ALTERATIONS OF SACSIN RNA-BINDING PROPERTIES ARE CONNECTED TO THE DEVELOPMENT OF ARSACS

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease mainly characterized by cerebellar ataxia, progressive spasticity and peripheral neuropathy. It is a childhood onset disease caused by point mutations in the SACS gene (13q11) that codifies the protein SACSIN. The loss of SACSIN expression has been reported to affect the proper structure and functions of the neuronal cytoskeleton and mitochondria. However, it is still under debate whether this is a cause or a consequence. SACSIN is a multidomain protein that was suggested to bind to RNAs. However, the RNA-binding properties of SACSIN have never been investigated. Thus, we decided to investigate whether the putative alteration of SACSIN RNA-binding ability can be at the basis of the molecular mechanisms that lead to ARSACS etiology. To this extent, we are currently characterizing the structural and stability properties of SACSIN domains, as well as its RNA-binding ability through in silico, in vitro and in cells strategies. We aim at unveiling key molecular aspects that can eventually be exploited to restore SACSIN altered RNA-binding properties as innovative strategies to treat ARSACS patients