Leslie M. Thompson, PhD
Huntington’s disease: basic mechanisms to treatment strategies
University of California, Irvine
Professor, Psychiatry & Human Behavior, School of Medicine
Director, Interdepartmental Neuroscience Program
Huntington’s disease (HD) is a devastating, neurodegenerative disease that strikes in the prime of life and is caused by a CAG repeat expansion within the coding region of a single gene. The mutation within the HD gene is translated into a polyglutamine repeat expansion within the corresponding Huntingtin (HTT) protein and primarily results in neurodegeneration of medium spiny neurons within the striatum and atrophy of the cortex. The Thompson group focuses on understanding mechanisms that underlie HD onset and progression in order to identify ways in which to treat the disease. Because the genetic cause is known, it has been possible to perform mechanistic studies to understand the pathogenic basis of HD in a variety of model systems, including induced pluripotent stem cells from individuals affected with HD. Diverse cellular processes are impacted by expression and accumulation of mutant HTT (mHTT) and post-translational modifications of the mutant protein contribute to normal and abnormal protein levels and function. A number of these processes are involved in the accumulation of mutant HTT, which can be targeted experimentally. These include the posttranslational modification, SUMO, which is implicated in HD and other neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS), and proteins that modify protein folding and clearance. Further, by applying the power of human stem cell biology to more closely model disease symptoms in a dish, new insights into disease have emerged. We used a genomics approach to examine the impact of mutant HTT expression in neuronal cultures of differentiated HD patient-derived induced pluripotent stem cells to reveal significant alterations in critical gene networks. These types of findings are leading to novel approaches to identify therapeutic targets and steps for treatments. Finally, transplantation of neural stem cells into the brain is under investigation as therapeutic option for HD.