Modeling and Phenotypic analysis of Pelizaeus-Merzbacher disease using patient-derived iPS cells

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08265
• 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: National Center of Neurology and Psychiatry
• Principal Investigator: Suzuki Sadafumi 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 疾病研究第二部, リサーチフェロー (70465003)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 病態再現 / iPS細胞 / 先天性大脳白質形成不全症 / オリゴデンドロサイト

Outline of Final Research Achievements

To address cellular pathology of PMD more precisely, we have been generating human induced pluripotent stem cells (hiPSCs) from patients with PMD harboring PLP1 duplication and aim to differentiate them into oligodendrocytes to recapitulate the cellular pathology of PMD in culture.
At this point we have generated hiPSCs from 4 PMD patients. In the early differentiation phase of OL, we observed increase of reactive oxygen species (ROS) accumulation and a partially depolarized inner mitochondrial membrane in OLs in a PMD-derived hiPSC line comparison with a normal control. Also we observed ROS accumulation in oligodendrocyte precursor cells (OPCs). We found abnormalities of process number and length of OPCs.
These findings suggest that the cellular phenotypes of PMD-derived hiPSCs may occur at early stage of OL differentiation, which is earlier than previously thought.

Free Research Field

神経変性疾患

Academic Significance and Societal Importance of the Research Achievements

PLP1重複変異によるPMDの病態理解における大きな疑問は、なぜ野生型PLP1の発現量が1コピー分増加しただけで重篤な髄鞘化不全を来すのか、という点であり、その機序は変異の発見から四半世紀経っても全く分かっていなかった。適切な病態解析ツールがなかったという点が大きな要因であったが、疾患特異的iPS細胞を用いることで、病態モデルの構築、PLP1遺伝子重複変異が及ぼす細胞病態解析が可能となった。前駆細胞から蓄積する活性酸素が病態の分子機序に関係する可能性を見出したことで、本疾患の細胞病態の一端を捉えることができたと考える。