Grant: Project Grant

Huntington's disease (HD) is a devastating autosomal dominant inherited neurodegenerative disorder that is characterized by progressive motor, cognitive, and psychiatric impairments. A polyglutamine (CAG) expansion/repeat at the amino-terminus of the huntingtin protein is the cause of HD, and the length of this repeat is inversely correlated with the age of disease onset and directly correlates with the severity of disease symptoms. However, the underlying mechanism(s) responsible for mutant huntingtin pathogenicity remain largely unknown. Glutamate is the primary excitatory neurotransmitter in the brain and is essential for a wide variety of physiological processes, such as integrative brain functions and neuronal cell development. We have preliminary data to show that antagonism of metabotropic glutamate receptor 5 (mGluR5) with a mGluR5-selective inhibitor significantly improves locomotor behaviour and reduces huntingtin aggregates in a zQ175 knock-in mouse model of HD. We also have evidence that a process termed autophagy can be active by blocking mGluR5 signaling with CTEP and may contribute to a reduction in huntingtin protein aggregation. In addition, we have identified optineurin, a regulatory of autophagy as a mGluR5 regulatory protein. Therefore, this application will focus on the following three specific aims: 1) To repurpose mGluR5 antagonists for the treatment of HD and 2) To determine how mGluR5 antagonism alters a GPCR regulated autophagy pathway in HD mice and genetic deletion of optineurin alters HD disease progression. The proposed experiments will guide both the validation and repurposing of mGluR5 selective antagonists to treat HD. In addition, the proposed experiments will allow us to examine the role autophagy in HD, as well as help determine whether huntingtin aggregates are contributory to the HD disease process.