Stem Cell Internship: Finkbeiner Lab, Gladstone Institutes
Project Title: Identification of Genetic Modifiers in Huntington's Disease
Project Abstract: Huntington’s Disease (HD) is an inherited autosomal disease that affects about one in every 10,000 people. HD is caused by an expansion of 40 or more CAG repeats in the huntingtin gene (mHtt). Symptoms often emerge between the ages of 30-50 and life expectancy after diagnosis is about 15-20 years. There is a correlation between the CAG repeat expansion and age of onset. However, it is known that other genes play a role in disease trajectory. In order to find other genes that modulate the toxic effects of mHtt, we performed Whole Genome Sequence analysis on families with HD and found numerous genetic variants that segregate with disease onset.
One variant that was found in individuals with unusually late onset was in the Neuronal PAS Domain Protein 3 (NPAS3) gene. NPAS3 has been reported to have roles in neurogenesis, and toxin metabolism, among others. To test if NPAS3 may act as a modifier of mHtt, we knocked down NPAS3 using small interfering RNA (siRNA) in medium spiny neurons (MSNs) derived from induced pluripotent stem cells (iPSCs) from unaffected and HD patients. The cells were longitudinally imaged with our Robotic Microscope and assessed survival and neurite length. Our analysis will help us to understand if NPAS3 modulates the cellular pathology caused by mHtt and may act as a genetic modifier of HD.
