Elucidating Mechanisms Underlying Motor Coordination Rescue in a Mouse Model of ARSACS- Dr. Alanna Watt and Dr. Anne McKinney

Description Aim 1 Elucidate mechanism underlying MitoQ rescue of motor coordination in Sacs-/- mice: (i)test mitochondrial dynamics and morphology using Mito-tracker administered intracellularly in Purkinje cells in treated and untreated Sacs−/− mice, (ii) test mitochondrial function using assays for mitochondrial respiration and energy consumption, and (iii) determine whether MitoQ rescues the abnormal somatodendritic localization of phosphorylated neurofilament in Sacs−/− mice.In addition to understanding the mechanism by which MitoQ rescues motor behaviour, the work will continue with the Brais lab to understand how and if a drug recently identified by a drug screen they conducted with V151 improves Purkinje cell morphological and physiological deficits. Aim 2 Identify mechanism(s) underlying Purkinje cell firing deficits in Sacs-/- mice. Over the coming 2018/2019 year we expect to make substantial advances in understanding the following 5 questions: (a) How does MitoQ lead to behavioral improvements in Sacs−/− mice? (b) Does V151 rescue physiological abnormalities in Sacs−/− mice? (c) Are glutamate transporters altered in Sacs−/− mouse cerebellum? (d) Does rescue of firing rate directly ameliorate behavioral phenotype in Sacs−/− mice? (e) Is zebrin neuroprotective in Sacs−/− mouse cerebellum? Duration : One year Grant: $125,000 Contacts: Dr. Alanna Watt, Department of Biology McGill University Bellini Life Sciences Bldg. 3469 Sir William Osler, Montreal, Quebec Canada H3G 0B1 Office: Rm. 265 | Lab: Rm. 257 Tel: (514)-398-2806; Fax: (514)-398-5069; Email: alanna.watt@mcgill.ca Dr. Anne McKinney, Department of Pharmacology and Therapeutics, McGill University Bellini Life Sciences Bldg 3469 Sir William Osler, Montreal, Quebec Canada H3G 0B1 Tel: (514)-398-5685; Fax: (514)-398-2045; Email: anne.mckinney@mcgill.ca