Molecular basis of aberrant RNA metabolism in familial ALS type6

2015 Fiscal Year Final Research Report

• Project/Area Number: 25430080
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Hiroshima Bunkyo Women's University
• Principal Investigator: Fujii Ritsuko 広島文教女子大学, 人間科学部, 教授 (90342716)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: ALS / FUS/TLS / RNA代謝 / RNA輸送

Outline of Final Research Achievements

Familial amyotrophic　lateral　sclerosis type6 (FALS6)is　caused　by aberrant　expression　of　TLS/FUS with ALS-specific point　mutations, which leads to intracellular aggregations of the dysfunctional TLS proteins. The protein aggregation of the ALS mutant TLS is not rescued by an expression of wild type TLS. Furthermore, overexpression of ALS mutant TLS does not induce autophagy in spinal cord motor neuron-derived cells, suggesting that pathogenesis of FALS6 is distinct from that of other FALS. Here we show that dysfunctional TLS cannot regulate the expression of Ca2+channel proteins such as specific types of NMDA receptor 1 subunits with high Ca2+ permeability, and also that D-serine content in TLS knockout mouse brains is elevated due to the higher expression of serine racemase. Our findings provide the evidence that motor neurons expressing the mutant TLS responsible for the defective RNA metabolism are susceptible to ALS development.

Free Research Field

神経科学