Principal Investigator: Hiroko Yano (WashU Neurosurgery)
Collaborator: Ting Wang (WashU Genetics)
Our long-term goal is to discover therapeutic strategies targeting abnormal gene regulation causing neuronal dysfunction and death in Huntington’s disease (HD), a progressive and fatal neurodegenerative disease with no cure to date. Early in the course of disease progression, brains of HD patients and mice show abnormal gene expression, which is thought to play a critical role in disease pathogenesis. Recent studies using disease models have identified extensive changes in several chromatin modifications, including aberrant DNA methylation and histone modifications, which can alter gene expression and potentially contribute to HD pathogenesis. However, we still do not know which chromatin modifications play a dominant and causal role in neurodegeneration in HD, which has significant implications for therapy development. Based on our preliminary results demonstrating the important role of DNA methylation pathways in the death of HD neurons in culture, we hypothesize that the mutant HD protein triggers aberrant DNA methylation, thereby causing dysregulation of genes important for neuronal survival; therefore, DNA methylation pathways can be therapeutically manipulated to restore normal gene expression and protect neurons from HD-mediated neuronal death. The objective of this project is to determine how manipulation of DNA methylation pathways causes neuroprotection. Successful completion of these studies will advance our molecular understanding of gene regulation in HD neurons and lead to the development of new therapeutic strategies to halt disease progression in HD and, potentially, in other progressive neurodegenerative diseases in which aberrant DNA methylation plays a role.
Pan Y, Daito T, Sasaki Y, Chung YH, Xing X, Pondugula S, Swamidass, SJ, Wang T, Kim AH, Yano H. Inhibition of DNA methyltransferases blocks mutant huntingtin-induced neurotoxicity. Sci Rep.;6:31022, (2016).
Updated August 2016
Pilot project teams include Hope Center faculty members and others. For more about Hope Center faculty on this team, click below.