Identification of proteins associated with ATXN8OS-related amyotrophic lateral sclerosis and treatment of iPS cell models

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07984
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Kindai University
• Principal Investigator: Hirano Makito 近畿大学, 医学部, 教授 (50347548)
• Co-Investigator(Kenkyū-buntansha): 竹原 俊幸 近畿大学, 大学病院, 助教 (60580561)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 核酸医薬品 / 筋萎縮性側索硬化症

Outline of Final Research Achievements

This study was aimed to elucidate the pathogenesis of ATXN8OS-related amyotrophic lateral sclerosis (ALS), to establish an iPS cell-derived motor neuron model, and to develop a therapeutic approach. We received tissue samples of pathologically confirmed ALS from the Brain Bank and analyzed their DNA. We identified an ATXN8OS mutation in one patient. In this patient, TDP43 aggregation was found in the anterior horn motoneurons of the spinal cord. In addition, induced pluripotent stem (iPS) cells from another ATXN8OS-related ALS patient were induced into motor neurons. A substantial decrease in the number of viable cells was observed, as compared to normal controls. In situ hybridization using fluorescent probes to detect repetitive sequences revealed intracellular aggregates, which were co-localized with TDP43. For therapeutic intervention, strand-specific siRNAs were expressed, and two siRNAs significantly increased the number of viable cells in patient-derived motor neurons.

Free Research Field

脳神経内科

Academic Significance and Societal Importance of the Research Achievements

今回の研究成果により、ATXN8OS関連ALSは、古典的ALSと共有するTDP43が介在する病態機序が考えられた。また、患者iPS由来運動ニューロンでは、細胞生存率が低下しており、細胞内凝集も再現されたことから、この細胞はALSのモデル細胞として使用できると考えられた。また、遺伝子発現低下を目指したsiRNA導入にて細胞死が減少することから、ATXN8OS変異による毒性が病態に関与していることが示唆された。さらに、モデル細胞をsiRNAにより治療させることができる可能性を示した点で、今後の治療開発に対して、重要な知見であると考えられる。