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DEPARTMENT OF NEUROBIOLOGY & BEHAVIOR
Ph.D. DISSERTATION DEFENSE
Dr. Thompson’s Lab
PIAS1 modulates the transcriptional landscape and DNA damage repair in Huntington’s disease
Monday, November 25th
Gross Hall, Thorp Conference Center (room 4000), (Building 845 on the campus map)
Abstract: Disruption of protein homeostasis, leading to accumulation of insoluble high molecular weight protein complexes containing the Huntingtin (HTT) protein and SUMOylated proteins, and transcriptional dysregulation are key features in Huntington’s disease (HD). Genetic modifiers contributing to HD age of onset have recently been identified and have critical roles in DNA damage repair (DDR) pathways. The mechanisms involved in DDR rely strongly on signaling cascades and post-translational modifications such as SUMO to maintain genomic integrity. Further, the Huntingtin (HTT) protein itself scaffolds DDR proteins. We previously showed that striatal reduction of the E3 SUMO ligase PIAS1 was neuroprotective and modulated disease associated pathologies including accumulation of mutant HTT in a mouse model of HD. However, the exact mechanistic contributions of PIAS1 towards HD pathogenesis have not yet been fully elucidated. To further evaluate PIAS1 function in the context of HD, knock-down was investigated in human patient medium spiny neurons differentiated from induced pluripotent stems cells and two disease mouse models. My findings suggest that PIAS1 functions as a key regulator of post-translational modification and protein homeostasis in HD neurons and mediates the functional activity of the transcription-coupled DNA damage repair complex in the striatum. Reduction of PIAS1 facilitated DNA repair, normalized aberrant transcriptional profiles related to synaptic function, and may stabilize the CAG-repeat within HTT. The results of this research provide the first mechanistic link between SUMOylation and DNA damage repair in the central nervous system. Specifically, they provide insight into how DNA damage repair pathways and post-translational modifications might contribute towards HD, and overall for targeting pathway mediators to restore homeostatic balance, with broad implications for HD and other neurodegenerative diseases.