Funding Agency:

National Institute of Health

Total Project Period:

5/1/11 - 3/31/14

Total Project Award:

$395,280

Principal Investigator:

Hiroko Yano, PhD

Co-Investigator:

Robert Friedlander, MD

Project Summary:

Huntington's Disease is one of several progressive and fatal neurodegenerative diseases. Selective neuronal loss is driven by genetic and environmental factors exacerbated by advancing age. Transcriptional dysregulation is central to many neurodegenerative diseases (Huntington's Disease among them) and to normal aging. We are interestedinneuronal death in Huntington's Disease, a process driven by abnormal polyglutamine expansions in the huntingtin protein (Htt).

Our studies have demonstrated a central role for the serine/threonine kinase Rip2 in Huntington's Disease pathogenesis. Rip2 also drive neuronal death elicited by other apoptotic stimuli, suggesting that Rip2 kinase is a common mediator of diverse neurological insults.

To understand the molecular mechanisms of Rip2's pro-apoptotic effects, we performed a yeast two-hybrid screen using Rip2 as bait. We found that Rip2 directly binds EED, a component of the majof epigenetic regulator PRC2. PRC2 tri-methylates histone H3 at lysine 27 (H3-K27me3), thereby remodeling chromatin and repressing gene transciprtion. This activity of EED suggests that Rip2 may cause cell death by altering an epigenetic pathway as a putative mechanism by which Rip2 affests Huntington's Disease and aging.

We envision that our findings will suggest novel targets for therapies for Huntington's Disease and, potentially, other neurological diseases and aging.