Development of CRAG gene therapy for neurodegenerative diseases

2014 Fiscal Year Final Research Report

• Project/Area Number: 25640040
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: YANAGI Shigeru 東京薬科大学, 生命科学部, 教授 (60252003)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: CRAG / 遺伝子治療

Outline of Final Research Achievements

CRAG facilitated degradation of expanded polyglutamine protein (polyQ) via the nuclear ubiquitin-proteasome pathway. Taking advantage of this feature, lentivirus-mediated CRAG expression in the Purkinje cells of mice expressing polyQ resulted in clearance of the polyQ aggregates and rescue from ataxia, suggesting usefulness in targeted delivery of CRAG as a gene therapy for neurodegenerative diseases. However, a physiological relevant of CRAG in vivo are unknown. Here, we analyzed CRAG/Centaurin-γ3 KO mice. CRAG/Centaurin-γ3 KO mice spontaneously developed severe neurodegenerative phenotypes including hind-limb clasping, neuronal atrophy, cell death and lethality within 1 month of birth. Furthermore, we found that CRAG enhances neuronal cell survival against the accumulation of unfolded proteins through not only proteasome activation but also SRF-mediated c-fos activation in vivo. Our results may contribute to development of CRAG gene therapy for neurodegenerative diseases.

Free Research Field

生化学