Grant: Emerging Team Grant: Rare Diseases - Basic/Clinical

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a progressive neurological disease in which certain types of neurons die and patients thus have problems with balance and coordination. It was originally identified in the Charlevoix and Saguenay regions of Quebec and remains more common in French-Canadians, but is in fact found worldwide. Although in 2000 a Quebec research team identified the gene that is altered in ARSACS, there had been little progress in understanding what actually goes wrong in neurons from patients. The proposed New Emerging Team builds on a four-year collaboration that has demonstrated that the protein made by the ARSACS gene, called sacsin localizes to mitochondria in normal cells. Mitochondria are an important type of organelle found in neurons and in fact all cells, and when the function of sacsin is lost in experimental systems, as occurs in the patients, mitochondrial fail to function properly. This disrupt the development of neurons and they eventually die. We thus hypothesize that as for other major neurodegenerative diseases including Parkinson's and Alzheimer's, ARSACS results from a deficit in mitochondrial function. We will test this hypothesis in a way that ensures that improved knowledge of the biological basis of ARSACS allows us to screen for drugs that reverse the cellular problems seen in the disease. To allow the rapid launch of clinical trials of these drugs, we will develop a Canadian patient registry and validate a scale to measure the severity of the disease. Together the objectives of this New Emerging Team is to shape an integrated research program to uncover treatments for an orphan disease that shares features with both rare and more common neurodegenerative disorders.