Understanding of defective developmental gene regulation responsible for motor neuron degeneration

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03545
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Nagoya University
• Principal Investigator: Kentaro Sahashi 名古屋大学, 医学部附属病院, 講師 (90710103)
• Co-Investigator(Kenkyū-buntansha): 勝野 雅央 名古屋大学, 医学系研究科, 教授 (50402566) ; 井口 洋平 名古屋大学, 医学部附属病院, 助教 (80790659)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 脊髄性筋萎縮症 / 運動ニューロン / 核酸 / 髄液

Outline of Final Research Achievements

The mechanism of death of spinal motor neurons in SMA remains elusive. Considering a potential developmental component of SMA pathogenesis, we performed gene expression analysis of the neurons isolated from model mouse embryos, and found dysregulation of motor neuron-specific Gene A. Overexpression of Gene A rescued axonal defects and cell death observed in the mouse cell model. Mechanistic analysis using patient iPS cells are ongoing. Next, using patients’ CSFs, we identified a cluster of nucleic acids whose expressions are perturbed in SMA and are partially normalized by treatment; so, these may stand as therapeutic biomarkers. Based on this finding, we further uncovered that genes associated with neuronal development and transmission may confer motor neuron vulnerability in SMA.

Free Research Field

神経内科

Academic Significance and Societal Importance of the Research Achievements

モデルマウスや患者サンプルを用いて、脊髄性筋萎縮症（SMA）の発症機序に迫る、神経関連の遺伝子群の変化が見出されており、重症度を規定する因子の同定や、治療効果を判定する指標の開発に今後つながる可能性がある。さらに患者iPS細胞の活用を通じ、上記遺伝子を標的とした新たな治療法の開発と、この知見が、運動神経細胞が障害される他の疾患に対しても応用されることが期待され、学術的・社会的意義の高い成果が上がっている。