“Structural Determination of Sacsin” – Dr. Walid Houry

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a non-treatable neurodegenerative genetic disorder of early childhood and adulthood. When first reported in 1978, ARSACS was described as a unique form of ataxia, accompanied with motor speech anomalies, muscle wasting phenotypes, and peripheral nerve complications. ARSACS symptoms worsen in adulthood, with most individuals losing the ability to walk by the age of 50. Genetic studies have established that ARSACS is caused by mutations in Sacsin – a protein whose biology is poorly known. Current research suggests that Sacsin supports cytoskeletal and mitochondrial organization. To shed light on Sacsin function, one needs to study Sacsin structure in both native and mutated states. However, no published research has described the purification of Sacsin protein for in vitro and structural investigations. This technical gap in research is due to the large size of Sacsin (~520 kDa). Our laboratory has now solved this issue. We have carried out early in vitro characterizations of Sacsin, and we are working to obtain its three-dimensional (3D) structure using cryogenic electron microscopy. Our current focus is to increase the resolution of our 3D model and, subsequently, begin in silico drug screening.