Therapeutic strategy for ALS with nucleic acid technology focusing on the vulnerability of TDP-43 autoregulation

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09751
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Niigata University
• Principal Investigator: Sugai Akihiro 新潟大学, 脳研究所, 助教 (70758903)
• Co-Investigator(Kenkyū-buntansha): 石原 智彦 新潟大学, 医歯学総合病院, 講師 (70612232)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 筋萎縮性側索硬化症 / TDP-43 / アンチセンスオリゴ

Outline of Final Research Achievements

In amyotrophic lateral sclerosis (ALS), the nuclear protein TDP-43 accumulates in the cytoplasm. TDP-43 binds to its pre-mRNA, induces alternative splicing, and autoregulates its expression levels. Here, we first constructed a mathematical model and predicted that transcriptional redundancy that underpins TDP-43 autoregulation could drive TDP-43 pathology. Then, we used an antisense oligo to suppress TDP-43 alternative splicing and manifested transcriptional redundancy. As a result, in the mouse spinal cord, the increase and fragmentation of insoluble TDP-43 and decrease in the number of motor neurons were observed. These results, which recapitulate part of the ALS pathology, suggested that this alternative splicing could be a promising therapeutic target for ALS.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

筋萎縮性側索硬化症（ALS）は、病理学的にTDP-43の凝集と蓄積によって特徴付けられる。しかし、このTDP-43病理がどのように駆動されているのかはほとんど分かっていない。本研究は、TDP-43量調節に潜在する脆弱性に着目し、遺伝子を改変せずに、マウス脊髄において、TDP-43の病態を模倣させた。これにより、TDP-43量調節に潜在する脆弱性が、ALSの治療標的となる可能性を示した。これらの成果は、難病であるALSの治療法の開発に向けた基盤を提供する。