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 expansion/repeat at the beginning of the huntingtin protein (Htt) 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 (mHtt) pathogenicity remain largely unknown. Glutamate is the primary excitatory neurotransmitter in the brain and is essential for a wide variety of physiological brain functions including the regulation of movement and memory. We have data to show that antagonism of metabotropic glutamate receptor 5 (mGluR5) with a mGluR5-selective inhibitor significantly improves locomotor behavior and reduces mHtt aggregates in a zQ175 knock-in mouse model of HD. We also have evidence that the mGluR5-interacting protein Optineurin (OPTN) regulates mGluR5 signaling and contributes to a process termed autophagy that may be impaired in HD. In addition, we have identified OPTN as a mGluR5 regulatory protein. Therefore, this application will focus on the following two specific aims: to 1) determine whether OPTN contributes to mGluR5-mediated impairment of signaling, autophagy, and both motor and cognitive dysfunction in zQ175 HD mice, as well as identify OPTN modular signaling domains that regulate mGluR5 signaling and disease progression in zQ175 HD mice and 2) elucidate the contribution of vesicular glutamate transporter 3 to HD pathology and disease progression in zQ175 HD mice. This application will provide important insight into the molecular mechanisms that drive HD pathology and disease progression using a well characterized zQ175 genetic knock-in mouse model of HD.