The biological significance of the cleavage of ALS-associated protein TDP-43

2014 Fiscal Year Final Research Report

• Project/Area Number: 25670419
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Osaka University
• Principal Investigator: KAWAHARA Yukio 大阪大学, 医学(系)研究科(研究院), 教授 (80542563)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 脳神経疾患 / 筋萎縮性側索硬化症 / 痴呆 / カスパーゼ / 細胞死 / 前頭側頭葉変性症 / ネクローシス / アポトーシス

Outline of Final Research Achievements

TDP-43 and its C-terminal fragment of 25 kDa (CTF25) play critical roles in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although overexpression of TDP-43 in cultured cells and animals results in the production of CTF25, the cleavage site that generates CTF25 and biological significance of the cleavage remain undetermined. In this study, we identify Asp174 as a predominant cleavage site for CTF25. TDP-43 is cleaved initially after Asp174, which activates caspase-3/7 to accelerate TDP-43 fragmentation. Consequently, blockage of this cleavage results in a severe delay in TDP-43 clearance and prolonged necrotic cell death. We further show that endoplasmic reticulum membrane-bound caspase-4 is the enzyme responsible for the cleavage after Asp174 and inhibition of caspase-4 activity slows TDP-43 fragmentation and reduces cell viability. These findings suggest that caspase-4-mediated cleavage after Asp174 is an initiator of TDP-43 clearance.

Free Research Field

神経内科