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New Enzyme Target Helps Prevent DNA Damage in Huntington’s Disease Models

An interdisciplinary team of scientists led by Donald Bren Professor Leslie Thompson have discovered a new link between the protein inhibitor of activated STAT-1 (PIAS1) and DNA damage repair (DDR) pathways. They also found that the inhibition of PIAS1 reverses some of the adverse effects of mutant Huntingtin (HTT) on transcriptional regulation in mouse and human cell culture models. Their findings offer new insights into the molecular machinery that regulates DNA damage repair responses in neurodegenerative disease. The study was recently published in the Proceedings of the National Academy of Sciences of the United States of America.

Professor Thompson has worked on Huntington’s disease (HD), a neurodegenerative disease triggered by expanded polyglutamine repeats within the Huntingtin (HTT) protein, since her time as a postdoctoral researcher. Over the years, she has investigated the mechanisms that drive HD. In the new study, she and her collaborators explored how HTT posttranslational modification involving small ubiquitin-like modifier (SUMO) modification contributes to its pathological effects. Using a combination of in vivo and in vitro techniques, the researchers, including UCI co-first authors Eva Morozko and Charlene Smith-Geater, focused on PIAS1, an enzyme that enhances the SUMOylation of HTT. The study found that a knock-down of the Pias1 gene in a mouse model of HD rescued disease-associated DDR modules, suggesting that Pias1 may regulate DNA repair pathways in vivo. Reducing the enzyme levels in HD patient-derived induced pluripotent stem cells (iPSCs), differentiated into neurons, showed a similar effect on DDR pathways. Their findings offer new insights into the role SUMOylation plays in modulating neuronal homeostasis in neurodegenerative disease.

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