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Investigations into the cellular function of C9orf72

Webster, Christopher (2016) Investigations into the cellular function of C9orf72. PhD thesis, University of Sheffield.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by degeneration of the upper and lower motor neurons. Cognitive impairment in ALS is common and as such ALS and frontotemporal dementia (FTD) now constitute a spectrum of disorders ranging from pure ALS through to pure FTD. The hallmark of these diseases is the presence of neuronal cytoplasmic inclusions immunoreactive for a range of cellular proteins, suggesting defective protein clearance may contribute to disease. Indeed, damage to the cellular degradation pathway of autophagy, and disrupted protein clearance, is a potential causative mechanism in many familial inherited cases of ALS. The most common genetic cause of ALS and FTD is a hexanucleotide repeat expansion of GGGGCC within the first intron of C9orf72. How this repeat expansion causes disease is unknown but it has been shown to correlate with reduced expression of C9orf72. Thus, loss of functional C9orf72 protein could contribute to disease pathogenesis. As C9orf72 codes for two conserved, but uncharacterised, protein isoforms this thesis set out to investigate the cellular function of C9orf72. C9orf72 was found to interact with FIP200, ULK1 and ATG13, all of which are members of the autophagy initiation complex. In line with this, C9orf72 protein levels were found to modulate autophagy initiation by regulating Rab1a dependent trafficking of the ULK1 autophagy initiation complex. Knockdown of C9orf72 by targeted siRNA resulted in defective autophagy initiation, which led to the accumulation of p62, similar to the inclusion pathology specifically associated with C9orf72 ALS/FTD. Furthermore, iNeurons derived from C9orf72 ALS/FTD patient induced neural progenitor cells were shown to have a basal autophagy deficit, which correlated with reduced expression of C9orf72. Thus haploinsufficiency of C9orf72, leading to reduced C9orf72 protein levels and defective autophagy, could lead to the accumulation of protein aggregates, such as p62, and the development of ALS/FTD. This thesis has therefore identified a possible cellular mechanism by which reduced levels of C9orf72 may contribute to disease pathogenesis.

Item Type: Thesis (PhD)
Keywords: Amyotrophic Lateral Sclerosis, Autophagy, C9orf72, Frontotemporal Dementia, Rab GTPase
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Depositing User: Mr Christopher Webster
Date Deposited: 02 Nov 2016 10:46
Last Modified: 02 Nov 2016 10:46
URI: http://etheses.whiterose.ac.uk/id/eprint/14385

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