Mechanism analyses of progressive neurological diseases in xeroderma pigmentosum group A patients using their iPSCs-derived cerebral organoids

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K12168
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 63020:Radiation influence-related
• Research Institution: Nara Medical University
• Principal Investigator: Mori Toshio 奈良県立医科大学, 医学部, 研究員 (10115280)
• Co-Investigator(Kenkyū-buntansha): 森 英一朗 奈良県立医科大学, 医学部, 准教授 (70803659) ; 松井 健 島根大学, 学術研究院医学・看護学系, 特任講師 (90528605)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 神経障害 / サイクロプリン / 酸化的DNA損傷 / 修復欠損

Outline of Final Research Achievements

Xeroderma pigmentosum group A (XP-A) is a genetic disorder associated with defects in the nucleotide excision repair pathway which eliminates various helix-distorting DNA lesions. XP-A patients develop progressive neurological disease. To understand the mechanism, we studied the involvement of oxidatively generated DNA damage (cyclopurine; cyclo-dA) in neurological degeneration using cerebral organoids from XP-A-derived iPSCs. However, this study was not completed because of withdrawal of the co-investigator responsible for organoid generation. Cyclo-dA levels in brains were then measured by the immunological assay. There were more cyclo-dA lesions in Xpa mice than wild-type mice at 12 and 26 months of age. Autopsy analysis of an XP-A brain revealed the cyclo-dA levels are low at sites with atrophy, but high at a less atrophic site.

Free Research Field

放射線・化学物質影響科学

Academic Significance and Societal Importance of the Research Achievements

色素性乾皮症患者の神経障害発症機序として、酸化的DNA損傷サイクロプリンの関与説を補強する。これはヒト老化の機序としても適応できると考えられる。