The role of nuclear corepressors in cerebellum and thyroid hormone action

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15340
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Gunma University
• Principal Investigator: Amano Izuki 群馬大学, 大学院医学系研究科, 准教授 (10765275)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: NCoR / 甲状腺ホルモン / 神経発達障害 / 抑制型転写共役因子 / SMRT / 小脳プルキンエ細胞

Outline of Final Research Achievements

Recent reports have indicated that abnormalities in the nuclear corepressor, SMRT (NCoR2), which is crucial for the function of nuclear receptors including thyroid hormone receptors, are a contributing factor to neurodevelopmental disorders. However, the underlying mechanisms remain unclear. In this study, we focused on the cerebellum, which is considered one of the brain regions associated with neurodevelopmental disorders. Mice with a cerebellar Purkinje cell-specific deletion of SMRT did not exhibit any abnormalities in motor coordination but did show abnormalities in social behavior. Furthermore, electrophysiological experiments revealed that SMRT deletion increased spontaneous firing activity and spine density of Purkinje cells. These results indicate that deletion of SMRT in Purkinje cells causes various cerebellar dysfunction by inducing neurophysiological abnormalities.

Free Research Field

内分泌生理

Academic Significance and Societal Importance of the Research Achievements

自閉症スペクトラム障害(ASD)をはじめとする神経発達障害は、発症率の増加に伴い世界的に深刻な社会問題となっている。多因子疾患である一方で、遺伝的素因が大きな要因の一つであるとされる。本研究成果で注目したSMRT(NCoR2)の変異は、ヒトでASD症状を呈することが報告されているが、本研究で作出したマウスモデルでも同様の症状を呈することを明らかにした。また、その行動変容の細胞基盤が小脳プルキンエ細胞の電気生理学的特性の変化に起因していることが明らかとなった。本知見が、現在は有効な治療手段に乏しい神経発達障害の治療アプローチに大きく寄与することが期待できる。