The identification of novel mutations causing familial ALS and the elucidation of common disease mechanisms
File(s)
Author(s)
Salman, Midhat
Type
Thesis or dissertation
Abstract
Amyotrophic lateral sclerosis (ALS) is a late onset fatal disease resulting from upper and lower motor neuron degeneration. The lack of an effective treatment for ALS indicates the need for a greater understanding of the pathogenesis underlying the disease. We, therefore, started this thesis with the aim of characterising putative novel familial ALS mutations for elucidating the mechanisms through which they contribute to the disease pathogenesis. We focused on the mutations obtained from the Imperial College FALS cohort and selected mutations in two genes, RUBCN and CLCN6 for characterisation. We performed expression profiling of RUBCN in spinal cord samples from SALS cases and found a significant difference in the expression of RUBCN compared to controls at both mRNA and protein levels. This encouraged us to characterise the mutation in lymphoblastoid cell lines (LCLs) derived from the individuals of the relevant FALS pedigree. We were highly encouraged by a significant downregulation at basal levels in the mRNA expression of three genes that belong to different neuroprotective pathways in the presence of the mutation. In the case of CLCN6, we found a significant downregulation in its protein expression with the presence of ER stress in SALS cases. In LCLs derived from the individuals of relevant FALS pedigree, we found a significant downregulation in mRNA and protein expression of the UPR pathway genes in the presence of the mutation under cell stress. We also found a significant decrease in cell survival at basal and under cell stress conditions. We concluded that the disruption of the UPR pathway is the molecular mechanism underlying the pathogenesis caused by the CLCN6 mutation leading to cell death. Hence, our novel findings in SALS and FALS for the mutations in both genes provide a strong evidence of their association with Familial ALS.
Version
Open Access
Date Issued
2018-11-16
Date Awarded
2019-03-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
de Belleroche, Jacqueline
Sponsor
Imperial College London
Pakistan High Commission
Charles Wallace Pakistan Trust
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)