Therapeutics for polyglutamine diseases through protein degradation pathway: Targeting the nucleus

2015 Fiscal Year Final Research Report

• Project/Area Number: 24390220
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: The University of Tokyo
• Principal Investigator: Iwata Atsushi 東京大学, 医学部附属病院, 講師 (40401038)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Keywords: polyglutamine / ubiquitin proteasome / HDAC3 / UHRF2

Outline of Final Research Achievements

Polyglutamine diseases are caused by cytosine-adenine-guanine (CAG) trinucleotide expansions that are translated to a polyglutamine (pQ) chain in specific genes. This pQ chains tend to destabilize the entire proteins making them aggregate. The aggregates are especially toxic in the nucleus for a variety of reasons. Thus, for treating pQ diseases, targeting the nuclear pQ aggregates for degradation seems to be a promising approach. The nuclear ubiquitin proteasome system is the only major protein degradation machinery in the nucleus since the autophagy lysosome system, cannot function in the nucleus. We found that ubiquitin ligase UHRF2 recognizes and promotes nuclear pQ degradation, thus activation of these ubiquitin ligases could be one of the therapeutic approaches. In addition, we also found that one of the histone deacetylases (HDAC), HDAC3, regulates the nuclear ubiquitin proteasome system.

Free Research Field

神経内科学