| dc.description.abstract | Proteins containing a J-domain, (known as DnaJ proteins) act to recruit the Hsp70 molecular chaperone machinery to multiple cellular processes. Mutations in several J-domain proteins cause neurological disorders, that are considered “chaperonopathies” as the molecular pathology is believed to be associated with loss of chaperone activity. This thesis focuses on two of these conditions that have cerebellar ataxia as a core component of their phenotype: Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), caused by mutations in the SACS gene, which encodes DNAJC29/sacsin; and an ataxia syndrome that also presents with early-onset diabetes mellitus, caused by mutations in DNAJC3. The overarching aim of this thesis was to better understand the cellular consequences of sacsin and DNAJC3 dysfunction, with a focus on metabolic pathways. The first part of the thesis investigated alterations in cellular metabolism in a neuronal cell model of ARSACS. This identified metabolic rewiring as a consequence of sacsin knockout and highlighted potential targets for therapeutic interventions, such as modulation of GABA neurotransmitter levels. Further investigation of the cellular phenotype associated with loss of sacsin, characterised disruption of the microtubule cytoskeleton and its regulators (e.g., tau), altered integrin trafficking and impaired focal adhesion dynamics. These aspects of the loss of sacsin phenotype were further investigated in the mouse retina, which was selected based on the presence of a retinal phenotype in ARSACS patients. In the final part of the thesis, a novel cellular model for DNAJC3 loss of function was developed. Molecular characterisations of this model were then performed by metabolomic and transcriptomic analysis. In summary, defining cellular deficits associated with the loss of sacsin and DNAJC3 is a valuable first step towards understanding molecular mechanism of disease and identification of potential therapeutic strategies for these ataxias. It also broadens our understanding of the cellular roles of J-domain proteins. | en_US |
