exploration of CRAG gene therapy for neurodegenerative diseases

2015 Fiscal Year Final Research Report

• Project/Area Number: 25460074
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Inatome Ryoko 東京薬科大学, 生命科学部, 研究員 (90408691)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 神経変性疾患

Outline of Final Research Achievements

We previously demonstrated that CRAG facilitated the degradation of expanded polyglutamine protein via the nuclear ubiquitin-proteasome pathway and suggested that targeted delivery of CRAG may be useful as a gene therapy for neurodegenerative diseases such as polyglutamine diseases. However, the physiological relevance of CRAG in vivo is unknown. Here, we analyzed CRAG KO mice. Both whole-body and neuron-specific CRAG KO mice spontaneously developed severe neurodegenerative phenotypes cell death and lethality, within 1 month of birth. Kainic acid–induced c-fos expression was intensively suppressed in the hippocampus in these KO mice. Furthermore, CRAG interacted with ELK1, a coactivator of SRF, leading to ELK1-dependent SRF-c-fos induction. We conclude that CRAG plays a critical role in neuronal development and survival, at least in part through ELK1-dependent SRF-c-fos activation, and therefore suggesting the usefulness of CRAG gene therapy for neurodegenerative diseases.

Free Research Field

生化学