The study of novel cell pathology of congenital dysplasia of cortical white matter focusing on globally impaired membrane trafficking

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08358
• 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: Li Heng 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, 科研費研究員 (70621994)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 先天性大脳白質形成不全 / カルシウム恒常性 / 細胞内輸送

Outline of Final Research Achievements

Pelizaeus-Merzbacherdisease (PMD) is an X linked recessive leukodystrophy characterized by diffuse hypomyelination in the central nervous system. Missense mutations in the proteolipid protein 1 (PLP1) gene cause misfolded protein accumulating in the ER, leading to ER stress, unfolded protein response（UPR）and apoptosis of oligodendrocytes. However, blockade of the UPR signal pathway cannot suppress apoptosis in mouse model of PMD, which potentially suggest other factors contributing to the pathology of this ER stress-related disease. Here we investigate the impairment of ER-Golgi trafficking as a cellular pathogenesis of PMD. The results of this study suggest that mutant PLP1 protein may alter ER calcium homeostasis to disturb the ER-Golgi transport or membrane trafficking. Elucidating the mechanism of this pathology may contribute to the identification of new therapeutic targets not only for PMD, but also for other diseases involving similar ER stress pathology.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

学術的及び社会的意義は、①これまで検証されていないPelizaeus-Merzbacher病の細胞カルシウム恒常性破綻と細胞内輸送障害に対して、生理機能と病態表現の面で検証することができるということである。②新規細胞病態のメカニズムを解明することにより、当疾患の治療法開発のための基盤になる知見を得ることが出来る点である。③本研究の成果は、新しい治療法の評価手段としても応用できる。