Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS

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.

Hereditary Ataxias: From Bench to Clinic, Where Do We Stand?

“…For instance, heat shock protein 90 (Hsp90) inhibitors (e.g., BIIB021) have been shown to be effective in reducing polyQ accumulation in SCA1 [180]. Similarly, targeting the heat-shock response through Hsp90 inhibition (using the KU-32 compound) has been shown to reduce intermediate filament bundles in the fibroblasts of patients with ARSACS, leading to the recovery of mitochondrial membrane potential [218]. However, the absence of evidence regarding the effectiveness of this treatment in pre-clinical animal studies has, thus far, hindered the translation of this approach to the clinical setting.…”

Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

“…Since higher inductions of Hsp90 are observed in neurodegenerative diseases, a Hsp90 inhibitor was investigated for a possible reduction in disease progression and toxicity. A potential therapeutic candidate was KU-32, a Hsp90 inhibitor [ 137 ]. Hence, inhibiting Hsp90 was contemplated for its possible benefits in patients with ARSACS and different neurodegenerative disorders [ 138 ].…”

“…Hence, inhibiting Hsp90 was contemplated for its possible benefits in patients with ARSACS and different neurodegenerative disorders [ 138 ]. Ku-32 treatment improved the mitochondrial functions (electron transport, mitochondrial membrane potential) in cells among ARSACS patients [ 137 ].…”

Proteomics and lipidomic analysis reveal dysregulated pathways associated with loss of sacsin

“…Leveraging on previous RNA-Seq ( Morani et al, 2019 ) and aptamer-based proteomic ( Morani et al, 2021 ) studies, we observed that loss of sacsin impacts autophagic flux, bioenergetics, neuroinflammation, synaptogenesis, and engulfment of cells, mechanisms whose involvement was further confirmed by organelle-based quantitative proteomics in neuronal-like cells ( Morani et al, 2022 ). Nonetheless, these new clues have not led to advances in our therapeutic approaches, which remain largely speculative or limited to preclinical models ( Martinelli et al, 2020 ; Naef et al, 2021 ; Nethisinghe et al, 2021 ; Del Bondio et al, 2023 ; Toscano Márquez et al, 2023 ).…”