Pathological and therapeutic research of sporadic ALS

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08077
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Veterinary medical science
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Morimura Toshifumi 滋賀医科大学, 神経難病研究センター, 助教 (20333338)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: TDP-43 / ALS / ノックダウン / 細胞質凝集体 / SOD1 / VHL

Outline of Final Research Achievements

Cytoplasmic mis-aggregation and nuclear-loss of TAR DNA binding protein of 43KDa (TDP-43) are observed in the lesions of sporadic amyotrophic lateral sclerosis (ALS). To understand a mechanism how nuclear-loss of TDP-43 involves in the pathogenesis of sporadic ALS, transcriptome analysis was performed. I found a gene whose transcript and translation products are drastically reduced in the TDP-43 silenced HeLa and HEK293A cells. The gene product preferentially associated with aggregated TDP-43 species and superoxide dismutase (SOD1) mutants with mutations related to familial ALS, and it was also co-precipitated with von Hipple-Lindau (VHL), a substrates recognition unit of Cullin-2 E3 ligase complex, which had been identified as an E3 of C-terminal truncated TDP-43 and ALS associated SOD1 mutants. These results suggest that the TDP-43 deficiency may associate with clearance of misfolded TDP-43 and SOD1 through regulating VHL.

Free Research Field

分子神経科学

Academic Significance and Societal Importance of the Research Achievements

孤発性ALSは、 原因蛋白質であるTDP-43の凝集塊形成による蛋白質毒性とその機能不全により引き起こされるものと考えられている。本研究期間に、TDP-43により発現制御を受ける遺伝子産物の一つが、高凝集性TDP-43や家族性ALSの原因蛋白質による凝集塊に共局在し、これら異常蛋白質の除去に関与している可能性を見出した。即ち、異常蛋白質からの毒性とTDP-43の機能不全はそれぞれ異なる分子メカニズムによりALSの病理基盤を形成すると考えられてきたが、本研究により共通のプレイヤーが存在する可能性が示唆された。