Caley Burrus Lane (Eroglu Lab) will present her dissertation seminar What is the role of Huntingtin in CNS development and function? on Zoom, Wednesday May 6 at 10:00 a.m. Please email DGSA LaDonna Huseman for connection details.
Abstract: Huntington’s Disease (HD) is a fatal, inherited disease caused by an autosomal dominant polyglutamine expansion mutation near the N-terminus of the Huntingtin (Htt) protein. Patients with HD suffer from progressive motor, cognitive, and psychiatric impairments, along with significant degeneration of the striatal projection neurons (SPNs) of the striatum. The dominant nature of the Htt mutation has led to the widely-accepted hypothesis that HD is caused by a toxic gain-of-function of mutant Htt protein. Recent findings suggest that loss of Htt function due to dominant-negative effects of the mutant protein also play important roles in HD. However, the role of Htt in the health and function of the SPNs is not yet known, leaving critical aspects of HD pathology unexplored. To investigate this question, I conditionally deleted Htt from specific subpopulations of striatal projection neurons (SPNs) using the Cre-Lox system. I determined that loss of Htt in SPNs leads to aberrant synaptic connectivity and function within the basal ganglia, along with dysregulated motor function. I also discovered that SPNs require Htt for survival, as SPNs lacking Htt (Htt cKO) degenerate in an aging-dependent manner. While Htt cKO SPNs do not appear to die via apoptosis, there is significant reactive gliosis present in the striatum at the time when SPNS are degenerating, reminiscent of HD. Collectively, these results demonstrate that SPNs require Htt for their health, function, and survival with aging. My ongoing investigations attempt to determine the mechanism by which Htt contributes to synapse development and function, and how the HD-causing mutation in Htt interferes with these fundamental processes.