ARSACS is an early-onset neurodegenerative disease caused by SACS loss-of-function.

SACS mutations alter mitochondrial dynamics and neurofilament networks in ARSACS.

Advanced disease models and multilayered omics will refine our understanding of ARSACS.

Gene correction strategies offer promise in developing future ARSACS therapeutics.

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.

ARSACS

Chaperone-like activity

Disease models

Intermediate filaments

Mitochondrial dynamics

Quantitative omics

Sacsin

SACS mutations

© 2022 The Author(s). Published by Elsevier Ltd.