最終更新日2017年02月01日

氏名

サワムラ ナオヤ

澤村 直哉

職名

主任研究員(研究院准教授)

所属研究院(研究機関)/附属機関・学校

(ナノ・ライフ創新研究機構)

連絡先

住所・電話番号・fax番号

住所
〒162-8480新宿区 若松町2-2 早稲田大学 先端生命医科学センター03C309号室
電話番号
03-5369-7327
fax番号
03-5369-7327

URL等

WebページURL

http://asahi-lab.jp/member/staff/sawamura.html

研究者番号
40449351

本属以外の学内所属

学内研究所等

欧州バイオメディカルサイエンス研究所

研究所員 2009年-2011年

ライフサポートイノベーション研究所

研究所員 2014年-2014年

欧州バイオメディカルサイエンス研究所

研究所員 2011年-2012年

欧州バイオメディカルグリーンサイエンス研究所

研究所員 2012年-2014年

欧州バイオメディカルグリーンサイエンス研究所

研究所員 2015年-2016年

グローバルバイオメディカルグリーンサイエンス研究所

研究所員 2016年-2017年

学歴・学位

学歴

-1994年 東京理科大学 理工学部 応用生物科学科
-1996年 筑波大学 医科学研究科 医科学
-2000年 東京大学 医学系研究科 脳神経医学

学位

博士(医学) 課程 東京大学 神経解剖学・神経病理学

経歴

2000年04月-国立長寿医療研究センター 痴呆疾患研究部 臨床研究室
2000年04月-2000年12月長寿科学振興財団 リサーチレジデント
2001年01月-2002年03月科学技術振興事業団 科学技術特別研究員
2002年04月-2003年02月日本学術振興会 科学技術特別研究員
2003年03月-ジョンズホプキンス大学医学部 精神医学部門、Postdoctoral Fellow
2003年03月-2005年03月日本学術振興会 海外特別研究員
2006年07月-早稲田大学 先端科学・健康医療融合研究機構、生命医療工学研究所 講師
2008年10月-早稲田大学 先端科学・健康医療融合研究機構、生命医療工学研究所 准教授
2009年04月-早稲田大学 理工学術院 研究院准教授
2013年04月-早稲田大学 理工学術院 准教授

所属学協会

北米神経科学会

日本神経化学会

受賞

上原記念生命科学財団 研究奨励金

2007年

National Alliance for Research on Schizophrenia & Depression (NARSAD), Young Investigator Award

2005年

研究分野

キーワード

神経化学、神経変性疾患、統合失調症、精神疾患、アルツハイマー病、発達障害、ミトコンドリア

科研費分類

総合生物 / 神経科学 / 神経化学・神経薬理学

研究シーズ

CHRNA7断片を用いたアミロイドß検出法

シーズ分野:ライフサイエンス

研究テーマ履歴

精神神経疾患の分子メカニズムの解明

個人研究

論文

Arctic Aβ40 blocks the nicotine-induced neuroprotective effect of CHRNA7 by inhibiting the ERK1/2 pathway in human neuroblastoma cells.

Ju Ye;Asahi Toru;Sawamura Naoya

Neurochemistry international1102017年-2017年

PubMedDOI

詳細

ISSN:1872-9754

概要::Amyloid β protein (Aβ) plays a central role in Alzheimer's disease (AD) pathogenesis. Point mutations in the Aβ sequence, which cluster around the central hydrophobic core of the peptide, are associated with familial AD (FAD). Several mutations have been identified, with the Arctic mutation exhibiting a purely cognitive phenotype that is typical of AD. Our previous findings suggest that Arctic Aβ40 binds to and aggregates with CHRNA7, thereby inhibiting the calcium response and signaling pathways downstream of the receptor. Activation of CHRNA7 is neuroprotective both in vitro and in vivo. Therefore, in the present study, we investigated whether Arctic Aβ40 affects neuronal survival and/or death via CHRNA7. Using human neuroblastoma SH-SY5Y cells, we found that the neuroprotective function of CHRNA7 is blocked by CHRNA7 knockdown using RNA interference. Furthermore, Arctic Aβ40 blocked the neuroprotective effect of nicotine by inhibiting the ERK1/2 pathway downstream of CHRNA7. Moreover, we show that ERK1/2 activation mediates the neuroprotective effect of nicotine against oxidative stress. Collectively, our findings further our understanding of the molecular pathogenesis of Arctic FAD.

Ohgata, the single Drosophila ortholog of human cereblon, regulates insulin signaling-dependent organismic growth

Wakabayashi, Satoru; Sawamura, Naoya; Sawamura, Naoya; Voelzmann, André; Broemer, Meike; Asahi, Toru; Asahi, Toru; Hoch, Michael

Journal of Biological Chemistry査読有り291(48)p.25120 - 251322016年11月-2016年11月 

PubMedDOIScopusWoS

詳細

ISSN:00219258

概要:© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that is highly conserved in animals and plants. CRBN proteins have been implicated in various biological processes such as development, metabolism, learning, and memory formation, and their impairment has been linked to autosomal recessive non-syndromic intellectual disability and cancer. Furthermore, human CRBN was identified as the primary target of thalidomide teratogenicity. Data on functional analysis of CRBN family members in vivo, however, are still scarce. Here we identify Ohgata (OHGT), the Drosophila ortholog of CRBN, as a regulator of insulin signaling-mediated growth. Using ohgt mutants that we generated by targeted mutagenesis, we show that its loss results in increased body weight and organ size without changes of the body proportions. We demonstrate that ohgt knockdown in the fat body, an organ analogous to mammalian liver and adipose tissue, phenocopies the growth phenotypes. We further show that overgrowth is due to an elevation of insulin signaling in ohgt mutants and to the down-regulation of inhibitory cofactors of circulating Drosophila insulin-like peptides (DILPs), named acid-labile subunit and imaginal morphogenesis protein-late 2. The two inhibitory proteins were previously shown to be components of a heterotrimeric complex with growth-promoting DILP2 and DILP5. Our study reveals OHGT as a novel regulator of insulin-dependent organismic growth in Drosophila.

Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

Takeyoshi Wada, Toru Asahi, Naoya Sawamura

Biochemical and Biophysical Research Communications477(3)p.388 - 3942016年08月-2016年08月 

PubMedDOIScopus

詳細

ISSN:0006291X

概要:© 2016 Elsevier Inc.The gene coding cereblon (CRBN) was originally identified in genetic linkage analysis of mild autosomal recessive nonsyndromic intellectual disability. CRBN has broad localization in both the cytoplasm and nucleus. However, the significance of nuclear CRBN remains unknown. In the present study, we aimed to elucidate the role of CRBN in the nucleus. First, we generated a series of CRBN deletion mutants and determined the regions responsible for the nuclear localization. Only CRBN protein lacking the N-terminal region was localized outside of the nucleus, suggesting that the N-terminal region is important for its nuclear localization. CRBN was also identified as a thalidomide-binding protein and component of the cullin-4-containing E3 ubiquitin ligase complex. Thalidomide has been reported to be involved in the regulation of the transcription factor Ikaros by CRBN-mediated degradation. To investigate the nuclear functions of CRBN, we performed co-immunoprecipitation experiments and evaluated the binding of CRBN to Ikaros. As a result, we found that CRBN was associated with Ikaros protein, and the N-terminal region of CRBN was required for Ikaros binding. In luciferase reporter gene experiments, CRBN modulated transcriptional activity of Ikaros. Furthermore, we found that CRBN modulated Ikaros-mediated transcriptional repression of the proenkephalin gene by binding to its promoter region. These results suggest that CRBN binds to Ikaros via its N-terminal region and regulates transcriptional activities of Ikaros and its downstream target, enkephalin.

Mitochondrial cereblon functions as a Lon-type protease

Kosuke Kataoka, China Nakamura, Toru Asahi, Naoya Sawamura

Scientific Reports査読有り6p.299862016年07月-2016年07月 

PubMedDOIScopus

詳細

ISSN:2045-2322

概要:Lon protease plays a major role in the protein quality control system in mammalian cell mitochondria. It is present in the mitochondrial matrix, and degrades oxidized and misfolded proteins, thereby protecting the cell from various extracellular stresses, including oxidative stress. The intellectual disability-associated and thalidomide-binding protein cereblon (CRBN) contains a large, highly conserved Lon domain. However, whether CRBN has Lon protease-like function remains unknown. Here, we determined if CRBN has a protective function against oxidative stress, similar to Lon protease. We report that CRBN partially distributes in mitochondria, suggesting it has a mitochondrial function. To specify the mitochondrial role of CRBN, we mitochondrially expressed CRBN in human neuroblastoma SH-SY5Y cells. The resulting stable SH-SY5Y cell line showed no apparent effect on the mitochondrial functions of fusion, fission, and membrane potential. However, mitochondrially expressed CRBN exhibited protease activity, and was induced by oxidative stress. In addition, stably expressed cells exhibited suppressed neuronal cell death induced by hydrogen peroxide. These results suggest that CRBN functions specifically as a Lon-type protease in mitochondria.

Cereblon is recruited to aggresome and shows cytoprotective effect against ubiquitin-proteasome system dysfunction.

Sawamura N., Wakabayashi S., Matsumoto K.,Yamada H., Asahi T.

Biochemical and biophysical research communications464(4)p.1054 - 10592015年-2015年

PubMedDOIScopusWoS

詳細

ISSN:1090-2104

概要::Cereblon (CRBN) is encoded by a candidate gene for autosomal recessive nonsyndromic intellectual disability (ID). The nonsense mutation, R419X, causes deletion of 24 amino acids at the C-terminus of CRBN, leading to mild ID. Although abnormal CRBN function may be associated with ID disease onset, its cellular mechanism is still unclear. Here, we examine the role of CRBN in aggresome formation and cytoprotection. In the presence of a proteasome inhibitor, exogenous CRBN formed perinuclear inclusions and co-localized with aggresome markers. Endogenous CRBN also formed perinuclear inclusions under the same condition. Treatment with a microtubule destabilizer or an inhibitor of the E3 ubiquitin ligase activity of CRBN blocked formation of CRBN inclusions. Biochemical analysis showed CRBN containing inclusions were high-molecular weight, ubiquitin-positive. CRBN overexpression in cultured cells suppressed cell death induced by proteasome inhibitor. Furthermore, knockdown of endogenous CRBN in cultured cells increased cell death induced by proteasome inhibitor, compared with control cells. Our results show CRBN is recruited to aggresome and has functional roles in cytoprotection against ubiquitin-proteasome system impaired condition.

Arctic mutant Aß40 aggregates on α7 nicotinic acetylcholine receptors and inhibits their functions

Ye Ju, Toru Asahi and Naoya Sawamura

Journal of Neurochemistry131(5)p.667 - 6742014年12月-2014年

PubMedDOIWoS

詳細

ISSN:0022-3042

概要::Amyloid β protein (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). Point mutations within the Aβ sequence associated with familial AD (FAD) are clustered around the central hydrophobic core of Aβ. Several types of mutations within the Aβ sequence have been identified, and the 'Arctic' mutation (E22G) has a purely cognitive phenotype typical of AD. Previous studies have shown that the primary result of the 'Arctic' mutation is increased formation of Aβ protofibrils. However, the molecular mechanism underlying this effect remains unknown. Aβ42 binds to a neuronal nicotinic acetylcholine receptor subunit, neuronal acetylcholine receptor subunit alpha-7 (CHRNA7), with high affinity and, thus, may be involved in the pathogenesis of AD. Therefore, to clarify the molecular mechanism of Arctic mutation-mediated FAD, we focused on CHRNA7 as a target molecule of Arctic Aβ. We performed an in vitro binding assay using purified CHRNA7 and synthetic Arctic Aβ40, and demonstrated that Arctic Aβ40 specifically bound to CHRNA7. The aggregation of Arctic Aβ40 was enhanced with the addition of CHRNA7. Furthermore, the function of CHRNA7 was detected by measuring Ca(2+) flux and phospho-p44/42 MAPK (ERK1/2) activation. Our results indicated that Arctic Aβ40 aggregation was enhanced by the addition of CHRNA7, which destabilized the function of CHRNA7 via inhibition of Ca(2+) responses and activation of ERK1/2. These findings indicate that Arctic Aβ mutation may be involved in the mechanism underlying FAD. This mechanism may involve binding and aggregation, leading to the inhibition of CHRNA7 functions.

A label-free electrical assay of fibrous amyloid β based on semiconductor biosensing.

Hideshima, S., Kobayashi, M., Wada, T., Kuroiwa, S., Nakanishi, T., Sawamura, N., Asahi T., Osaka, T.

Chemical Communications50(26)p.3476 - 34792014年-2014年

DOIWoS

詳細

ISSN:1359-7345

Construction of photoenergetic mitochondria in cultured mammalian cells

Hara, K. Y., Wada, T., Kino, K., Asahi, T., Sawamura, N.

Scientific Reports3p.16352013年-2013年

DOIWoS

詳細

ISSN:2045-2322

Cereblon accumulates in aggresomes due to proteasome impairment

Wakabayashi, S., Yamada, H., Asahi, T., Sawamura, N.

Journal of Neurochemistry123p.25 - 252012年-

Construction of new energy synthesis system in SH-SY5Y cells: application for the treatment of Parkinson's disease.

Wada, T., Hara, K., Asahi, T., Sawamura, N.

Journal of Neurochemistry123p.24 - 252012年-

The fruitfly Drosophila melanogaster: a promising model to explore molecular psychiatry

Sawamura, N., Ishida, N., Tomoda, T., Hai, T., Furukubo-Tokunaga, K., Sawa, A.

Molecular Psychiatry13p.1069 - 10692008年-

Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly

Sawamura N, Ando T, Maruyama Y, Fujimuro M, Mochizuki H, Honjo K, Shimoda M, Toda H, Sawamura-Yamamoto T, Makuch LA, Hayashi A, Ishizuka K, Cascella NG, Kamiya A, Ishida N, Tomoda T, Hai T, Furukubo-Tokunaga K, Sawa A.

Molecular Psychiatry13p.1138 - 11482008年-

Molecules regulated by patterns of electrical activity

Ozaki, M. Sawamura, N. Ichikawa, M.

Neuroscience Research58p.S1422007年-

DOI

Disrupted-In-Schizophrenia (DISC1): a key susceptibility factor for major mental illnesses

Sawamura N and Sawa A

Annals of the New York Academy of Sciences1086p.126 - 1332006年-

Primate disrupted-in-schizophrenia-1 (DISC1): High divergence of a gene for major mental illnesses in recent evolutionary history.

Bord L., Wheeler J., Paek M., Saleh M., Lyons-Warren A., Ross C.A., Sawamura N., Sawa A.

Neuroscience Research56p.286 - 2932006年-

DISC1からみた統合失調症の分子病態 (特集 統合失調症の分子医学)

疋田 貴俊, 澤村 直哉, 尾関 祐二

細胞37(14)p.573 - 5762005年12月-

Production of DISC1 transgenic and knockout mice

Hikida, T., Sawamura, N., Paek, M., Cascio, M., Sawa, A.

American Journal of Medical Genetics Part B-Neuropsychiatric Genetics138B(1)p.134 - 1352005年09月-

A form of Disrupted-In-Schizophrenia-1 (DISC1) enriched in the nucleus has altered subcellular distribution in schizophrenia brains.

Sawamura N., Sawamura-Yamamoto T., Ozeki Y., Ross C.A., Sawa A

Proceedings of the National Academy of Sciences102p.1187 - 11922005年-

A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development.

Kamiya A., Kubo K., Tomoda T., Takaki M., Youn R., Ozeki Y., Sawamura N., Park U., Kubo C., Okawa M., Ross C.A., Hatten M.E., Nakajima K., Sawa A

Nature Cell Biology7p.1167 - 11782005年-

Disrupted-In-Schizophrenia-1 (DISC1): A promising lead in molecular analyzes of schizophrenia

Sawa A., Sawamura N., Balkissoon R

Clinical Neuroscience Research5p.23 - 302005年-

Modulation of amyloid precursor protein cleavage by cellular sphingolipids

Sawamura N., Ko M., Yu W., Zou K., Hanada K., Suzuki T., Gong J.S., Yanagisawa K., Michikawa M

Journal of Biological Chemistry279p.11984 - 119912004年-

Amyloid beta-protein (Aß)1-40 protects neurons from damage induced by Aß1-42 in culture and in rat brain

Zou K., Kim D., Kakio A., Byun K., Gong J.S., Kim J., Kim M., Sawamura N., Nishimoto S., Matsuzaki K., Lee B., Yanagisawa K., Michikawa M

Journal of Neurochemistry87p.609 - 6192003年-

Promotion of tau phosphorylation by MAP kinase Erk1/2 is accompanied by reduced cholesterol level in detergent-insoluble membrane fraction in Niemann-Pick C1-deficient cells.

Sawamura N., Gong J.S., Chang T.Y., Yanagisawa K., Michikawa M

Journal of Neurochemistry84p.1086 - 10962003年-

統合失調症とDISC1

澤村 直哉、澤 明

実験医学 −脳・神経研究2004, 増刊−21p.2469 - 24732003年-

Amyloid ß-protein affects cholesterol metabolism in cultured neurons: Implications for pivotal role of choleterol in the amyloid cascade.

Gong J.S., Sawamura N., Zou K., Sakai J., Yanagisawa K., Michikawa M.

Neuroscience Research70p.438 - 4462002年-

Apolipoprotein E (apoE)-Isoform-Dependent Lipid Release from Astrocytes Prepared from Human-apoE3- and apoE4-Knock-in Mice

Gong J.S., Kobayashi M., Hayashi H., Zou K., Sawamura N., Fujita S.C., Yanagisawa K., Michikawa M

Journal of Biological Chemsistry277p.29919 - 299262002年-

Cholesterol-dependent modulation of dendrite outgrowth and microtubule stability in cultured neurons

Fan Q.W., Yu W., Gong J.S., Zou K., Sawamura N., Senda T., Yanagisawa K., Michikawa M

Journal of Neurochemistry80p.178 - 1902002年-

A novel action of alzheimer's amyloid beta-protein (Aß): oligomeric Aß promotes lipid release

Michikawa M., Gong J.S., Fan Q.W., Sawamura N., Yanagisawa K

Journal of Neuroscience21p.7226 - 72352001年-

Site-specific phosphorylation of tau accompanied by activation of mitogen-activated protein kinase (MAPK) in brains of Niemann-Pick type C mice

Sawamura N., Gong J.S., Garver W.S., Heidenreich R.A., Ninomiya H., Ohno K., Yanagisawa K. Michikawa M

Journal of Biological Chemistry276p.10314 - 103192001年-

Mutant presenilin 2 transgenic mice: A large increase in the levels of Aß42 is presumably associated with the low density membrane domain that contains decreased levels of glycerophospholipids and sphingomyelin

Sawamura N., Morishima-Kawashima M., Waki H., Kobayashi K., Kuramochi T., Frosch M.P., Ding K., Ito M., Kim T.W., Tanzi R.E., Oyama F., Tabira T., Ando S., Ihara Y

Journal of Biological Chemistry275p.27901 - 279082000年-

Mutant presenilin 2 transgenic mouse: Effect on an age-dependent increase of amyloid ß-protein (Aß) 42 in the brain

Sawamura N., Oyama F., Kobayashi K., Morishima-Kawashima M., Kuramochi T., Ito M., Tomita T., Maruyama K., Saido T.C., Iwatsubo T., Capell A., Walter J., Grunberg J., Ueyama Y., Haass C., Ihara Y (The first three authors contributed equally to this study)

Journal of Neurochemistry71p.313 - 3221998年-

Amyloid ß protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease

Tamaoka A., Sawamura N., Fukushima T., Shoji S., Matsubara E., Shoji M., Hirai S., Furiya Y., Endoh R., Mori H

Journal of Neurological Sciences148p.41 - 451997年-

Characterization of amyloid ß protein species in cerebral amyloid angiopathy of a cynomolgous monkey by immunocytochemistry and enzyme-linked immunosorbent assay

Sawamura N., Tamaoka A., Shoji S., Koo E.H., Walker L.C., Mori H

Brain Research764p.225 - 2291997年-

Deposition of amyloid ß protein (Aß) subtypes [Aß40 and Aß42(43)] in canine senile plaques and cerebral amyloid angiopathy

Nakamura S., Tamaoka A., Sawamura N., Kiatipattanasakul W., Nakayama H., Shoji S., Yoshikawa Y., Doi K

Acta Neuropathol (Berl)94p.323 - 3281997年-

Amyloid ß protein in plasma from patients with sporadic Alzheimer's disease

Tamaoka A., Fukushima T., Sawamura N., Ishikawa K., Oguni E., Komatsuzaki Y., Shoji S

Journal of the Neurological Sciences151p.65 - 681996年-

Amyloid ß protein 1-42/43 (Aß1-42/43) in cerebellar diffuse plaques: enzyme-linked immunosorbent assay and immunocytochemical study

Tamaoka A., Sawamura N., Odaka A., Suzuki N., Mizusawa H., Shoji S., Mori H

Brain Research679p.151 - 1561995年-

Carboxyl end-specific monoclonal antibodies to Amyloid ß protein (Aß) subtypes (Aß40 and Aß42(43)) differentiate Aß in senile plaques and amyloid angiopathy in brains of aged cynomolgus monkeys

Nakamura S., Tamaoka A., Sawamura N., Shoji S., Nakayama H., Ono F., Sakakibara I., Yoshikawa Y., Mori H., Goto N., Doi K

Neuroscience Letters201p.151 - 1541995年-

Biochemical evidence for the long-tail form (Aß1-42/43) of amyloid ß protein as a seed molecule in cerebral deposits of Alzheimer's disease

Tamaoka A., Kondo T., Odaka A., Sahara N., Sawamura N., Ozawa K., Suzuki N., Shoji S., Mori H

Biochemical and Biophysical Research Communications205p.834 - 8421994年-

書籍等出版物

KEYWORD 精神第4版

澤村 直哉, 尾崎美和子 他

先端医学社2007年-

生命科学概論

澤村直哉, 朝日透 他

朝倉書店2012年 04月-

外部研究資金

科学研究費採択状況

研究種別:基盤研究(C)

Arctic AβによるCHRNA7を介したアルツハイマー病発症の分子メカニズム

2015年-2017年

研究分野:神経化学・神経薬理学

配分額:¥4940000

研究種別:若手研究(B)

新規統合失調症候補遺伝子産物CHRNA7の機能解析

2009年-2011年

研究分野:神経化学・神経薬理学

配分額:¥4290000

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