Investigating the impact of Parkinson’s Disease linked mutations of DNAJC6 in vivo

Alshammari, F. M. (2023) Investigating the impact of Parkinson’s Disease linked mutations of DNAJC6 in vivo. PhD thesis, University of Reading. doi: 10.48683/1926.00119106

Abstract/Summary

The DNAJC6 gene encoding the brain-specific Auxilin protein, has an essential role in the disassembly of the clathrin-coat on cellular vesicles. Because of the growing evidence for the pathogenesis of Parkinson’s disease (PD), this study is focused on the investigation of the impact of a specific mutation (R927G) in DNAJC6 previously described in PD patients. The main aim is to investigate further the role of Auxilin in the pathogenesis of PD using genetically modified Caenorhabditis elegans (C.elegans), (dnj-25(knu577[R743G])) and (dnj-25 (ok422)) mutants in the DNAJC6 orthologue dnj-25. The results suggest that mutations in dnj-25 cause modest motor impairment, resulting in slower speeds than the wild-type. The dnj-25 mutations also present impaired food sensing. These findings imply that dnj-25 mutations disrupt dopamine signalling, indicating that dnj-25 is important for sensory and motor functions in C. elegans. Moreover, the ageing of the dnj-25 mutated worms appeared to impair physiological systems, such as the distribution and overall level of clathrin, and α-synuclein aggregation in the muscle wall, likely due to a deficiency in the Auxilin protein. It is concluded that Auxilin plays a crucial function in the function of CME neurons based on the weak expression of vit-2 GFP in the oocytes expressing Auxilin. Finally, RNA-seq analysis highlighted the disruption of the dnj-25(knu577[R743G]) mutant and the aberrant activation of the physiological system in C. elegans by inducing an oxidoreductase activity in the dnj-25(knu577[R743G]) mutant. Taken together, these data provide insights into the mechanisms linking DNAJC6 to Parkinson’s and highlight the utility of C. elegans for investigating neurodegeneration.

Item Type	Thesis (PhD)
URI	https://reading-clone.eprints-hosting.org/id/eprint/119106
Identification Number/DOI	10.48683/1926.00119106
Divisions	Life Sciences > School of Biological Sciences
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