Insights into SACS pathological attributes in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)☆

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early-onset neurodegenerative disease caused by mutations in the SACS gene, encoding Sacsin. Initial functional annotation of Sacsin was based on sequence homology, with subsequent experiments revealing the Sacsin requirement for regulating mitochondrial dynamics, along with its domains involved in promoting neurofilament assembly or resolving their bundling accumulations. ARSACS phenotypes associated with SACS loss-of-function are discussed, and how advancements in ARSACS disease models and quantitative omics approaches can improve our understanding of ARSACS pathological attributes. Lastly in the perspectives section, we address gene correction strategies for monogenic disorders such as ARSACS, along with their common delivery methods, representing a hopeful area for ARSACS therapeutics development.