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Faculty of Medicine School of Medicine Department of Medical Sciences, Biochemistry and Molecular Biology |
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Assistant Professor |
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MURAO Naoya
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Research Areas 【 display / non-display 】
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Life Science / Neuroscience-general
Papers 【 display / non-display 】
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The Derlin-1-Stat5b axis maintains homeostasis of adult hippocampal neurogenesis Reviewed
Murao N., Matsuda T., Kadowaki H., Matsushita Y., Tanimoto K., Katagiri T., Nakashima K., Nishitoh H.
EMBO Reports 25 ( 8 ) 3678 - 3706 2024.8
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：EMBO Reports
Adult neural stem cells (NSCs) in the hippocampal dentate gyrus continuously proliferate and generate new neurons throughout life. Although various functions of organelles are closely related to the regulation of adult neurogenesis, the role of endoplasmic reticulum (ER)-related molecules in this process remains largely unexplored. Here we show that Derlin-1, an ER-associated degradation component, spatiotemporally maintains adult hippocampal neurogenesis through a mechanism distinct from its established role as an ER quality controller. Derlin-1 deficiency in the mouse central nervous system leads to the ectopic localization of newborn neurons and impairs NSC transition from active to quiescent states, resulting in early depletion of hippocampal NSCs. As a result, Derlin-1-deficient mice exhibit phenotypes of increased seizure susceptibility and cognitive dysfunction. Reduced Stat5b expression is responsible for adult neurogenesis defects in Derlin-1-deficient NSCs. Inhibition of histone deacetylase activity effectively induces Stat5b expression and restores abnormal adult neurogenesis, resulting in improved seizure susceptibility and cognitive dysfunction in Derlin-1-deficient mice. Our findings indicate that the Derlin-1-Stat5b axis is indispensable for the homeostasis of adult hippocampal neurogenesis.
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Epigenetic regulation of neural stem cell aging in the mouse hippocampus by Setd8 downregulation Reviewed
Matsubara S., Matsuda-Ito K., Sekiryu H., Doi H., Nakagawa T., Murao N., Oda H., Nakashima K., Matsuda T.
EMBO Journal 44 ( 13 ) 3645 - 3668 2025.7
Language：English Publishing type：Research paper (scientific journal) Publisher：EMBO Journal
Neural stem cells (NSCs) in the mammalian brain decline rapidly with age, leading to impairment of hippocampal memory function in later life. However, the relationship between epigenetic remodeling and transcriptional regulation that compromises hippocampal NSC activity during the early stage of chronological aging remains unclear. Here, we performed single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) on NSCs and newly generated neurons across different stages. Integrated data analysis revealed continuous alterations in the chromatin profile of hippocampal NSCs and their progeny from neonatal to mature adult stages, accompanied by consistent changes in transcriptional profiles. Further, decreased expression of Setd8, encoding the enzyme for histone H4 monomethylation at lysine 20 (H4K20me1), underlies age-related changes in mouse hippocampal NSCs. Notably, depletion of Setd8 elicits alterations in gene expression and epigenetic regulation that phenocopy age-related changes, and impairs NSC activity, leading to hippocampal memory deficits. Together, our study provides a global map of longitudinal chromatin and transcriptome changes during brain aging and identifies mechanistic insights into early-onset decline of NSC activity and hippocampal neurogenesis that precedes functional aging.
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特集 ストレス応答の分子メカニズム--最新知見と臨床応用への展望 小胞体ストレス応答の分子機構および疾患治療を見据えた研究の現状と課題 Reviewed
村尾 直哉, 西頭 英起
医学のあゆみ 293 ( 7 ) 594 - 598 2025.5
Publishing type：Research paper (scientific journal) Publisher：医歯薬出版
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Sugiyama T, Murao N, Kadowaki H, Nishitoh H
Scientific reports 12 ( 1 ) 21840 2022.12
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
There are no available therapies targeting the underlying molecular mechanisms of neurodegenerative diseases. Although chaperone therapies that alleviate endoplasmic reticulum (ER) stress recently showed promise in the treatment of neurodegenerative diseases, the detailed mechanisms remain unclear. We previously reported that mice with central nervous system-specific deletion of Derlin-1, which encodes an essential component for ER quality control, are useful as models of neurodegenerative diseases such as spinocerebellar degeneration. Cholesterol biosynthesis is essential for brain development, and its disruption inhibits neurite outgrowth, causing brain atrophy. In this study, we report a novel mechanism by which chemical chaperones ameliorate brain atrophy and motor dysfunction. ER stress was induced in the cerebella of Derlin-1 deficiency mice, whereas the administration of a chemical chaperone did not alleviate ER stress. However, chemical chaperone treatment ameliorated cholesterol biosynthesis impairment through SREBP-2 activation and simultaneously relieved brain atrophy and motor dysfunction. Altogether, these findings demonstrate that ER stress may not be the target of action of chaperone therapies and that chemical chaperone-mediated improvement of brain cholesterol biosynthesis is a promising novel therapeutic strategy for neurodegenerative diseases.
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Takashi Sugiyama, Naoya Murao, Hisae Kadowaki, Keizo Takao, Tsuyoshi Miyakawa, Yosuke Matsushita, Toyomasa Katagiri, Akira Futatsugi, Yohei Shinmyo, Hiroshi Kawasaki, Juro Sakai, Kazutaka Shiomi, Masamitsu Nakazato, Kohsuke Takeda, Katsuhiko Mikoshiba, Hidde L. Ploegh, Hidenori Ichijo, Hideki Nishitoh
iScience 24 ( 7 ) 102758 - 102758 2021.7
Authorship：Lead author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Elsevier BV
Citation: Sugiyama T, Murao N, Kadowaki H, Takao K, Miyakawa T, Matsushita Y, Katagiri T, Futatsugi A, Shinmyo Y, Kawasaki H, Sakai J, Shiomi K, Nakazato M, Takeda K, Mikoshiba K, Ploegh HL, Ichijo H, Nishitoh H. ERAD components Derlin-1 and Derlin-2 are essential for postnatal brain development and motor function. iScience. 2021 Jun 19;24(7):102758. doi: 10.1016/j.isci.2021.102758. PMID: 34355142; PMCID: PMC8324814.
Books 【 display / non-display 】
Presentations 【 display / non-display 】
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精子形成におけるDerlin familyを介した小胞体プロテオスタシスの役割の解明
村尾直哉
第47回日本分子生物学会
Event date： 2024.11.27 - 2024.11.29
Presentation type：Poster presentation
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Homeostasis mechanism of adult neural stem cells regulated by endoplasmic reticulum membrane proteins Invited
Event date： 2024.11.6 - 2024.11.8
Presentation type：Symposium, workshop panel (public)
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小胞体膜タンパク質 Derlin-1 は成体ニューロン新生の維持を介しててんかん発作感受性と認知機能を制御する
村尾直哉
第17回神経発生討論会・第20回成体脳のニューロン新生懇談会 合同大会
Event date： 2024.3.8 - 2024.3.9
Presentation type：Poster presentation
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小胞体膜分子 Derlin-1 による成体神経新生制御を介した脳機能維持機構
村尾直哉
第16回小胞体ストレス研究会
Event date： 2023.9.29 - 2023.9.30
Presentation type：Oral presentation (general)
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An endoplasmic reticulum protein Derlin-1 maintains neural stem cell populations in the adult hippocampus
村尾直哉、西頭英起
第64回 日本神経化学会大会 合同大会
Event date： 2023.7.6 - 2023.7.8
Presentation type：Poster presentation
Awards 【 display / non-display 】
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若手最優秀発表賞
2022.7 小胞体ストレス研究会
村尾直哉
Award type：Award from Japanese society, conference, symposium, etc.
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医学部長奨励賞
2022.3 宮崎大学医学部
村尾直哉
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優秀発表賞
2020.2 成体脳ニューロン新生懇談会
村尾直哉
Award type：Award from Japanese society, conference, symposium, etc.
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若手研究奨励賞
2017.11 臨床ストレス応答学会
村尾直哉
Award type：Award from Japanese society, conference, symposium, etc. Country：Japan
Grant-in-Aid for Scientific Research 【 display / non-display 】
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神経幹細胞の休眠状態の獲得を制御する小胞体品質管理機構の役割
Grant number： 22K06254 2022.04 - 2025.03
独立行政法人日本学術振興会 科学研究費基金 基盤研究(C)
Authorship：Principal investigator
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病態脳における小胞体プロテオスタシス破綻によるコレステロール合成不全と脳萎縮
Grant number：22H02954 2022.04 - 2025.03
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(B)
Authorship：Coinvestigator(s)