Yash Patel
McMaster University, Canada
Title: High Content Screening of an Epigenetics Compound Library in two Huntington’s disease cell lines: The Importance of p53 in HD cell lines
Biography
Biography: Yash Patel
Abstract
Huntington’s disease (HD) is characterized by a variety of aberrations in basic cellular processes, including epigenetic dysregulation –attributed to the downstream effects of mutant huntingtin. The phosphorylation of two serine residues within the first 17 amino acids (N17) in huntingtin is critical in modulating the toxicity of mutant huntingtin. Increase in N17 phosphorylation has been shown to ameliorate HD pathology, presenting a novel pharmaceutical target. Epigenetic compound inhibitors were screened for N17 phosphorylation, and restoration of normal epigenetic regulation within two cellular models of HD; ST Hdh Q111/Q111 (inactive p53) and TruHD hTERT fibroblasts (active p53). There is a drastic effect by histone deacetylase inhibitors (HDAC) on the level of N17 phosphorylation. Furthermore, the p53-active TruHD hTERT cell line is affected by a variety of different epigenetic compound classes such as, PARP, Aurora kinase inhibitors etc., in addition to the HDAC inhibitors found only to be effective in the p53-inactive ST Hdh Q111/Q111 cell line. The difference in compound hits between the hTERTs and ST Hdh demonstrates the importance of having active p53 to model the true cellular physiology in Huntington’s disease. Most importantly, high content screening for molecular therapeutics should screen through TruHD hTERTs, rather than the commonly used striatals ST Hdh Q111/Q111s.