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Title: The contribution of ANG and CHMP2B to motor neurone disease pathogenesis
Author: Cox, Laura Elizabeth
ISNI:       0000 0004 2718 7733
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2010
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available