Exploiting SACSIN HEPN domain functions to revert ARSACS cellular defects.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease mainly characterized by cerebellar ataxia, progressive spasticity and peripheral neuropathy. The disease is caused by mutations in the SACS gene (13q11) that alter the expression of the protein SACSIN. The first signs of the disease occur during childhood, and the disease rapidly progresses over the years. Currently, no treatment is available for ARSACS patients. Recently, we discovered that a specific portion of the SACSIN protein can bind to cellular RNAs. This interaction is required for the correct localization and stability of the protein in human cells. When mutations affect the HEPN domain, SACSIN becomes unstable and shows a strange distribution in cells. Moreover, the mutated protein generates abnormal aggregates of HEPN proteins. These findings demonstrate that the HEPN domain is essential for the normal biological functions of SACSIN. With this new project, we aim to restore the RNA-binding properties of SACSIN that are altered in ARSACS cells. To achieve this, we will develop molecular tools specific for the SACSIN HEPN domain and test their effectiveness in both cellular and animal models of ARSACS. Overall, this project aims to develop a strategy that could be used as a molecular therapy for ARSACS patients.