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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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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
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Np95/Uhrf1 regulates tumor suppressor gene expression of neural stem/precursor cells, contributing to neurogenesis in the adult mouse brain. Reviewed
Murao N, Matsubara S, Matsuda T, Noguchi H, Mutoh T, Mutoh M, Koseki H, Namihira M, Nakashima K
Neuroscience research 143 31 - 43 2019.6
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)
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Kimura A., Matsuda T., Sakai A., Murao N., Nakashima K.
Developmental Dynamics 247 ( 1 ) 229 - 238 2018.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Developmental Dynamics
© 2017 Wiley Periodicals, Inc. Background: Although quiescent neural stem cells (NSCs) in the adult hippocampus proliferate in response to neurogenic stimuli and subsequently give rise to new neurons continuously throughout life, misregulation of NSCs in pathological conditions, including aging, leads to the impairment of learning and memory. High mobility group B family 1 (HMGB1) and HMGB2, HMG family proteins that function as transcriptional activators through the modulation of chromatin structure, have been assumed to play some role in the regulation of adult NSCs; however, their precise functions and even expression patterns in the adult hippocampus remain elusive. Results: Here we show that expression of HMGB2 but not HMGB1 is restricted to the subset of NSCs and their progenitors. Furthermore, running, a well-known positive neurogenic stimulus, increased the proliferation of HMGB2-expressing cells, whereas aging was accompanied by a marked decrease in these cells. Intriguingly, HMGB2-expressing quiescent NSCs, which were shifted toward the proliferative state, were decreased as aging progressed. Conclusions: HMGB2 expression is strongly associated with transition from the quiescent to the proliferative state of NSCs, supporting the possibility that HMGB2 is involved in the regulation of adult neurogenesis and can be used as a novel marker to identify NSCs primed for activation in the adult hippocampus. Developmental Dynamics 247:229–238, 2018. © 2017 Wiley Periodicals, Inc.
DOI： 10.1002/dvdy.24559
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)