar så bibehålls ögonmusklernas funktion mycket bättre vid ALS i jämförelse med andra muskler och är hos merparten av patienter i stort sett opåverkade. Ögonmusklerna är mycket specialiserade muskler som skiljer sig från andra muskler i kroppen på flera sätt, bland annat genom deras unika nervförsörjning och genom de satellitceller – muskelspecifika stamceller, som finns i dem. En ökad förståelse för hur dessa faktorer inverkar på ögonmusklernas motståndskraft vid ALS skulle kunna ge värdefulla ledtrådar till hur man skulle kunna sakta ned sjukdomens fortskridande i andra muskler vid ALS. Ögonmuskler och extremitetsmuskler från avlidna ALS-patienter och åldersmatchade friska kontroller, tillsammans med transgena möss med den sjukdomsalstrande mutationen SOD1G93A, studerades genom immunfluorescens och efterföljande mikroskopering. Antikroppar mot molekylerna Pax7, NCAM, MyoD, myogenin, Ki-67, laminin och dystrofin användes för att identifiera satellitceller och deras dotterceller i ögonmuskler och extremitetsmuskler. Antikroppar mot neurofilament och synaptofysin användes för att identifiera nerver och neuromuskulära synapser hos transgena SOD1-möss. Antikroppar mot toniska (tonic) och ryckande (twitch) muskelmyosinkedjor användes för att bestämma proportionen av och storleken på dessa typer av muskelfibrer i ögonmuskler från avlidna ALS-patienter och friska kontroller. Mängden satellitceller varierade mellan de främre och de mer bakre delarna i friska, humana ögonmuskler och var dubbelt så många i den främre delen av muskeln jämfört med den mellersta och bakre delen av muskeln. Celler som uttryckte satellitcellsmarkören Pax7 hittades även i icke-traditionella satellitcellspositioner i ögonmusklerna. Mängden satellitceller i ögonmusklerna från ALS-patienter var samma som hos friska kontroller. I extremitetsmusklerna hos ALS-patienter varierade mängden satellitceller mellan låga nivåer (liknande de hos friska åldrade, inaktiva individer) till höga nivåer, särskilt i muskler där sjukdomen fortskridit under lång tid. Dessutom varierade mängden satellitceller mellan övre och nedre extremiteter. Hos symptomatiska SOD1G93A-möss hade ögonmusklerna en mycket välbevarad innervation jämfört med bakbensmusklerna, där många neuromuskulära synapser saknade kontakt mellan nerven och motorändplattan. Proportionen muskelfibrer med toniska muskelmyosinkedjor var lägre hos ALS-patienter jämfört med friska kontroller. Denna minskning var tydligare hos patienter där sjukdomssymtomen hade debuterat i tugg- och ansiktsmuskulaturen – så kallad bulbär ALS. Dessutom fanns det i den här gruppen, men ingen annan studerad grupp, en stark korrelation mellan nedgången i toniska fibrer och patientens ålder. Värt att notera är att minskningen av toniska muskelfibrer saknade korrelation med hur länge patienten hade varit sjuk i ALS. Den generellt välbevarade innervationen i ögonmusklerna hos SOD1G93A-möss kan spegla distinkta inneboende egenskaper hos ögonmusklerna som är av vikt för bevarandet av ögonrörligheten vid ALS. Gällande satellitceller så antyder våra data att satellitceller och deras regenerativa kapacitet spelar en försumbar roll vid ALS i allmänhet och vid ögonmusklernas bevarande i synnerhet. Slutligen, även om ögonmuskler generellt är välbevarade vid ALS så är toniska muskelfibrer märkbart påverkade och detta kan spegla skillnader mellan olika nervcellsgruppers känslighet vid ALS.
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Valbuena, Gabriel. "Metabolomic studies of amyotrophic lateral sclerosis." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/49719.
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Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive neurodegenerative disease, and is fatal within 3-5 years of onset. Metabolic dysfunctions have consistently been identified in ALS, although its role in pathogenesis remains unclear. In this thesis, I apply a metabolomic approach using 1H NMR spectroscopy and Gas Chromatography-Mass Spectrometry in a range of disease models of increasing biological complexity, as well as patient tissues, in order to reveal perturbations to the metabolic network that may impact the course of the disease. I examined alterations to metabolism in the motor neuron-like NSC-34 cell line, and found that mutant SOD1 led to increased glycolysis to divert glucose from oxidative metabolism, and a broad intracellular amino acid depletion. The contribution of non-cell autonomous processes were also investigated in an astrocyte-motor neuron co-culture model, where mutant SOD1 produced varying perturbations to glycolysis and oxidative stress responses in each cell type, together with decreased branched-chain amino acid catabolism and glutamine-glutamate production that may indicate impaired neurotransmitter recycling. I also found different metabolic responses to mutant SOD1 in two strains with varying rates of disease progression, suggesting a role for early metabolic responses to mutant SOD1 in affecting the course of disease. In addition, I identify a metabolic signature for C9ORF72 ALS in cerebellum tissue, providing evidence that the hexanucleotide repeat expansion leads to distinctive metabolic changes in the CNS. Overall, I demonstrate the applicability of metabolomics in ALS research, particularly in revealing hidden metabolic subtypes of the disease. This opens opportunities to improve our understanding of the processes leading to motor neuron death in ALS, and highlights the potential use of metabolomics as a tool to develop therapies targeted to the individual metabolic responses of individuals susceptible to ALS.
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Seals, Ryan M. "Risk Factors for Amyotrophic Lateral Sclerosis." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:23205175.
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Amyotrophic lateral sclerosis (ALS) is a progressive debilitating disease of the upper and lower motor neurons. Median survival of ALS patients is consistently estimated at between 2-3 years from symptom onset, with some evidence that survival is increasing due to improved care. There are few well-established risk factors for ALS, and there is conflicting evidence regarding the trends in ALS incidence and mortality over the past several decades.
In Chapter I we investigate the trends in ALS incidence and mortality in Denmark between 1970 and 2009. We employed age-period-cohort models to model both the incidence and mortality rates of ALS over time for the first time. We found a significant rise in ALS incidence and mortality over several decades, and we observed evidence for a birth cohort component to the rise in ALS, which is consistent with an environmental cause of ALS.
In Chapter II we investigate the role of physical trauma – both head and other – in the development of ALS. We employed the Danish registries and linked health data from the hospital system to prior diagnoses for physical trauma. We found a borderline significant association between physical trauma and ALS, which grew stronger upon restricting to physical traumas before the age of 55.
Chapter III concerns the risk of ALS in those employed by the military in Denmark. We linked occupational records from the Danish Pension Fund to health records of the hospital system. We found a significantly elevated rate of ALS among those who had been previously employed by the military, with the highest rates in the decade immediately following cessation of employment.
These analyses strengthen the knowledge base for the epidemiology of ALS, and suggest future avenues of research to further understand the etiology of the disease.
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Fang, Fang. "Epidemiologic studies of amyotrophic lateral sclerosis." Stockholm, 2010. http://diss.kib.ki.se/2010/978-91-7409-671-2/.
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Johnston, Pamela. "Echovirus aetiology in amyotrophic lateral sclerosis." Thesis, Glasgow Caledonian University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.688246.
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McHenry, Kristen L. "Respiratory Compromise in Amyotrophic Lateral Sclerosis." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/2539.
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Jonsson, P. Andreas. "Superoxide dismutase 1 and amyotrophic lateral sclerosis." Doctoral thesis, Umeå : Medical Biosciences, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-611.
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Enayat, Zinat Ellaheh. "Superoxide dismutase mutations and amyotrophic lateral sclerosis." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400500.
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Mather, Mary Srikanti. "Putative protein abnormalities in amyotrophic lateral sclerosis." Thesis, University of Sussex, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239078.
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Sundara, Rajan Sandeep. "Role of peroxiredoxins in amyotrophic lateral sclerosis." Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/3784/.
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Puigdomenech, Poch Maria. "Development of therapeutic strategies for amyotrophic lateral sclerosis." Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/670740.
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L’esclerosis lateral amiotròfica (ELA) és una malaltia neurodegenerativa devastadora, per la qual actualment no existeix cap tractament. L’ELA es caracteritza per la pèrdua progressiva de motoneurones (MN) tan superiors com inferiors i la consegüent atrofia muscular. A dia d’avui es desconeix el mecanisme molecular específic que promou la mort de les MN, però s’ha relacionat amb diferents processos que inclouen tant les MN com les cèl·lules del voltant com pot ser l’estrès oxidatiu, la inflamació o l’agregació de proteïnes com la superòxid dismutasa 1 (SOD1). En aquesta tesis nosaltres proposem dues estratègies terapèutiques per L’ELA: incrementar l’eficiència de silenciament de la proteïna mutada SOD1 mitjançant teràpia gènica i estudiar el rol de l’àcid lisofosfatídic (LPA) com a mediador de la inflamació, en la fisiopatologia de l’ELA.
En el primer capítol, amb l’objectiu de reduir els nivells de RNA de la proteïna mutada SOD1, nosaltres administrem oligonucleòtids antisentit (ASO) conjugats a lligands específics per tal d’incrementar la seva internalització a les cèl·lules. Els resultats presentats revelen la eficient internalització d’aquesta teràpia a neurones i cèl·lules glials. A més, la conjugació del ASO amb el lligand DCPP redueix de manera més eficient els nivells de RNA de SOD1 que no pas els ASO no conjugats. Tot i això l’administració del ASO conjugat al lligand DCPP en els ratolins SOD1G93A, el model experimental de ALS, no presenten afectes terapèutics.
Pel que fa el segon capítol, com que la inflamació és un tret comú de la majoria de les condicions neurològiques i sabent que el receptor LPA2 contribueix en la fisiopatologia de la lesió medul·lar, ens preguntem si l’LPA podria contribuir en la fisiopatologia de l’ELA. Per això vam creuar ratolins nuls pel receptor LPA2 amb ratolins SOD1G93A. Els resultats demostren que l’absència del receptor LPA2 retarda la progressió de la malaltia i evita l’atròfia muscular en ratolins SOD1G93A.
Col·lectivament els resultats que presentem en aquesta tesis aporten nova informació que podria servir per desenvolupar estratègies pel tractament de l’ELA.La esclerosis lateral amiotrófica (ELA) es una enfermedad neurodegenerativa devastadora, por la cual actualmente no existen ningún tratamiento. La ELA se caracteriza por la pérdida progresiva de motoneuronas (MN) superiores e inferiores y la consiguiente atrofia muscular. Hoy en día se desconocen los mecanismos moleculares específicos que promueven la muerte de estas MN, aunque se han relacionado con múltiples procesos que incluyen tanto las MN como las células subyacentes, tales como el estrés oxidativo, la inflamación o la agregación de proteínas como la superóxido dismutasa 1. En esta tesis nosotros proponemos dos estrategias terapéuticas para el ELA: incrementar la eficiencia del silenciamiento de la proteína mutada SOD1 mediante terapia génica y estudiar el rol del ácido lisofosfatídico (LPA) como mediador de la inflamación, en la fisiopatología del ELA. En el primer capítulo, con el objetivo de reducir los niveles de RNA de la proteína mutada SOD1, administramos oligonucleótidos antisentido (ASO) conjugados a ligandos específicos, por así incrementar su internalización a las células. Los resultados presentados revelan la eficiente internalización de esta terapia en neuronas y células gliales. Además, la conjugación del ASO con el ligando DCPP reduce de manera más eficiente que los ASO no conjugados, los niveles de RNA de SOD1 en los ratones SOD1G93A. Sin embargo, la administración del ASO conjugado con el ligando DCPP en los ratones SOD1G93A no presenta efectos terapéuticos. En el segundo capítulo, como la inflamación es un factor común en varias condiciones neurológicas y sabiendo que el receptor LPA2 contribuye en la fisiopatología de la lesión medular, nos preguntamos si el LPA podría contribuir en la fisiopatología del ELA. Por esto cruzamos ratones nulos por el receptor LPA2 con ratones transgénicos SOD1G93A. Nuestros resultados demuestran que la ausencia del receptor LPA2 retarda la progresión de la enfermedad y evita la atrofia muscular en ratones SOD1G93A. Colectivamente los resultados presentados en esta tesis aportan nueva información que podrían servir para desarrollar estrategias para el tratamiento de la ELA.
Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder with no effective treatment currently available. ALS is characterized by the progressive loss of both upper and lower motoneuron (MN) and the consequent muscle atrophy. Nowadays the specific molecular mechanism that underline the MN death is unknown, however has been related several dysfunction mechanisms in MNs and the surrounding cells, such: oxidative stress, inflammation or aggregation of aberrant proteins like superoxide dismutase 1 (SOD1). In this thesis we propose two therapeutic strategies for ALS: increase the silencing efficiency of the mutated SOD1, by means of gene therapy and study the role of the lysophosphatidic acid (LPA) in the pathophysiology of ALS. In the first chapter, with the aim to reduce the RNA levels of the SOD1 mutated, we administrated antisense oligonucleotide (ASO) conjugated to specific ligands to increase the internalization of the molecule. The results present here reveal the efficient internalization of the therapy in neurons and glia cells. Furthermore, the conjugated- ASO with the ligand DCPP reduce more efficiently than the unconjugated ASO, the SOD1 RNA levels in the SOD1G93A mice, an experimental model of ALS. However, the administration of the conjugated-ASO with the ligand DCPP in the SOD1G93A mice, does not present therapeutic effects. In the second chapter, since inflammation is a hallmark of most neurological conditions and LPA2 has been reported that contribute to the pathophysiology of spinal cord injury, we wonder if LPA could be involved in the pathophysiology of ALS. To assess whether activation of LPA2 contributes to ALS, we crossed LPA2 null with SOD1G93A mice. Our results reveal that the absence of LPA2 delays onset and progression of the disease and prevent the muscle atrophy in ALS mice. Collectively the results presented here provide more novel data that could underline new therapeutic strategies for ALS.
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Zetterström, Per. "Misfolded superoxide dismutase-1 in amyotrophic lateral sclerosis." Doctoral thesis, Umeå universitet, Klinisk kemi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-43898.
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Amyotrophic lateral sclerosis (ALS) is a disease in which the motor neurons die in a progressive manner, leading to paralysis and muscle wasting. ALS is always fatal, usually through respiratory failure when the disease reaches muscles needed for breathing. Most cases are sporadic, but approximately 5–10% are familial. The first gene to be linked to familial ALS encodes the antioxidant enzyme superoxide dismutase-1 (SOD1). Today, more than 160 different mutations in SOD1 have been found in ALS patients. The mutant SOD1 proteins cause ALS by gain of a toxic property that should be common to all. Aggregates of SOD1 in motor neurons are hallmarks of ALS patients and transgenic models carrying mutant SOD1s, suggesting that misfolding, oligomerization, and aggregation of the protein may be involved in the pathogenesis. SOD1 is normally a very stable enzyme, but the structure has several components that make SOD1 sensitive to misfolding. The aim of the work in this thesis was to study misfolded SOD1 in vivo. Small amounts of soluble misfolded SOD1 were identified as a common denominator in transgenic ALS models expressing widely different forms of mutant SOD1, as well as wild-type SOD1. The highest levels of misfolded SOD1 were found in the vulnerable spinal cord. The amounts of misfolded SOD1 were similar in all the different models and showed a broad correlation with the lifespan of the different mouse strains. The misfolded SOD1 lacked the C57-C146 intrasubunit disulfide bond and the stabilizing zinc and copper ions, and was prinsipally monomeric. Forms with higher apparent molecular weights were also found, some of which might be oligomers. Misfolding-prone monomeric SOD1 appeared to be the principal source of misfolded SOD1 in the CNS. Misfolded SOD1 in the spinal cord was found to interact mainly with chaperones, with Hsc70 being the most important. Only a minor proportion of the Hsc70 was sequestered by SOD1, however, suggesting that chaperone depletion is not involved in ALS. SOD1 is normally found in the cytoplasm but can be secreted. Extracellular mutant SOD1 has been found to be toxic to motor neurons and glial cells. Misfolded SOD1 in the extracellular space could be involved in the spread of the disease between different areas of the CNS and activate glial cells known to be important in ALS. The best way to study the interstitium of the CNS is through the cerebrospinal fluid (CSF), 30% of which is derived from the interstitial fluid. Antibodies specific for misfolded SOD1 were used to probe CSF from ALS patients and controls for misfolded SOD1. We did find misfolded SOD1 in CSF, but at very low levels, and there was no difference between ALS patients and controls. This argues against there being a direct toxic effect of extracellular SOD1 in ALS pathogenesis. In conclusion, soluble misfolded SOD1 is a common denominator for transgenic ALS model mice expressing widely different mutant SOD1 proteins. The misfolded SOD1 is mainly monomeric, but also bound to chaperones, and possibly exists in oligomeric forms also. Misfolded SOD1 in the interstitium might promote spread of aggregation and activate glial cells, but it is too scarce to directly cause cytotoxicity.
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Wootz, Hanna. "Amyotrophic Lateral Sclerosis – A Study in Transgenic Mice." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7342.
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Ekegren, Titti. "Transmethylation, Polyamines and Apoptosis in Amyotrophic Lateral Sclerosis." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3952.
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Van, Der Hulst Egberdina Jozefa. "Heterogeneity of cognitive impairment in amyotrophic lateral sclerosis." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6388.
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This PhD thesis examines the relationship between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). ALS is a rapidly progressive neurodegenerative movement disorder characterized by muscle weakness, spasticity and abnormal reflexes. In a very small subset of patients (5-15%), ALS is associated with FTD. Furthermore, a larger subset of patients who do not suffer from overt dementia, develop subtle deficits in cognition and behaviour (up to 50%). The changes have mostly been observed in the domains of executive functions, language and behavioural functioning. These observations have led some researchers to propose a continuum of dysfunction between ALS and FTD, ranging from an absence of neuropsychological abnormalities to mild, subclinical changes to a profile consistent with a full-blown FTD-syndrome in ALS. FTD consists of three subsyndromes; the first ‘executive-behavioural’ type, frontal variant FTD (fvFTD), is predominantly characterized by behaviour abnormalities, difficulties with using strategies and social judgement. In contrast, the other two types mainly involve problems with ‘language’, including a central degradation of knowledge for words, objects, people (semantic dementia; SD) as well as complications with speaking, spelling and the sounds of language (progressive non-fluent aphasia; PNFA). The current study aims to explore whether the cognitive-behavioural deficits found in nondemented ALS-patients can be classified as subclinical forms of the first two FTDsyndromes, i.e. fvFTD and SD. In addition, the study further examined whether executive and language impairments co-exist or rather occur independently. To answer the research questions, a battery of neuropsychological tests was employed, adapted to patients’ speech and motor disabilities, as well as behavioural questionnaires. The data revealed there was evidence of both executive and language involvement characteristic of FTD, albeit to a subtle extent. ALS-patients showed deficits on a test of Theory of Mind (ToM). On this test, participants were asked to judge the thoughts and feelings of another, using the direction of eye gaze, a cue considered to be important for social interaction. Results indicated that ALS patients had difficulties with affective ToM, i.e. recognizing feelings of others, and this effect was not driven by perceptual or attentional difficulties. In addition, patients exhibited a subtle deficit with empathy as well as a range of behavioural abnormalities. Furthermore, ALS-patients showed abnormal performance on a complex multi-modal semantic association task which involved assigning the correct picture iii to the sound of an object. This central deficit emerged in the presence of normal audio-visual information processing and episodic memory functions. Moreover, a category-specific deficit for man-made objects was detected in patients. Individual case-analyses showed that various subsets of patients were impaired on the language and executive tasks. These analyses also showed that executive and language problems can occur independently as well as simultaneously in patients with ALS. In addition, analysis of individual cases revealed that some patients’ performance on the decision making tasks was similar to that found in patients with either orbitofrontal or dorsolateral dysfunction, while there was little if any evidence of a pattern of impairment similar to that seen with anterior cingulate dysfunction. The observed difficulties with social cognition and semantic processing indicate that executive and language problems, characteristic of the two FTD syndromes, can be detected in patients with classical ALS.
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Lorente, Pons Alejandro. "Investigation of oligodendroglial pathology in amyotrophic lateral sclerosis." Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/20854/.
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Background: Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease. TDP-43 is found in pathological protein aggregates in neurons and glia in ALS and it is part of some mRNA transport granules. MBP messenger RNA (mRNA) must be transported to the oligodendrocyte processes for correct myelination. If TDP-43 were part of MBP mRNA transport granules, its aggregation could lead to loss of MBP in the CNS. Additionally, C9orf72 is a gene whose GGGGCC expansion mutation causes ALS. The expansion binds hnRNP-A2, a protein essential for the transport of MBP mRNA. This interaction may lead to the sequestration of hnRNP-A2, reducing its availability and causing a shortage of MBP in the CNS. Aims: To characterise the oligodendroglial pathology and the loss of MBP in our cohort of ALS cases, and to create zebrafish lines to investigate the development of oligodendroglial degeneration in sporadic ALS and C9orf72 ALS. The overarching hypothesis of the project is that the observed oligodendrocyte degeneration in ALS is primarily caused by a dysfunction of MBP mRNA transport, causing demyelination. Methods & Results: Using immunohistochemistry in human post mortem tissue, this project reports a greater, distinct ubiquitin-related glial pathology in the primary motor cortex of C9orf72-ALS cases. This C9orf72-related glial pathology was independent of the dipeptide-repeat protein inclusions usually found in the motor neurones of these patients. Using Western blot and qPCR, the levels of MBP and PLP, another myelin protein that is translated in the oligodendrocyte cell body, were measured. A reduction in the levels of MBP, but not those of PLP, was found in the spinal cord lateral corticospinal tracts of ALS cases, which was more pronounced in C9orf72 ALS. This reduction of the MBP levels was not accompanied by either a reduction in the number of axons panning that area or the levels of MBP mRNA. Conclusions: These results suggest that an impairment of mRNA transport is the main cause of the reduced MBP levels in the spinal cord of ALS patients and that oligodendrocyte degeneration precedes axonal degeneration in ALS. Were this confirmed using in vivo models of ALS, it would imply that ALS begins as a myelinopathy which later causes the apparition of neuronal pathology and death. None of the in vivo models trialled in this project were successful, but others have created promising models that will surely help understand oligodendroglial degeneration in ALS.