Abstract
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by mutations in the SACS gene, encoding the 520 kDa modular protein sacsin, which comprises multiple functional sequence domains that suggest a role either as a scaffold in protein folding or in proteostasis. Cells from patients with ARSACS display a distinct phenotype including altered organisation of the intermediate filament cytoskeleton and a hyperfused mitochondrial network where mitochondrial respiration is compromised. Here, we used vimentin bundling as a biomarker of sacsin function to test the therapeutic potential of Hsp90 inhibition with the C-terminal-domain-targeted compound KU-32, which has demonstrated mitochondrial activity. This study shows that ARSACS patient cells have significantly increased vimentin bundling compared to control, and this was also present in ARSACS carriers despite them being asymptomatic. We found that KU-32 treatment significantly reduced vimentin bundling in carrier and patient cells. We also found that cells from patients with ARSACS were unable to maintain mitochondrial membrane potential upon challenge with mitotoxins, and that the electron transport chain function was restored upon KU-32 treatment. Our preliminary findings presented here suggest that targeting the heat-shock response by Hsp90 inhibition alleviates vimentin bundling and may represent a promising area for the development of therapeutics for ARSACS.
Highlights
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS; OMIM 270550) is an inherited neurodegenerative disorder characterised by early-onset cerebellar ataxia with spasticity, peripheral neuropathy, dysarthria and nystagmus [1]
It has previously been observed that ARSACS patient dermal fibroblasts display a collapsed, disorganised vimentin intermediate filament network [9], like the abnormal neurofilament bundling found in neurons from Sacs-knockout mice and ARSACS patients [7]
We used the striking phenotype of vimentin bundling as a biomarker of the disease state to assess the efficacy of a C-terminal-targeted Heat-shock protein 90 (Hsp90) inhibitor, KU-32, in treating ARSACS
Summary
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS; OMIM 270550) is an inherited neurodegenerative disorder characterised by early-onset cerebellar ataxia with spasticity, peripheral neuropathy, dysarthria and nystagmus [1]. The function of sacsin is still to be elucidated, the presence of these conserved domains, often found in molecular chaperones and components of the ubiquitin–proteasome pathway, suggest a role in proteostasis. The striking bundling and collapse of the vimentin intermediate filament network observed in patient dermal fibroblasts mirrors the abnormal bundling of neurofilaments in multiple neuronal populations in Sacs knockout mice and patients with ARSACS [7]. Neurofilaments are, type IV intermediate filaments found in neuronal axons [10]. A recent study has proposed that there are distinct, but complementary, functions of sacsin domains in intermediate filament organisation and turnover [8]. That study proposed the upregulation of heat-shock protein chaperones could compensate for the loss of sacsin function and restore the intermediate filament network [8]
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