Investigation of pathomechanism and novel therapeutic strategy for ALS on the basis of optineurin dysfunction

2015 Fiscal Year Final Research Report

• Project/Area Number: 24300132
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Wakayama Medical University
• Principal Investigator: Ito Hidefumi 和歌山県立医科大学, 医学部, 教授 (20250061)
• Co-Investigator(Kenkyū-buntansha): KAWAMOTO YASUHIRO 京都大学, 医学研究科, 非常勤講師 (40335253)
• Co-Investigator(Renkei-kenkyūsha): KAWAKAMI HIDESHI 広島大学, 原爆放射線医科学研究所, 教授 (70253060) ; RYOSUKE TAKAHASHI 京都大学, 医学研究科, 教授 (90216771)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Keywords: オプチニューリン / 筋萎縮性側索硬化症 / NF-κB / ゴルジ装置断片化 / 炎症性サイトカイン

Outline of Final Research Achievements

We knocked down OPTN in neuronal cells and examined the resulting NF-κB activity and phenotype. First, we confirmed the loss of the endogenous OPTN expression after siRNA treatment and found that NF-κB activity was increased in OPTN-knockdown cells. Next, we found that OPTN knockdown caused neuronal cell death. Then, overexpression of OPTN WT or OPTN E50K with intact NF-jB-suppressive activity, but not overexpression of ALS-related OPTN mutants, suppressed the neuronal death induced by OPTN knockdown. This neuronal cell death was inhibited by withaferin A, which selectively inhibits NF-κB activation. Lastly, involvement of the mitochondrial proapoptotic pathway was suggested for neuronal death induced by OPTN knockdown. Taken together, these results indicate that inappropriate NF-jB activation is the pathogenic mechanism underlying OPTN mutation-related ALS.

Free Research Field

神経内科学