The Role of Sacsin as a Molecular Chaperone

The central pathological finding in neurodegenerative disease is loss of neurons. In many disorders, this loss of neurons appears to be related to protein misfolding, comprising a large public health burden. For example, the two most common neurodegenerative diseases, Alzheimer’s and Parkinson’s diseases, possess protein misfolding as a core component of their pathology. In order to properly fold, many proteins require the assistance of molecular chaperones. While substantial gains in our knowledge of the function of general chaperones have been made in the last two decades, the role of molecular chaperones in brain-specific processes is not clearly defined. In this study, we examined the function of the protein sacsin, mutated in autosomal recessive spastic ataxia of Charlevoix-Saguenay. Pathologically, these patients demonstrate loss of neurons in the cerebellum and cervical spinal cord along with inclusions reminiscent of misfolded proteins in the remaining neurons. Sacsin contains regions of similarity to both molecular chaperones and co-chaperones. Thus, this disease may represent a useful model to study the role of molecular chaperones in neurodegenerative disease. We performed bioinformatics and biochemical investigations to determine the function of sacsin. We found that this protein contains a novel supra-domain present three times. We show that this domain is both ATPase active and contains molecular chaperone activity. Additionally, we determined that a region of sacsin possesses co-chaperone activity. Thus, sacsin is a novel molecular chaperone, with built-in co-chaperone modules, directly involved in a neurodegenerative disease.