Dissertations / Theses on the topic 'Motoer Neuron Disease'
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1
Parton, Matthew James. "Disease-modifying factors in motor neuron disease." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289882.
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Martin, Joanne Elizabeth. "Cellular pathology of the lower motor neuron in motor neuron disease." Thesis, Queen Mary, University of London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266426.
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Kwok, Alice. "Unfolded protein responses in models of Motor Neuron Disease." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:2f3efba7-dce1-4521-bda6-4db8ee81094d.
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Motor neuron disorders are a heterogeneous group of diseases characterized by the selective degeneration of motor neurons leading to muscle wasting and atrophy. Amyotrophic Lateral Sclerosis (ALS) is the most common amongst these disorders and is characterized by the selective loss of both upper and lower motor neurons in the brain and spinal cord. 20% of familial cases of ALS are caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1), a ubiquitously expressed enzyme responsible for scavenging superoxide radicals. The exact mechanisms underlying mutant SOD1-mediated neurotoxicity are unknown. Misfolded mutant SOD1 accumulates in the cytosol and mitochondrial intermembrane space (IMS) indicating the involvement of unfolded protein responses in ALS pathogenesis. Unfolded protein responses (UPRs) are complex signal transduction cascades which detect perturbations in protein folding and couple them to the expression of protein quality control machinery thereby allowing individual compartments to adapt to stress. In the cytosol, this study has shown that HspB8 was upregulated by SOD1 mutants, where it induced the clearance of aggregates by macroautophagy. This is a protective mechanism, as overexpression of HspB8 suppressed mutant-SOD1 mediated toxicity. In contrast, HspB8 mutants were impaired in macroautophagy and are toxic to NSC-34 cells. The mechanisms for the IMS-UPR have not been previously identified. To address this issue, a model for the accumulation of misfolded mutant SOD1 within the IMS was created and candidate proteins involved in protein quality control within the IMS were explored at the transcriptional level and at the level of protein expression. Preliminary results revealed some possible candidates that may have a role in the adaptation to mitochondrial stress. Interestingly, increased mitophagy was also found in IMS-G93A expressing cells, advocating the central role of macroautophagy in eliminating protein aggregates and damaged mitochondria in SOD1-FALS.
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Simoes, Fabio Andre Amaral Lopes. "Cytoskeleton and molecular motors in the causation of motor neuron diseases." Thesis, University of Brighton, 2018. https://research.brighton.ac.uk/en/studentTheses/2629bd8d-bbba-4360-9ba2-d77733e431ad.
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Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy with lower extremity predominance (SMA-LED) are motor neuron diseases defined by the loss of motor neurons. RNA metabolism and molecular transport have both become increasingly implicated in the pathogenesis of motor neuron diseases. As such, this thesis explores the role of TAR-DNA binding protein 43 (TDP-43) in the regulation of peripherin expression in ALS, and the molecular consequences of mutations in DYNC1H1, a component of the cytoplasmic dynein motor complex, in SMA-LED. TDP-43 is a DNA/RNA binding protein implicated in ALS pathogenesis. Recent evidence suggests that TDP-43 regulates peripherin, an ALS associated intermediate filament protein. Here, analysis of peripherin in the lumbar spinal cord of TDP-43+/F210I mice revealed a significant increase in the levels of Per-45, a shift towards an increase in Per-58 in the Triton X-100 soluble fraction that did not reach statistical significance, and an increase in an isoform of 50 kDa in the insoluble fraction. These changes in the expression of peripherin in TDP-43+/F210I mice may indicate a regulatory role for TDP-43 in peripherin expression, which could contribute to ALS pathology. Furthermore, there is evidence that defects in neurodevelopment are present in SMA-LED. Analysis of paxillin, a key focal adhesion protein in mouse embryonic fibroblasts from the Legs at odd angles (Loa) model of SMA-LED was performed, which indicated a reduction in its expression which may underpin the previously reported migration phenotypes in these cells. This data provides further evidence that SMA-LED may be a neurodevelopmental disorder. Furthermore, analysis revealed that the Golgi apparatus in DYNC1H1+/D338N patient fibroblasts was significantly condensed, while in BICD2+/I189F fibroblasts there was a decrease in localisation of dynein to the Golgi. The lack of dynein at the Golgi in BICD2+/I189F fibroblasts indicates that BICD2 may be necessary for the recruitment of the molecular motor to the organelle. These Golgi phenotypes may also contribute to impaired migration in disease. Importantly, analysis of DYNC1H1+/D338N patient fibroblasts and mouse embryonic fibroblasts (MEFs) from the Loa mouse strain showed a significant decrease in α-tubulin acetylation, a phenotype previously seen in another DYNC1H1 substitution. In conclusion, these data support previous data which suggested that peripherin expression is altered in the context of TDP-43 mutations, potentially contributing to ALS pathology. Additionally, Golgi phenotypes were found in both DYNC1H1+/D338N and BICD2+/I189F fibroblasts with potential consequences for cellular migration. Finally, decreased microtubule acetylation may be a common factor in SMA-LED linked with DYNC1H1 mutations. The conserved nature of this phenotype could indicate a potential target for therapeutics.
5
Christou, Yiota Apostolou. "Generation of motor neurons from embryonic stem cells : application in studies of the motor neuron disease mechanism." Thesis, University of Sheffield, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505426.
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Embryonic stem cells are pluripotent cells with the potential to differentiate into any cell type in the presence of appropriate stimulatory factors and environmental cues. Their broad developmental potential has led to the proposal that in the future, the use of human embryonic stem cells or their differentiated progeny may be beneficial in regenerative medicine. In particular, a current goal in the field of clinical neurology is to use stem cells in cell-based therapies for motor neuron disease (MND) or amyotrophic lateral ~clerosis. MND is a progressive neurodegenerative disease that specifically affects upper and lower motor neurons and leads ultimately to death from respiratory failure. Stem cellderived motor neurons could conceivably be used to replace the degenerated cells, to provide authentic substrates for drug development and screening and for furthering our understanding of disease mechanisms. However, to reliably and accurately culture motor neurons, the complex pathways by which differentiation occurs in vivo must be understood and reiterated in vitro to direct embryonic stem cells towards motor neurons. This thesis presents the work I have performed on the directed differentiation of embryonic stem cells towards motor neuron fates. I describe the various experimental approaches I took in attempts to produce motor neurons in vitro. My studies reveal that it is possible to deploy the signals used during normal development to direct the differentiation of both human and mouse embryonic stem cells into neural and neuronal cells, including motor neurons. Two major limitations precluded my analysis of pure motor neuron cultures: first, the high concentrations of the ventralising morphogen, SHH, apparently required to direct embryonic stem cells towards motor neuron fates, and second, the difficulties encountered in culturing purified motor neurons. However, using a mixed culture, I obtained evidence that motor neurons and their progenitors fail to survive in medium conditioned by mutant SOD1-G93A astrocytes.
6
Bäumer, Dirk. "Functional genetic analysis of motor neuron disease." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:859016f8-5eff-4a8e-bfda-48afb8695646.
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Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the commonest motor neuron diseases of adult- and childhood onset. Alterations of the RNA binding protein TDP-43 are associated with most cases of ALS, while SMA is caused by deletion of the Survival Motor Neuron (SMN1) gene. SMN has been well characterised in its role in the assembly of the cellular machinery that carries out splicing of pre-mRNA, but is thought to have other functions in RNA metabolism unrelated to pre-mRNA splicing. It is conceivable that specific aspects of RNA handling are disrupted in both SMA and ALS. A variety of genetic, molecular and neuropathological approaches were applied to investigate a potential common pathway in these diseases. The spectrum of genetic mutations underlying motor neuron disorders were explored by screening patient DNA. Cell culture and mouse models were used to test the hypothesis that altered pre-mRNA splicing causes motor neuron death. Human neuropathological specimens were examined for changes in proteins involved in RNA metabolism. The results indicate that altered pre-mRNA splicing is a late occurrence in disease and more likely to be a consequence rather than the cause of motor neuron degeneration. However, the notion that RNA metabolism is highly relevant to motor neuron diseases was strengthened by the discovery of mutations in another RNA binding protein, FUS, in cases of ALS without TDP-43 pathology. Overall the findings highlight the need to consider disruption of mRNA transport and regulation of mRNA translation in future motor neuron disease research.
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Sargsyan, Siranush Anna. "Microglial activationas a potential contributor to motor neuron injury in motor neuron disease." Thesis, University of Sheffield, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444237.
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Tennant, Maria Elizabeth. "Axonal transport in motor neurone disease." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424667.
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Aspin, Jacqueline Patricia. "Immunological studies in motor neurone disease." Thesis, University of Bath, 1986. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376335.
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Gopinath, Sumana. "Finding new genes causing motor neuron diseases." University of Sydney, 2006. http://hdl.handle.net/2123/1624.
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Doctor of PhilosophyAbstract Neurodegenerative disorders are a diverse group of disorders that affect specific subsets of neurons. Motor neuron diseases, neurodegenerative disorders of motor neurons, are seen commonly as sporadic cases and less frequently as familial disease forms. The familial forms show genetic and phenotypic heterogeneity. Clinically motor neuron diseases may be seen as rapidly progressive disorders like amyotrophic lateral sclerosis, ALS or slowly progressive disorders like hereditary motor neuropathies, HMN. The only proven causes for motor neuron diseases are gene mutations that lead to motor neuron degeneration in familial disease forms. Only some of these genes have been identified and have contributed greatly to our understanding of the neurobiology of familial and sporadic disease forms. Identification of additional disease causing genes would help enhance our knowledge of the pathophysiological mechanisms underlying all forms of motor neuron disorders, which would lead to early diagnoses, effective prophylaxis and efficient therapies for these disorders. This study aimed to find gene mutations that cause rapid and slowly progressive familial motor neuron disorders in Australian families and to determine their relevance to sporadic forms of motor neuron disease. The familial forms of ALS show reduced disease penetrance, that is, not all gene mutation carriers manifest the disease. This study examines ALS penetrance in a group of Australian families. The most frequently observed mutations in ALS families are cytosolic superoxide dismutase/SOD1 gene mutations. In a collection of ALS families in our centre, families without the common SOD1 gene mutations were genotyped for other ALS genes and loci and studied using genetic linkage and haplotype analyses. Studies in a large Australian ALS family further confirmed genetic heterogeneity in non-SOD familial ALS, all known autosomal dominant ALS genes and chromosomal loci were excluded as cause of disease in this family. Such families can be studied further to identify additional disease genes and loci mapped in other ALS families. These families represent powerful resources for identification of additional ALS genes. Identifying the pathogenic genes in families with reduced disease penetrance may be more relevant to sporadic forms of disease. dHMN is a chronic neurodegenerative disorder predominantly affecting motor neurons. In a large Australian dHMN family, all the known dHMN genes and chromosomal loci were excluded as cause of disease. A genome wide microsatellite screen was performed in this family and genetic linkage was established to a novel 12.98 Mb locus on chromosome 7q34.2-q36. Candidate genes in this large interval will be screened based on their function and expression profile. Identification of a new dHMN locus provides the basis for future identification of a novel gene involved in motor neuron degeneration. Genes in dHMN have been shown to be pathogenic in ALS and Charcot Marie Tooth syndromes. The new locus for dHMN mapped in this project would lead to identification of a novel dHMN gene, which may elucidate the pathogenesis underlying a wide range of neurodegenerative disorders.
11
Stephens, Benjamin. "Pathology of spinal interneurons in motor neuron disease." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251759.
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Günther, Rene, Nicole Richter, Anna Sauerbier, Kallol Ray Chaudhuri, Pablo Martinez-Martin, Alexander Storch, and Andreas Hermann. "Non-Motor Symptoms in Patients Suffering from Motor Neuron Diseases." Frontiers Research Foundation, 2016. https://tud.qucosa.de/id/qucosa%3A30109.
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Background
The recently postulated “disease spreading hypothesis” has gained much attention, especially for Parkinson’s disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND.
Methods
We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls.
Results
In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression.
Conclusion
NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated “disease spreading hypothesis.” The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.
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Günther, Rene, Nicole Richter, Anna Sauerbier, Kallol Ray Chaudhuri, Pablo Martinez-Martin, Alexander Storch, and Andreas Hermann. "Non-Motor Symptoms in Patients Suffering from Motor Neuron Diseases." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-217311.
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Background
The recently postulated “disease spreading hypothesis” has gained much attention, especially for Parkinson’s disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND.
Methods
We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls.
Results
In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression.
Conclusion
NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated “disease spreading hypothesis.” The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.
14
Costa, Marc Michael John Da. "A zebrafish model of motor neurone disease." Thesis, University of Sheffield, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.548470.
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Mitchell, John Douglas. "Trace element studies in motor neurone disease." Thesis, University of Aberdeen, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261363.
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The first part of the thesis reviews previous literature relating to motor neurone disease (MND), the cause of which remains obscure more than 150 years after it was first described. Historical aspects are presented drawing attention to the early descriptions of different facets of the clinical picture of MND which preceded its crystallisation into a single disease entity in the teaching and writing of Charcot. Much of this early work depended on knowledge of the toxic effects of lead on the peripheral nervous system. The epidemiology, blood group and HLA associations, pathology, immunology and virology of MND are discussed. Physical factors are also reviewed as are previous biochemical studies of MND. Knowledge regarding lead and mercury in relation to MND is discussed in detail. An analysis of previous literature concerning trace elements in MND is then presented to introduce the experimental section. This concerns the measurement of trace elements in spinal cord, liver, bone and cerebrospinal fluid (CSF) in MND patients and reference subjects by neutron activation analysis. Increased cervical cord, liver and bone selenium concentrations were found in the MND patients. Manganese content was increased in cervical and thoracic cord but reduced in liver. Low CSF cobalt concentration were also found. All other elements measured were striking by their concordance between the two groups in both tissue and CSF samples. These findings of an apparent alteration in the distribution of selenium and manganese in MND suggested that free radical mechanisms might be implicated in the pathogenesis of MND. CSF parameters of free radical activity were therefore studied but no differences found between reference subjects and MND patients. These results are discussed both in relation to the trace element studies and recent work on the possible importance of xenobiotics in the aetiology of the disease. Other aspects of the biological importance of selenium and manganese are described and some consideration is given to the DNA hypothesis of Bradley. This hypothesis is difficult to verify experimentally. A cytogenetic approach studying the sensitivity of lymphocytes obtained from control subjects and MND patients to mitomicin-C and ethyl methanesulphonate is described. This work did not yield any collateral evidence to support this hypothesis. In conclusion an attempt is made to bring the results of all this work together and consider how they might lead to a clearer understanding of the cause of this tragic and enigmatic disease.
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Ruddy, Deborah Marie. "Linkage studies in familiar motor neurone disease." Thesis, King's College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420083.
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Rafiq, Muhammad. "Mechanically assisted cough in motor neurone disease." Thesis, University of Sheffield, 2014. http://etheses.whiterose.ac.uk/6875/.
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Motor Neurone Disease (MND) is a disabling and inevitably fatal disease, usually with a life expectancy of 2-3 years from symptom onset. It is characterised by progressive wasting and weakness in bulbar, limb and respiratory muscles. There is no cure and treatment is mainly symptomatic. Neuromuscular respiratory failure, with or without a chest infection, is the commonest cause of death in MND patients. It has been shown that supporting respiratory function with non-invasive ventilation, improves survival and quality of life despite progression of the disease. The patients with respiratory muscle weakness may also have a weak cough and significant difficulty in clearing their airways of respiratory secretions. This causes much discomfort, predisposes to chest infections and adversely affects quality of life. Due to lack of evidence in this area, there is no clear consensus or guideline about how best to help such patients. This work aimed to establish the role of cough augmentation techniques in MND. A total of 40 eligible patients with MND were randomised to the breath-stacking technique (n=21) or Mechanical Insufflator-Exsufflator MI-E (n=19) and followed-up at 3 monthly intervals for at least 12 months or until death. All patients were diagnosed with respiratory failure and offered non-invasive ventilation (NIV). The primary outcome measure was the number of days with symptoms of chest infection, treated with antibiotics, in the community or in hospital. Survival and quality of life benefit, assessed by short form 36 mental component summary (MCS) and sleep apnoea quality of life index symptoms domain (sym), were the secondary outcome measures. There were 13 episodes of chest infection in the breath-stacking group and 19 episodes in MI-E group (p=0.87), requiring 90 and 95 days of antibiotics respectively (p=0.85). There were 6 episodes of hospitalisation in each group (p=0.87). The mean duration of symptoms per chest infection was 6.9 days in the breath-stacking group and 3.9 days in MI-E group (p=0.16). The chance of hospitalization, in the event of a chest infection was 0.46 in the breath-stacking group and 0.31 in MI-E group (p=0.47). Median survival in the breath-stacking group was 535 days and 266 days in the MI-E group. The MCS score was maintained above 75% of baseline for a median of 329 days in the breath-stacking group and 205 days in MI-E group (p=0.41). A non-significant improvement in quality of life, compared to baseline was observed in both interventional groups. In MND patients with respiratory failure, cough augmentation is likely to help maintain quality of life in the presence of the distressing symptom of weakened ability to cough. This study was not powered to assess the potential impact on life expectancy. There was no significant difference in terms of pulmonary morbidity between the two groups. A trend towards fewer chest infections was observed in the breath-stacking group, and a trend for reduced duration of antibiotic use and decreased chance of hospitalization in the event of a chest infection was observed in the MI-E group, though these changes did not reach statistical significance. These results are insufficient to draw firm conclusions, but support routine domiciliary use of a suitable cough augmentation technique in patients with ALS requiring respiratory support. The breath-stacking technique may be prescribed for domiciliary use with the onset of respiratory failure. MI-E may be useful in the event of a chest infection when it has the potential to reduce the duration of antibiotic use and chance of hospitalisation or when breath-stacking is no longer sufficient to maintain patient comfort. The results of this trial provide data useful for the power calculations required for a larger-scale multi-centre randomised trial.
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Blackburn, Daniel J. "The role of glial cells in motor neuron disease." Thesis, University of Sheffield, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531123.
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Shum, Carole Yick Lam. "Modelling motor neuron disease using induced pluripotent stem cells." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/modelling-motor-neuron-disease-using-induced-pluripotent-stem-cells(1686136a-d045-4edc-9439-1028b0ea47db).html.
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Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease. The majority of ALS cases are sporadic (SALS), but 10% of patients have a familial form of ALS (FALS). Mutations in Fused in Sarcoma (FUS) occur in approximately 4% of FALS and less than 1% of SALS. A hallmark feature of ALS is the degeneration of upper and lower motor neurons in the brain and spinal cord; however, the mechanism underlying this loss is not known. Studies of degenerative mechanisms have been impeded by the inaccessibility of human neural tissue. A possible solution is to use induced pluripotent stem cells (iPSCs) derived from patients, which may be differentiated into the cell types affected by disease. To test whether patient-specific stem cells can be used to model aspects of ALS pathogenesis, iPSC lines were generated from a patient carrying the pathogenic FUS R521C mutation. FUS iPSCs derived from patient fibroblasts and WT iPSCs derived from fibroblasts from two healthy controls were differentiated into neural progenitors and motor neurons. FUS iPSC-derived neuronal cells recapitulate key aspects of FUSassociated ALS, including mislocalisation of FUS protein, the redistribution of FUS protein into cytoplasmic stress granules, and increased apoptotic cell death. The second study uses this iPSC model to investigate the effects of mutant FUS on dendritic morphology and synaptic regulation. FUS iPSC-derived neurons display abnormal dendritic morphology, such as reduced neurite outgrowth and reduced density of dendritic protrusions. FUS iPSC-derived neurons also show differences in the localisation of synaptic proteins. This study suggests that physiological levels of mutant FUS protein affect the morphology and synaptic structure of human neurons. These studies validate the stem cell approach to disease modelling and provide support for the use of patient-specific stem cells for the study of disease mechanisms.
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Fratta, P. "Investigation of pathogenic mechanisms underlying motor neuron diseases." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1420275/.
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Motor neuron disease (MND) comprises a group of neurological disorders which include amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), primary muscular atrophy (PMA), spinal muscular atrophy (SMA) and spinal bulbar muscular atrophy (SBMA). These disorders have different etiology and clinical features, but share the striking feature of prevalently affecting motor neurons. A genetic cause has been identified for SBMA, SMA and mutations in a handful of genes currently explain a minority of ALS, PLS and PMA cases. Although many different mechanisms have been postulated to play a role in these diseases, the underlying pathogenetic mechanisms are largely unknown and therapeutic interventions are lacking. The research presented in this thesis focuses on two forms of MND (ALS and SBMA) and on the investigation of the causes and mechanisms underlying these diseases. Firstly, the known genetic causes and clinical features were screened and analysed in cohorts of SBMA and ALS patients. Secondly, the role of FUS, a gene known to cause ALS when mutated, as a potential link between ALS and SBMA, was investigated by using a mouse model of SBMA. Finally, the pathogenic mechanisms underlying ALS were analysed, focusing on two important genes: TARDBP and C9orf72. TARDBP mutations cause of <2% of ALS cases, but TDP43, the protein product of TARDBP, is found in the cytoplasmic inclusions of >98% of ALS patients, highlighting its importance in disease pathogenesis. TDP43 is an RNA binding protein and whether RNA defects are present in patient tissue is yet unclear, due to the poor quality of ALS post-mortem material. High quality biopsy material, from a muscle TDP43-disease, sporadic inclusion body myositis, is here used to analyze if RNA changes are associated with TDP43 mislocalization in patient tissue. The results highlight the complex role of TDP43 in this process. Expansions of a hexanucleotide repeat in a non-coding portion of C9orf72 have recently been identified as the underlying cause of 5-20% of ALS cases. The location of the mutation in a non-coding segment, have suggested a potential role for RNA toxicity. The structure of the expanded RNA sequence is therefore here investigated to gain insight in potential pathogenic mechanisms. In summary, a genetic and clinical characterisation of ALS and SBMA cohorts of patients is performed in order to gain insight in the clinical, genetic and molecular mechanisms of these diseases. Further, molecular biology and structural biology tools are used to progress our understanding of the pathogenetic mechanisms linked to two important players in ALS pathogenesis: TDP43 and C9orf72.
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King, Susan Jane, and mikewood@deakin edu au. "Negotiating life choices: living with motor neurone disease." Deakin University. School of Nursing, 2005. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20060719.144725.
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Motor neurone disease (MND) is an uncommon neurodegenerative disease that is terminal and has an insidious onset. With no known cause or cure, the disease triggers progressive death of motor neurones that causes increasing difficulties with mobility, communication, breathing and nutrition. Most research focuses on the disease process, but little is known of the illness experience from the perspective of those diagnosed with the disease. The aim of this study was to explore what it is like to live with MND and how people with the disease negotiate with others to exercise choice over the way they live.
A grounded theory methodology was used to explore the life world of people diagnosed and living with MND. Data were collected via in-depth interviews, their stories and photographs, poems and books participants identified as important and fieldnotes. The textual data were analysed using constant comparative analysis. The majority of participants experienced difficulty with verbal communication. Some invited a third person to interpret their speech and others used assistive technologies such as Lightwriters and computers.
Analysis revealed three constructs that, together, told the story of the MND illness experience. First, was the “diagnosis story” that described the devastating process of repeated tests had on the participants, shattering their trust in the competence of the health care system. The second construct revealed the process of living with MND as cyclical and repetitive requiring constant decision-making to adapt to the ongoing changes connected with the disease. The core theme and basic social process of “maintaining personal integrity” evolved as the third construct. This process underpinned and explained participants decision-making. Finally a substantive theory was conceptualised as the illness experience: “maintaining personal integrity in the face of ongoing change and adaptation”. This theory illustrates that the basic social process of maintaining personal integrity is central to decision and choice making while living with MND.
The findings have implications for people with MND, their carers, health professionals and service providers. Recommendations include improved counselling services for people at the time of diagnosis; the introduction of nurse specialists to support health professionals, people diagnosed with the disease and their families; open, accessible, realistic health and funding policies.
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Lloyd, Catherine Margaret. "Aspects of cortical function in motor neurone disease." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243835.
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Chhetri, Suresh Kumar. "Outcomes of enteral feeding in motor neurone disease." Thesis, University of Central Lancashire, 2015. http://clok.uclan.ac.uk/12862/.
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Motor Neurone Disease (MND) is a fatal neurodegenerative disease of unknown aetiology characterised by the degeneration of motor neurones leading to progressive wasting and weakness of the bulbar, limb and respiratory muscles. Symptomatic treatment remains the cornerstone of management. Malnutrition is a common occurrence and an independent risk factor for worse prognosis. Clinical guidelines recommend enteral feeding when there is deterioration in nutritional status and/or dysphagia. However, it remains unclear whether enteral feeding offers any survival advantage. Moreover, the impact of enteral feeding on patients’ quality of life remains unknown. This study was undertaken to assess the impact of enteral feeding on survival and quality of life of patients with MND and describe the clinico-demographic characteristics of MND in Lancashire and South Cumbria in North West England. The study has both retrospective and prospective arms. The retrospective study was undertaken by reviewing the Preston MND database and case notes to examine the demographic, clinical and survival characteristics of MND in Lancashire and South Cumbria. The prospective study was undertaken over a period of three years to explore the perspectives of 21 patients with enteral feeding and its impact on their quality of life. The overall crude incidence of MND was 3.15 per 100,000. The mean age of onset was 67.28 (S.D. 11.06; range 22.78-93.06) years. Median overall illness duration was 1.98 (range 1.18-3.05) years. The presentation was limb onset in 62.1% cases and bulbar onset in 37.9% cases. A total of 91 (26.8%) patients received enteral feeding of which 67.0% were bulbar onset. Enteral feeding was not associated with a statistically significant survival advantage (χ2 (1) = 1.73, p = 0.19). iii Enteral feeding was associated with improved quality of life, despite the attendant inconveniences. Enteral feeding was perceived as being essential to survival by some participants while others reported a sense of relief and security that their nutritional needs were met. The body mass index stabilised following enteral feeding. A key finding, relevant for clinical practice, is that most study subjects acknowledged the importance of enteral feeding and a vast majority did not wish for the feeding tube to be removed, indicating a positive attitude towards enteral feeding. In conclusion, this study demonstrates a positive impact of enteral feeding on quality of life but not on survival. The lack of survival advantage should however, not dissuade clinicians from offering enteral feeding to patients with MND who manifest dysphagia and/or malnutrition. Even if enteral feeding does not add months to life, this study provides preliminary evidence that that it helps to add life to months.
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Rewaj, Phillipa Jane. "Nature of language impairment in motor neurone disease." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9744.
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Background: Language impairment associated with Motor Neurone Disease (MND) has been documented since the late 19th century, yet little is understood about the pervasiveness or nature of these deficits. The common clinical view among healthcare professionals is that communication difficulties can be attributed solely to the motor speech disorder dysarthria. Recent literature raises the possibility of more central processing deficits. Impairments in naming ability and comprehension of complex grammatical constructs have been frequently reported in some patients with MND. However, there is now growing evidence of spelling impairment, which could suggest the contribution of a more phonologically based deficit. In addition, the close relationship between MND and frontotemporal dementia (FTD) raises questions about the connection between the language impairments seen in MND patients and those documented in patients with the primary progressive aphasia (PPA) syndromes associated with FTD. Aims: This thesis examines the nature of speech and language deficits in people with MND and the extent to which expressive communication impairment can occur above and beyond dysarthria. In particular, the study explores: i) to what extent these language impairments can be attributed to deficits in working memory, executive functioning and/or disease severity; ii) what spelling errors can reveal about the integrity of lexical, phonological and orthographic processing; iii) whether similar patterns of impairment can be seen in PPA syndromes; iv) the relationship between language impairment and bulbar onset; and v) the impact these findings have on clinical management of MND patients. Methods: MND patients from across Scotland with changes in speech and/or language were tested using a neuropsychological battery of experimental and standardised tests of naming, spelling, syntactic comprehension, prosody and phonological and orthographical awareness. Patients were also screened for levels of dysarthria, executive functioning and working memory deficits, and results compared to those of matched controls. Findings: As a group, MND participants performed significantly worse than matched controls on measures of naming, spelling, orthographical awareness, grammatical comprehension, affective prosody and verbal fluency, but not working memory. However, based on patterns of individual impairment, of which spelling impairment formed a distinctive marker, the patient group divided into dichotomous subgroups, with 44% of participants categorised as ‘linguistically impaired’, while the remainder displayed little to no impairment. Those participants identified as linguistically impaired did not differ significantly from other MND participants on measures of disease severity, disease duration or dysarthria severity, although significantly more bulbar onset than limb onset participants were linguistically impaired. Spelling error patterns were suggestive of deficits at both a lexical and sublexical level, and were comparable to those reported in PPA literature. These findings suggest that dysarthria may be masking linguistic deficits in almost half of dysarthric MND patients, and highlight the importance of multidimensional assessment of language for effective clinical management.
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Witherden, Abigail Sian. "Positional cloning of Loa, a mouse motor deficit mutation." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248151.
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Lyon, Alison Nicole. "Generation and Analysis of Motor Neuron Disease Models in Zebrafish." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1337276861.
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Friberg, Danielle. "Nerve lesions in pharynx - an aetiology of obstructive sleep apnoea /." Stockholm, 1997. http://diss.kib.ki.se/1997/91-628-2721-9.
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Bermingham, Nessan Anthony. "Genetic characterisation of the progressive motor neuron degeneration mouse 'Legs as odd angles' (Loa)." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264956.
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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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Sassi, Mohammed M. "Apolipoprotein-E genotype in major neurodegenerative diseases." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339716.
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Vance, Caroline. "Genetic linkage and association studies in motor neurone disease." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435086.
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Garcia-Willingham, Natasha E. "LANGUAGE DYSFUNCTION IN MOTOR NEURON DISEASE: COGNITIVE FEATURES AND SCREENING SENSITIVITY." UKnowledge, 2019. https://uknowledge.uky.edu/psychology_etds/168.
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Motor neuron disease (MND) is a set of neuromuscular diseases that affect the upper and/or lower motor neurons, resulting in progressive disability. Amyotrophic lateral sclerosis (ALS) and Primary lateral sclerosis (PLS) are two forms of MND that both involve upper motor neuron degeneration, which can also accompany extra-motor changes in cognitive, behavioral, and/or emotional functioning for some individuals. Characterization of the cognitive profile of MND is still evolving, with growing interest in cognitive subtypes. The development of cognitive screens targeted to the MND cognitive profile aim to provide efficient and accurate brief assessments. However, empirical evaluation of tailored MND cognitive screens is needed for cross-validation independent of tests’ original developers. The present study addresses the cognitive profile of MND and the utility of brief cognitive screens with a focus on impairments in the language domain. The two primary aims include: (1) comprehensive assessment and characterization of language dysfunction in MND, and (2) empirical evaluation of brief cognitive screens with regard to detecting language impairments.
Forty-one patients with MND (ALS n = 36; PLS n = 5) were administered a comprehensive language battery to classify cognitive impairment (MND/ALSci; Strong et al., 2017) in the language domain and/or verbal fluency. Patients also completed two tailored cognitive screens [ALS Cognitive Behavioral Screen (ALS-CBS), Edinburgh Cognitive and Behavioral ALS Screen (ECAS)] and one general screen (Montreal Cognitive Assessment; MoCA).
The current preliminary results suggest language dysfunction in MND is characterized by prominent difficulties with word retrieval (confrontation naming) and/or syntax comprehension. However, evidence of reduced word production resembling nonfluent/agrammatic aphasia was not found. In total, 19.5% of the sample met criteria for MND/ALSci in the language domain (n = 8, all ALS); 22.0% met criteria for MND/ALSci in the verbal fluency domain (n = 9). Patients were classified into three subgroups, those with broad language impairments (ALSci-L n = 4, 9.8%), phonemic fluency impairments (MNDci-VF n = 5, 12.2%), or both impairments (ALSci-L+VF n = 4, 9.8%). Results also revealed existing challenges in accurately classifying patients with language dysfunction using brief cognitive screens. The ECAS Language subscore offered limited classification of broad language impairments in the present MND sample (sensitivity 50%, specificity 70%). Among the broader cognitive screens, sensitivities to language impairments were: ALS-CBS (100%), ECAS ALS-Specific Score (75%), and MoCA (71%). Convergent validity was demonstrated between outcomes on the ALS-CBS and ECAS ALS-Specific Score (rФ = .59). Discriminant validity was also demonstrated between outcomes on ALS-CBS compared to the MoCA (rФ = .11).
Future research is needed to assess whether language dysfunction reflects a distinct MND cognitive phenotype(s) and potential relationships with disease prognosis. Naming and syntax comprehension may be fruitful language screening targets for future research.
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Åkerblom, Ylva. "Experiences of pain and associations between pain, disease severity and individual quality of life in people with motor neuron diseases." Licentiate thesis, Uppsala universitet, Institutionen för neurovetenskap, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-396033.
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Many people with the incurable and often times fatal motor neuron diseases have pain, but there is lack of knowledge about people’s experiences of living with pain. Further, the correlation between pain and their quality of life is not well understood, and previous studies have not used individual quality of life, namely that people with their own words express what quality of life is. The aim of these studies was to explore the experiences of pain and the association between pain and quality of life in people with MND. Methods: Study I was explorative about the individual experience of pain, while study II was correlational between pain, pain severity, disease severity and IQOL. Study I was qualitative, whereas study II used both qualitative and quantitative analysis. Results and conclusions: People with motor neuron diseases experienced pain to have multiple characteristics and impact. However, the results emphasise that the individual experienced some pain characteristics as difficult and that pain could worsen functions that were already affected by the disease. The experience was also that it could be challenging to manage pain. However, the symptom of pain could pass unnoticed in contacts with healthcare professionals (study I). The three most important areas for individual quality of life in both participants with and without pain were: Social relations, followed by Activities for amusement and relaxations, and Being in the outdoor environment. Individual quality of life was noticed to be good regardless of pain. Pain and pain severity were not found to be associated with satisfaction of individual quality of life in patients with motor neuron diseases, neither was disease severity. The results support previous findings, that strong associations between symptoms of MND and IQoL are not obvious. However, this does not infer that pain in people with MNDs should be neglected and undertreated. On the contrary, it seems to be important for healthcare to pay more attention to pain in people with motor neuron diseases and that pain continuously is measured, individually treated and followed. Regardless of whether persons with MND have pain or not, the results point to the importance of healthcare professionals providing support to not only the patient but also the patient’s family and friends, as well as assisting in various forms of relaxing activities and possibility of being in the outdoor environment.
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Bellouze, Sarah. "Mécanismes moléculaires de la fragmentation de l' appareil de Golgi dans les maladies du neurone moteur." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM4080.
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La fragmentation de l'appareil de Golgi représente un des changements les plus précoces et les plus répandus dans les maladies neurodégénératives. Afin de comprendre les mécanismes moléculaires de ces changements, j'ai étudié deux modèles expérimentaux de maladie du neurone moteur. 1. Les souris pmn (progressive motor neuronopathy) : Celles-ci sont atteintes d'une forme très grave de dégénérescence des neurones moteurs et des défauts moléculaires sont liés à une mutation faux-sens d'une protéine localisée au niveau du Golgi, la chaperonne des tubulines TBCE, identifiée par (Martin, Jaubert et al. 2002; Schaefer, Schmalbruch et al. 2007). Au cours de ma thèse, nous avons identifié des anomalies importantes du Golgi dans les neurones moteurs lombaires de souris pmn et déterminé leur relevance fonctionnelle ainsi que les mécanismes moléculaires. D'après les immunomarquages et la modélisation 3D des membranes, la fragmentation et l'atrophie du Golgi dans les neurones lombaires moteurs pmn ressemblent à celles rapportées dans la SLA et se produit dans des cinétiques similaires. Les analyses en microcopie électronique montrent que l'empilement des citernes golgiennes est progressivement remplacé par des petites vésicules. Les analyses biochimiques révèlent : 1/ une redistribution cytosolique des protéines d'arrimage tel que GM130, 2/ une diminution des protéines β-COP et 3/ une augmentation considérable des protéines golgiennes d'amarrage v-SNARE GS15 et GS28 contrôlant la fusion des vésiculesFragmentation of the Golgi apparatus represents one of the earliest and most constant pathological changes in neurodegenerative diseases. To understand the molecular mechanisms of these changes I investigated two experimental models of motor neuron diseases. 1. pmn mice with progressive motor neuronopathy. The pmn mice were chosen since they suffer from a very aggressive form of motor neuron degeneration and since their molecular defects represents a missense mutation in a Golgi-localized tubulin chaperone TBCE, as shown by previous (Martin et al 2002, Schäfer et al 2007). In the last years, we identified severe Golgi abnormalities in motor neurons of pmn mice and dissected out their functional relevance and molecular mechanisms. According to immunolabelings and 3D membrane modelings, Golgi fragmentation and atrophy in lumbar pmn motor neurons resembled those reported in human ALS and proceeded with similar kinetics. Electron microscopy illustrated that Golgi cisternae were progressively transformed into small vesicles. Biochemical analyses revealed : 1/ a cytosolic redistribution of tethering factor such as GM130, 2/ a decrease in β-COP protein level and 3/ a massive increase in the Golgi v-SNARE proteins GS15 and GS28 controlling vesicle fusion. These pathological changes were due to loss of TBCE expression since they could be rescued by transgenic expression of wildtype TBCE but not mimicked by sciatic nerve axotomy. They involved defective dynamics of Golgi-derived microtubules rather than accumulation of misfolded tubulins as shown by the differential effects of TBCE-depletion, Nocodazole and a folding-incompetent tubulin mutant
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Duffy, L. "Investigation of changes in mitochondrial dynamics in motor neuron diseases." Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/4286/.
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Changes in mitochondrial dynamics, including alterations in the fusion/fission balance, have repeatedly been observed in ageing and neurodegenerative disease, including ALS. We investigated the effect of ageing or disease on mitochondrial network complexity in primary dermal fibroblasts, derived from ALS patients or controls. Increased network complexity during ageing was observed in the control cohort, though motility was unaffected. Conversely, network complexity decreased in the sporadic ALS patient cohort upon ageing. We speculate that this alteration in mitochondrial dynamics may contribute to the significant detrimental effect age has on disease prognosis in ALS. In mutant TARDBP (mTARDBP) patient fibroblasts, a trend towards increased network complexity compared to age-matched controls was observed. Moreover, despite no discernible differences in ATP levels in the mTARDBP fibroblasts compared to control samples, microarray analysis hinted at changes in two metabolic pathways, glycolysis and the TCA cycle, both known to influence mitochondrial dynamics. Subtle changes in the interaction of the ER and mitochondria were also observed in the mTDP-43 fibroblasts. Furthermore, expression of two autophagy genes, MAP1S and Atg12, was significantly altered in the mTARDBP fibroblasts. However, LC3-II western blotting in either mTDP-43 or mC9ORF72 fibroblasts did not reveal any significant differences, suggesting that changes in autophagy is not the primary cellular process responsible for the mitochondrial morphology alterations. HSP is characterised by defects in axonal transport, including mitochondrial transport. A mouse model of SPG4-mediated HSP showed axonal swellings in cortical neurons, correlating with impaired axonal transport. We showed that Tro19622 (a microtubule-interacting drug) did not ameliorate the number of axonal swellings in the mutant neurons, though alterations in microtubule integrity were apparent. Conversely, HDAC6 inhibitor, Tubastatin A, reduced the number of axonal swellings in SPG4-mutant neurons to wild type levels, suggesting that microtubule acetylation state could be an interesting therapeutic target for future investigation in HSP.
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Wagner, Justin. "Whole Exome Sequencing to Identify Disease-Causing Mutations in Lower Motor Neuron Disease and Peripheral Neuropathy." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34124.
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Lower motor neuron diseases and peripheral neuropathies are two groups of diseases that include multiple rare disorders where many causes are unknown and definitive treatments are unavailable. Understanding the molecular etiology of these genetic diseases provides an opportunity for rapid diagnosis, preconception genetic counseling and, in a subset, direction for the development of future treatment options. The recent introduction of whole exome sequencing (WES) marks a new era in Mendelian genetic disease research as the majority of the coding region of the genome can be sequenced in a timely and cost-effective manner. In this study, WES was used to investigate the molecular etiology of a cohort of 37 patients presenting with lower motor neuron disease or peripheral neuropathy. A molecular diagnosis was determined for seven patients informing the diagnostic utility of WES. Novel phenotypes were found for three genes originally associated with a different disorder. Finally, the foundation has been laid, through the use of functional studies and large scale data-sharing, to identify novel disease-causing genes for lower motor neuron disease and peripheral neuropathy.
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Bourke, Stephen C. "Sleep, breathing and non-invasive ventilation in motor neurone disease." Thesis, University of Newcastle Upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433126.
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Broom, Lucy Jane. "Ubiquitinated proteins in a mouse model of motor neurone disease." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434369.
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Cikurel, Katia. "Threshold electrotonus and ion channel dysfunction in motor neurone disease." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248415.
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Bros, Virginie. "In-situ characterisation of the recessive motor neuron disease protein, ALS2/ALSIN." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420377.
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Turner, Martin Robert. "Understanding pathophysiologial mechanisms in sporadic and familial cases of motor neuron disease." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417085.
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Waterfall, Alan H. "The development of in vivo methods to measure the neuropeptide thyrotrophin releasing hormone in the central nervous system." Thesis, University of Nottingham, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.358269.
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Clarke, Janice Barbara. "Values of lay and professional care : an interpretive enquiry." Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324774.
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Griffiths, Lowri Ann. "Investigating the role of eEF1A2 in motor neuron degeneration." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5924.
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Abnormal expression of the eukaryotic translation elongation factor 1A (eEF1A) has been implicated in disease states such as motor neuron degeneration and cancer. Two variants of eEF1A are found in mammals, named eEF1A1 and eEF1A2. These two variants are encoded by different genes, produce proteins which are 92% identical but have very different patterns of expression. eEF1A1 is almost ubiquitously expressed while eEF1A2 is expressed only in specialised cell types such as motor neurons and muscle. A spontaneous mutation in eEF1A2 results in the wasted mouse phenotype which shows similar characteristics in the mouse to those seen in human motor neuron degeneration. This mutation has been shown to be a 15.8kb deletion resulting in the complete loss of the promoter region and first non coding exon of eEF1A2 which completely abolishes protein expression. The main aim of this project was to further investigate the role of eEF1A2 in motor neuron degeneration. Firstly, although the wasted phenotype is considered to be caused by a recessive mutation, I established a cohort of aged heterozygote mice to evaluate whether any changes are seen later in life that might model late onset motor neuron degeneration. A combination of behavioural tests and pathology was used to compare wild type and heterozygous mice up to 21 months of age. Whilst results indicate that there is no significant difference between ageing heterozygotes and wildtype controls, there is an indication that female heterozygote mice perform slightly worse that wildtype controls on the rotarod (a behavioural test for motor function). Secondly, I aimed to investigate the primary cause of the wasted pathology by generating transgenic wasted mice expressing neuronal eEF1A2 only. This would complement previous experiments in the lab which studied transgenic wasted mice expressing eEF1A2 in muscle only. Unfortunately the expression of eEF1A2 in the transgenic animals was not neuronal specific. However a transgenic line with expression of eEF1A2 in neurons and skeletal muscle but not cardiac muscle has been generated which clearly warrants further investigation. Thirdly, I wished to assess whether eEF1A2 has any role in human motor neuron degeneration. To achieve this, eEF1A2 expression was investigated in spinal cords from human motor neuron disease (MND) patients. Preliminary data suggests that motor neurons from some MND patients express significantly less eEF1A2 than motor neurons of control samples. Further work is required to confirm these findings. Finally, I investigated the individual roles of eEF1A1 and eEF1A2 in the heat shock response. I used RNAi to ablate each variant separately in cells and subsequently measured the ability of each variant individually to mount a heat shock response. Results indicate a clear role for eEF1A1 but not eEF1A2 in the induction of heat shock. This may explain in part why motor neurons exhibit a poor heat shock response as they express eEF1A2 and not eEF1A1. These experiments shed light on our understanding of the role of eEF1A2 in motor neuron degeneration and uncover many new avenues of future investigation.
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Cox, Laura Elizabeth. "The contribution of ANG and CHMP2B to motor neurone disease pathogenesis." Thesis, University of Sheffield, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555879.
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Motor neurone disease (MND) is the third most common adult-onset neurodegenerative disorder. It is relentlessly progressive and universally fatal, usually as a result of respiratory failure. In 3-5% of MND cases overt dementia is present, however, subtle impairment to cognitive function is present in up to 50% of sufferers. In approximately 10% of MND cases there is a clear pattern of inheritance, however, genetic causes are believed to make a substantial contribution to apparently 'sporadic' disease. Mutations in ANG were first identified in a large cohort of MND cases from several diverse geographical regions, four of the patients suffered from familial disease, whereas the remaining 11 had no family history of MND. A mutation in CHMP2B was originally identified in a Danish pedigree with autosomal dominant FTD, which was subsequently followed by the identification of missense mutations in two, unrelated, patients with familial MND, one of whom also showed features ofFTD. The initial aim of the present study was to determine whether mutations in ANG and CHMP2B contribute to MND pathogenesis by mutation screening a large cohort of MND patients for whom serial clinical details were available. Neuropathological tissue was available for a proportion of these cases. Sequencing of ANG revealed a mutation in one case diagnosed with an early-onset, classical amyotrophic lateral sclerosis (ALS) phenotype, who showed rapid deterioration and characteristic ALS neuropathology. Four cases carrying 3 missense mutations in CHlvfP2B, including one novel mutation, p. Thrl04Asn, \vere identified. Only 1 case had a family history of MND, the remaining 3 were affected by apparently sporadic disease. In all 4 cases analysis of clinical and neuropathological data was consistent \vith a diagnosis of the progressive muscular atrophy (PMA) variant of MND. To analyse the affect of mutant CHMP2B on the transcriptional response, gene expression profiling was performed on RNA extracted from motor neurones (MNs) from CHMP2B cases and controls. Significant changes in the expression of genes from multiple pathways were identified, including: axon guidance; actin cytoskeleton regulation and SNARE interactions in vesicular transport; cell cycle; apoptosis; mTOR signalling and autophagy regulation; MAPK signalling; calcium signalling and Wnt signalling. The alterations to these pathways were predicted to result in: disassembly of cell structure; increased calcium concentration in the ER lumen; decrease in the availability of A TP; downregulation of the classical and p38 MAPK signalling pathways; reduction in autophagy initiation and a global repression of translation. Finally, to determine the effect of CHMP2B mutations on cellular phenotypes, HEK- 293 cells were transiently-transfected. This demonstrated that mutant CHMP2B expression resulted in the formation of large cytoplasmic vacuoles and aberrant lysosomal localisation.
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Beaujeux, Timothy Paul. "Protein aggregation in a mouse model of familial motor neurone disease." Thesis, University of Sheffield, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427349.
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Nicholson, Sharon Joycelyn. "Mapping of Loa : a mouse motor deficit gene." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.344089.
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Couillard-Despres, Sebastien. "Transgenic mouse models to study the role of neurofilaments in motor neuron disease." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37882.
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Neurofilaments are the major type of intermediate filaments found in the adult nervous system of mammalians. Abnormalities of the neurofilament network constitute a common finding of many neurological disorders. For instance depositions of neurofilament aggregates in the perikarya and axons of motor neurons are observed in most amyotrophic lateral sclerosis (ALS) cases, sporadic and familial. The impact of such accumulation of neurofilaments on the course of motor neuron disease remains to be fully elucidated.In order to investigate the role of neurofilaments in motor neuron disease, transgenic mice expressing a mutant form of the Cu,Zn superoxide dismutase (SOD1) were used as an animal model of familial ALS. Increasing the perikaryal neurofilament content in these mutant SOD1 mice slowed down the motor neuron disease progression and increased their life span by up to 65%. To date, this approach constitutes the most efficient way to increase the life span of mutant SOD1 mice. Moreover, increasing the axonal neurofilament content in mutant SOD1 mice by human neurofilament-light subunit (hNF-L) overexpression demonstrated that axonal neurofilaments do not constitute an exacerbating factor in the neurodegeneration caused by mutant SOD1.
The pathogenicity of human neurofilament-heavy (hNF-H) proteins expressed in transgenic mice was also investigated. Two alleles of the NF-H gene are present in the normal human population. Expression of both alleles in transgenic mice provoked motor neuron dysfunction. The adverse property of NF-H overexpression is the result of an improper stoichiometry between the NF-L and the NF-H subunits. Restoration of an adequate stoichiometry, via the co-expression of NF-L and NF-H subunits, rescued mice from the motor neuron dysfunction. Finally, expression of the allele called NFH43, bearing less phosphorylation sites than the other allele called NFH44, was shown to be more pathogenic in transgenic mice.
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Larivière, Roxanne. "Transgenic approach to study the role of intermediate filaments in motor neuron disease." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84279.
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Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder characterized by the loss of upper and lower motor neurons. Many reports lead to the hypothesis that a high axonal neurofilament burden and a large axonal caliber account for the selective vulnerability of motor neurons affected in ALS (Kawamura et al., 1981; Sobue et al., 1981; 1987). Transgenic mice expressing a mutant form of SOD1-linked to familial ALS and having one disrupted allele for each neurofilament gene were generated to address this issue. Despite a 40% reduction in neurofilament content and a decrease of large axonal caliber from 5--9 mum to 1--5 mum, these mice did not show an extended life span, nor did they display an alleviated loss of motor axons. These results do not support the idea that high neurofilament content and large axonal caliber are responsible for the selective vulnerability of motor neurons in ALS.Peripherin, a type III intermediate filament (IF) protein is also expressed in spinal motor neurons, and is present together with neurofilaments in axonal spheroids of ALS patients, suggesting that this protein could be involved in the pathogenesis of ALS. Moreover, mice overexpressing a peripherin transgene develop a late-onset motor neuron death characterized by the presence of IF inclusion bodies (Beaulieu et al., 1999a). In a first attempt to clarify the role of peripherin in ALS, peripherin knockout mice were generated. Peripherin null mice were viable, reproduce normally and did not exhibit overt phenotype. However, they did show a 34% reduction in the number of L5 unmyelinated sensory fibers demonstrating a requirement of peripherin for the proper development of a subset of sensory neurons.
Finally, in order to investigate whether peripherin contributes to the pathogenesis of ALS, mutant SOD1 mice were generated in a peripherin overexpressing background and a peripherin depleted background. Unexpectedly, upregulation or suppression of peripherin expression had no effect on disease onset, mortality and motor neuron loss in mutant SOD1 mice. Taken together, these results provide compelling evidence that peripherin is not a key contributor of motor neuron degeneration associated with toxicity of mutant SOD1.
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Forrest, Vanessa Ann. "Aspects of serotonergic and glutamatergic neurotransmission in the human motor system and in motor neurone disease." Thesis, University of Newcastle Upon Tyne, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336814.
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