EXCEED THE SPACE PROVIDED. Metabotropic Glutamate Receptors in Neurodegeneration The genetic basis for Huntington's disease (HD) is a CAG repeat expansion that encodes an expanded polyglutamine repeat in the huntingtin protein. However, the normal function of the huntingtin protein, and how the mutant protein leads to disease, is still unknown. Dysregulation of glutamatergic signaling pathways has long been implicated in many disease processes of the nervous system, and there is considerable evidence that abnormal glutamate receptor function contributes to disease pathogenesis in HD. Both ionotropic and metabotropic glutamate receptors have been implicated in the neurodegenerative process, but the unacceptable side effects of drugs targeting ionotropic glutamate receptors have limited their use therapeutically. Since metabotropic glutamate receptors are neuromodulatory in function, it is thought that drugs targeted to these receptors will be better tolerated clinically. Our goal is to understand the complexities and therapeutic potential of mGluR signaling in HD neurodegeneration. Recent evidence indicates that the huntingtin protein interacts with NMDARs and IPSRs, which are important downsteam targets of Group I mGluR signaling. The functional coupling of Group I mGluRs to these proteins is also potentiated by molecular crosslinks among these proteins involving the PSD protein homer. Furthermore, adenosine A2Areceptors (A2aRs) also form functional heterodimers with mGluRS, with the activity of one receptor potentiating the activity of the other. These receptor signaling mechanisms are particularly relevant to HD, as the striatal neurons most affected in the disease are some of the few cells in the brain that have high expression of both these receptors. The association of mGluRS with A2aRs in the context of mutant huntingtin is of yet unstudied. We hypothesize that the intermolecular interactions of mGluRs with related signaling molecules play an important role in the neurodegenerative process in HD. Therefore, we are examining the molecular and functional association of Group I mGluRs with A2aR, NMDAR andIP3R signaling proteins in the context the mutant huntingtin, aswell asthe direct interaction of Group I mGluRs with the huntingtin protein itself. PERFORMANCE SITE ========================================Section End===========================================
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