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

Research Project

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
Project Status	Completed (Fiscal Year 2022)
Budget Amount *help	¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000) Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords	神経障害 / サイクロプリン / 酸化的DNA損傷 / 修復欠損 / 色素性乾皮症 / 脳オルガノイド / DNA修復欠損
Outline of Research at the Start	DNA修復欠損遺伝病である色素性乾皮症A群（XP-A）は運動失調や知能低下など進行性の神経障害を発症するが、その機序は不明である。本研究では、XP-A患者剖検脳やXpaマウス脳での損傷解析に加え、XP-A患者由来iPS細胞から作製した脳オルガノイドを長期培養する系を用い、進行性の神経変性が酸化的DNA損傷サイクロプリンの経時的蓄積により引き起こされるか検証する。
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.
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。