Analysis of motor neuron death focusing on nuclear body abnormality by dipeptide repeat protein

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09749
• 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: Yokoseki Akio 新潟大学, 医歯学総合研究科, 特任准教授 (90515719)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: ALS / Cajal小体 / GGGGCC / TDP-43 / ジペプチドリピート蛋白

Outline of Final Research Achievements

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative motor neuron disease characterized by systemic muscle atrophy and weakness. The cause of motor neuron death in ALS patients has been unclear. Approximately 10% of ALS patients is familial. The abnormal extension of the GGGGCC sequence in the C9orf72 gene on chromosome9 is the most common cause of familial ALS. To elucidate the pathophysiology of ALS, I studied the relationship between abnormal extension of the GGGGCC sequence and Cajal bodies, which is important intranuclear bodies. We used dipeptide repeat protein, glycine-arginine (GR), which was localized in the nucleus. The protein level of Coiled-Body Phosphoprotein 1 (NOLC1), which is a constituent protein of Cajal bodies, was decreased. In the cells with abnormal GR extension , NOLC1 was found to aggregate slightly in the nucleolus. Abnormal extension of GR may induce dysfunction of Cajal bodies.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

ALSは，致死性で治療法がない神経変性疾患であり，いまだに病態についても不明な点が多く，病態解明は極めて重要な医学領域の課題である．今回申請者が解明したGGGGCC配列の異常伸長により転写されるdipeptide repeat proteinによる細胞障害のメカニズムに，核内小体であるCajal小体の機能異常の関与が示された点は，これまで十分に研究されてこなかった知見であり，注目すべき成果であるといえる．また核内小体の機能異常の知見は，ALSだけでなく他の神経変性疾患の解明や神経細胞の正常機能の解明にも応用できる可能性があり，重要な研究結果である．