“Elucidating mechanisms underlying motor coordination rescue in a mouse model of ARSACS” -Dr. Alanna Watt, & Dr. Anne McKinney

In Current Research by ARSACS

Aim 1 Identifying druggable Targets for potential ARSACS treatment
We have recently identified that the endosomal Na+/H+ exchanger NHE6, which is involved in regulating pH, is downregulated in anterior Purkinje cells of Sacs/ mice. Interestingly, these are the Purkinje cells that are more susceptible to cell death in ARSACS. Could the loss of NHE6 contribute to Purkinje cell death? Proper pH is essential for endosomal function, and changes result in erroneous trafficking of cargo. NHE6 results in overacidifcation of recycling endosomes which prevents the trafficking of cargo to the appropriate sites in neurons resulting in their dysfunction. For example, endosomal trafficking is important for controlled transport of glutamate receptors that mediate synaptic transmission, which we previously reported was altered in in Sacs-/- mice. We will now restore endosome acidification and cargo mistrafficking in Sacs/ to see if this prevents synaptic deficits and cell loss. Additionally, we have evidence suggesting Mito-Q as a novel therapy to improve mitochondrial function, prevent cell loss, and improve cerebellar-related motor coordination in Sacs/ mice.

Aim 2 Characterize pathophysiology for future druggable target development
We continue to pursue the identification of novel druggable targets by understanding the pathophysiological alterations that give rise to dysfunction in Sacs/ mice. To this end, we are exploring whether changes in Purkinje cell firing, and/or their innervation of downstream targets in the DCN, contribute to Purkinje cell loss and motor coordination deficits in in Sacs/ mice.

Grant: $125,000
Second year of a 2 year project
Contact:
Dr. Alanna Watt

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

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

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