Analysis using direct reprogramming method for congenital hypomyelinating leukodystrophy

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K08270
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Tohoku University
• Principal Investigator: Uematsu Mitsugu 東北大学, 医学系研究科, 准教授 (90400316)
• Co-Investigator(Kenkyū-buntansha): 植松 有里佳 (沼田有里佳) 東北大学, 大学病院, 助教 (70735779)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 先天性大脳白質形成不全症 / ミトコンドリア / 低分子RNA / Direct reprogramming

Outline of Final Research Achievements

Abnormalities in small RNAs have been reported as a cause of congenital hypomyelinating leukodystrophy, but the pathogenesis is unknown. In this study, we used two methods to analyze the pathogenesis of the disease. First, we used direct reprogramming, a simple method to induce differentiation of fibroblasts into neurons, and found that the neurons in the case were less differentiated than those in controls and apoptotic at an early stage. In addition, we performed knockdown analysis of low-molecular-weight RNA-related genes such as PNPT1 and POLR3A using an early culture method of rat spinal dorsal root ganglion cells, and confirmed that myelination and axonal growth defects occur. We plan to apply these experimental analysis methods to the search for treatment methods in the future.

Free Research Field

小児神経学

Academic Significance and Societal Importance of the Research Achievements

本研究の学術的独自性について、まず低分子RNA の異常が大脳白質形成不全症に関連す
ることをPNPT1遺伝子変異症例の線維芽細胞を用いた解析によって明らかにしたことである。さらに、iPS細胞などと比較して簡便なDirect reprogramming法を用いて解析する系を確立できたことが、今後の大脳白質形成不全症の機能解析や、治療法の探索にも役立つ。
低分子RNAの異常に関与するPOLR3A,POLR3B遺伝子異常は症例数も多いため、本研究により神経細胞の異常が起こること確認できたことは、臨床へのインパクトも大きい。