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The Derlin-1-Stat5b axis maintains homeostasis of adult hippocampal neurogenesis 査読あり
Murao N., Matsuda T., Kadowaki H., Matsushita Y., Tanimoto K., Katagiri T., Nakashima K., Nishitoh H.
EMBO Reports 25 ( 8 ) 3678 - 3706 2024年8月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年12月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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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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 H.L., Ichijo H., Nishitoh H.
iScience 24 ( 7 ) 102758 - 102758 2021年7月
担当区分：筆頭著者 記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：iScience
Derlin family members (Derlins) are primarily known as components of the endoplasmic reticulum-associated degradation pathway that eliminates misfolded proteins. Here we report a function of Derlins in the brain development. Deletion of Derlin-1 or Derlin-2 in the central nervous system of mice impaired postnatal brain development, particularly of the cerebellum and striatum, and induced motor control deficits. Derlin-1 or Derlin-2 deficiency reduced neurite outgrowth in vitro and in vivo and surprisingly also inhibited sterol regulatory element binding protein 2 (SREBP-2)-mediated brain cholesterol biosynthesis. In addition, reduced neurite outgrowth due to Derlin-1 deficiency was rescued by SREBP-2 pathway activation. Overall, our findings demonstrate that Derlins sustain brain cholesterol biosynthesis, which is essential for appropriate postnatal brain development and function.
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Np95/Uhrf1 regulates tumor suppressor gene expression of neural stem/precursor cells, contributing to neurogenesis in the adult mouse brain. 査読あり
Murao N, Matsubara S, Matsuda T, Noguchi H, Mutoh T, Mutoh M, Koseki H, Namihira M, Nakashima K
Neuroscience research 143 31 - 43 2019年6月
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Kimura A., Matsuda T., Sakai A., Murao N., Nakashima K.
Developmental Dynamics 247 ( 1 ) 229 - 238 2018年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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
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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
開催年月日： 2024年11月27日 - 2024年11月29日
会議種別：ポスター発表
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小胞体膜タンパク質が制御する成体神経幹細胞の恒常性維持機構 招待あり
村尾直哉
第97回日本生化学大会
開催年月日： 2024年11月6日 - 2024年11月8日
会議種別：シンポジウム・ワークショップ パネル（公募）
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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
開催年月日： 2024年3月8日 - 2024年3月9日
会議種別：ポスター発表
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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
開催年月日： 2023年9月29日 - 2023年9月30日
会議種別：口頭発表（一般）
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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
開催年月日： 2023年7月6日 - 2023年7月8日
会議種別：ポスター発表
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若手最優秀発表賞
2022年7月 小胞体ストレス研究会
村尾直哉
受賞区分：国内学会・会議・シンポジウム等の賞
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医学部長奨励賞
2022年3月 宮崎大学医学部
村尾直哉
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優秀発表賞
2020年2月 成体脳ニューロン新生懇談会
村尾直哉
受賞区分：国内学会・会議・シンポジウム等の賞
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若手研究奨励賞
2017年11月 臨床ストレス応答学会
村尾直哉
受賞区分：国内学会・会議・シンポジウム等の賞 受賞国：日本国
科研費（文科省・学振・厚労省）獲得実績 【 表示 ／ 非表示 】
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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
研究課題/領域番号： 22K06254 2022年04月 - 2025年03月
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)
担当区分：研究代表者
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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
研究課題/領域番号：22H02954 2022年04月 - 2025年03月
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)
担当区分：研究分担者