Title : Cellular models of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) reveal mitochondrial dysfunction and cytoskeletal reorganisation
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset neurological disease, with pyramidal spasticity and cerebellar ataxia. ARSACS results from mutations in the SACS gene that encodes sacsin, a modular protein with conserved domains that indicate a molecular chaperone linked function.
We have used sacsin knockdown SH-SY5Y cells and ARSACS patient human dermal fibroblasts to investigate the cellular consequences of loss of sacsin function. These analyses initially identified mitochondrial dysfunction as a feature of sacsin null cells. Specifically, we have shown that loss of sacsin impairsoxidative phosphorylation and leads to increased levels of oxidative stress. In elucidating mechanism, we found that mitochondrial recruitment of the fission factor dynamin-related protein 1 (Drp1) is decreased in sacsin null cells. This suggests that impaired Drp1-mediated fission contributes to reduced mitochondrial health in cellular models of ARSACS.
Further investigation of our cellular models identified that loss of sacsin also leads to altered organisation and dynamics of the vimentin intermediate filament (IF) cytoskeleton. This is consistent with the observation that neurons from the sacsin knockout mouse have neurofilament abnormalities (Larivière et al. 2015; Hum Mol Genet. 24:727-39). The vimentin IF is important for maintenance of cellular architecture, and we observed altered organelle distribution in cells without functional sacsin. This included repositioning of lysosomes to a perinuclear localisation, where we also observed accumulation of components of protein quality control systems.
We will discuss how these phenotypes of ARSACS cellular models may be integrated and their relevance to the molecular pathogenesis of this neurodegenerative disease.
Audience take away:
- This talk will raise awareness of the recessive ataxia ARSACS. This disease was initially described in a Canadian population, but patients have now been identified worldwide.
- Knowledge of the ARSACS cellular phenotype will be useful for diagnosing patients with this ataxia. For example, if sequencing of the SACS gene identifies a variant that may or may not be pathogenic, it would be possible to screen patient fibroblasts for the phenotype we describe.
This talk will highlight similarities between molecular pathogenic mechanisms of ARSACS and other neurodegenerative conditions. Being able to cluster neuronal disorders based on common cellular mechanisms is likely to be relevant to the identification of potential strategies for pharmacological intervention. This is particularly relevant for rare conditions like ARSACS.