Molecular mechanism of alpha-synuclein aggregation in Lewy body disease

• Project/Area Number: 24300131
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Hirosaki University
• Principal Investigator: Wakabayashi Koichi 弘前大学, 医学(系)研究科(研究院), 教授 (50240768)
• Co-Investigator(Kenkyū-buntansha): TANJI Kunikazu 弘前大学, 大学院医学研究科, 助教 (10271800) ; MIKI Yasuo 弘前大学, 大学院医学研究科, 助教 (30709142) ; MORI Fumiaki 弘前大学, 大学院医学研究科, 准教授 (60200383)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2015: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: パーキンソン病 / レビー小体 / オートファジー / 神経変性疾患 / 脳神経疾患 / 神経科学 / 病理学

Outline of Final Research Achievements

In Lewy body disease (LBD), insoluble alpha-synuclein (AS) is widely deposited in the presynaptic terminals as well as in the neuronal cytoplasm. To test the possibility that activated autophagy can degrade abnormal molecules, we investigated the effect of trehalose on abnormal aggregation of AS in a model of LBD. Trehalose is a natural disaccharide composed of two glucose units. Trehalose increased level of the autophagosomal protein LC3, especially a lipidated form LC3-II in cultured cells and mice brain. Also, trehalose increased levels of several chaperon molecules, such as HSP90 and SigmaR1, in the brains of LBD model mice. Further studies revealed that level of detergent insoluble AS was suppressed in mice following oral administration of trehalose, despite an apparent alteration was not observed regarding abnormal aggregation of AS. These results suggest that oral intake of trehalose modulates propensity of molecules prior to aggregation formation.

Research Products

• [Journal Article] G protein-coupled receptor 26 immunoreactivity in intranuclear inclusions associated with polyglutamine and intranuclear inclusion body diseases (2016)
  • Author(s): Mori F, Tanji K, Miki Y, Toyoshima Y, Yoshida M, Kakita A, Takahashi H, Utsumi J, Sasaki H, Wakabayashi K.
  • Journal Title: Neuropathology Volume: 36 Pages: 50-55
  • DOI: 10.1111/neup.12237
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Accumulation of phosphorylated alpha-synuclein in subpial and periventricular astrocytes in multiple system atrophy of long duration (2016)
  • Author(s): Nakamura K, Mori F, Kon T, Tanji K, Miki Y, Tomiyama M, Kurotaki H, Toyoshima Y, Kakita A, Takahashi H, Yamada M, Wakabayashi K.
  • Journal Title: Neuropathology Volume: - Pages: 157-167
  • DOI: 10.1111/neup.12243
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The role of NUB1 in alpha-synuclein degradation in Lewy body disease model mice (2016)
  • Author(s): Tanji K, Miki Y, Maruyama A, Mori F, Mimura J, Itoh K, Kamitani T, Wakabayashi K.
  • Journal Title: Biochemical and Biophysical Research Communications. Volume: 470 Pages: 635-642
  • DOI: 10.1016/j.bbrc.2016.01.093
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Alteration of Upstream Autophagy-Related Proteins (ULK1, ULK2, Beclin1, VPS34 and AMBRA1) in Lewy Body Disease (2016)
  • Author(s): Miki Y, Tanji K, Mori F, Utsumi J, Sasaki H, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Brain Pathol, Volume: - Pages: 359-370
  • DOI: 10.1111/bpa.12297
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] alpha-Synuclein pathology in the cranial and spinal nerves in Lewy body disease (2016)
  • Author(s): Nakamura K, Mori F, Tanji K, Miki Y, Toyoshima Y, Kakita A, Takahashi H, Yamada M, Wakabayashi K.
  • Journal Title: Neuropathology Volume: -
  • DOI: 10.1111/neup.12269
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel eosinophilic neuronal cytoplasmic inclusions in the external cuneate nucleus of humans (2016)
  • Author(s): Ito M, Nakamura K, Mori F, Miki Y, Tanji K, Wakabayashi K.
  • Journal Title: Neuropathology Volume: -
  • DOI: 10.1111/neup.12292
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] p62 Deficiency Enhances α-Synuclein Pathology in Mice. (2015)
  • Author(s): Tanji K, Odagiri S, Miki Y, Maruyama A, Nikaido Y, Mimura J, Mori F, Warabi E, Yanagawa T, Ueno S, Itoh K, Wakabayashi K.
  • Journal Title: Brain Pathol Volume: 印刷中 Pages: 552-564
  • DOI: 10.1111/bpa.12214
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Isopentenyl diphosphate isomerase, a cholesterol synthesizing enzyme, is localized in Lewy bodies (2015)
  • Author(s): Nakamura K, Mori F, Tanji K, Miki Y, Yamada M, Kakita A, Takahashi H, Utsumi J, Sasaki H, Wakabayashi K
  • Journal Title: Neuropathology Volume: 35 Pages: 432-440
  • DOI: 10.1111/neup.12204
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Localization of nuclear receptor subfamily 4, group A, member 3 (NR4A3) in Lewy body disease and multiple system atrophy (2015)
  • Author(s): Kon T, Miki Y, Tanji K, Mori F, Tomiyama M, Toyoshima Y, Kakita A, Takahashi H, Utsumi J, Sasaki H, Wakabayashi K
  • Journal Title: Neuropathology Volume: 35 Pages: 503-509
  • DOI: 10.1111/neup.12210
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Filamentous aggregations of phosphorylated α-synuclein in Schwann cells (Schwann cell cytoplasmic inclusions) in multiple system atrophy (2015)
  • Author(s): Nakamura K, Mori F, Kon T, Tanji K, Miki Y, Tomiyama M, Kurotaki H, Toyoshima Y, Kakita A, Takahashi H, Yamada M, Wakabayashi K
  • Journal Title: Acta Neuropathol Comm Volume: 3 Pages: 29-29
  • DOI: 10.1186/s40478-015-0208-0
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Trehalose intake induces chaperone molecules along with autophagy in a mouse model of Lewy body disease. (2015)
  • Author(s): Tanji K, Miki Y, Maruyama A, Mimura J, Matsumiya T, Mori F, Imaizumi T, Itoh K, Wakabayashi K.
  • Journal Title: Biochemical and Biophysical Research Communications. Volume: 465 Pages: 746-752
  • DOI: 10.1016/j.bbrc.2015.08.076
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Sortilin-related receptor CNS expressed 2 (SorCS2) is localized to Bunina bodies in amyotrophic lateral sclerosis (2015)
  • Author(s): Mori F, Miki Y, Tanji K, Kakita A, Takahashi H, Utsumi J, Sasaki H, Wakabayashi K.
  • Journal Title: Neurosci Lett Volume: 608 Pages: 6-11
  • DOI: 10.1016/j.neulet.2015.09.030
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] FUS colocalizes with polyglutamine, but not with TDP-43 in neuronal intranuclear inclusions in spinocerebellar ataxia type 2 (2014)
  • Author(s): Mori F, Toyoshima Y, Tanji K, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Neuropathol Appl Neurobiol Volume: 40 Pages: 351-355
  • DOI: 10.1111/nan.12075
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Ubiquitin-negative, eosinophilic neuronal cytoplasmic inclusions associated with stress granules and autophagy: an immunohistochemical investigation of two cases. (2014)
  • Author(s): Mori F, Watanabe Y, Miki Y, Tanji K, Eto K, Wakabayashi K.
  • Journal Title: Neuropathology Volume: 34 Pages: 140-147
  • DOI: 10.1111/neup.12075
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Accumulation of the sigma-1 receptor is common to neuronal nuclear inclusions in various neurodegenerative diseases (2014)
  • Author(s): Miki Y, Mori F, Kon T, Tanji K, Toyoshima Y, Yoshida M, Sasaki H, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Neuropathology Volume: 34 Pages: 148-158
  • DOI: 10.1111/neup.12080
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An autopsy case of incipient Pick’s disease: Immunohistochemical profile of early-stage Pick body formation (2014)
  • Author(s): Miki Y, Mori F, Tanji K, Kurotaki H, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Neuropathology Volume: 34 Pages: 386-391
  • DOI: 10.1111/neup.12104
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An autopsy case of meningeal carcinomatosis with parenchymal invasion through the cranial and spinal nerve roots (2014)
  • Author(s): Kon T, Funamizu Y, Miki Y, Tomiyama M, Baba M, Kurotaki H, Wakabayashi K
  • Journal Title: Neuropathology Volume: 34 Pages: 499-503
  • DOI: 10.1111/neup.12127
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phosphorylation of serine 349 of p62 in Alzheimer’s disease brain (2014)
  • Author(s): Tanji K, Miki Y, Ozaki T, Maruyama A, Yoshida H, Mimura J, Matsumiya T, Mori F, Imaizumi T, Itoh K, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Acta Neuropathol Commun Volume: 2 Pages: 1-14
  • DOI: 10.1186/2051-5960-2-50
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Sigma-1 receptor is involved in degradation of intranuclear inclusions in a cellular model of Huntington’s disease (2014)
  • Author(s): Miki Y, Tanji K, Mori F, Wakabayashi K
  • Journal Title: Neurobiol Dis Volume: 74 Pages: 25-31
  • DOI: 10.1016/j.nbd.2014.11.005
  • NAID: 120005822595
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Analysis of microRNA from archived formalin-fixed paraffin-embedded specimens of amyotrophic lateral sclerosis (2014)
  • Author(s): Wakabayashi K, Mori F, Kakita A, Takahashi H, Utsumi J, Sasaki H
  • Journal Title: Acta neuropathologica communications Volume: 2 Pages: 173-173
  • DOI: 10.1186/s40478-014-0173-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and neuronal nuclear inclusions in polyglutamine and intranuclear inclusion body diseases. (2014)
  • Author(s): Kon T, Mori F, Yanji F, Miki Y, Toyoshima Y, Yoshida M, Sasaki H, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Neuropathology Volume: 34 Pages: 19-26
  • DOI: 10.1111/neup.12056
  • Peer Reviewed
• [Journal Article] Co-localization ofBunina bodies and TDP-43 inclusionsin lower motor neurons in amyotrophiclateral sclerosis (2014)
  • Author(s): Mori F, Kakita A, Takahashi H,Wakabayashi K
  • Journal Title: Neuropathology Volume: 34 Pages: 71-76
  • DOI: 10.1111/neup.12044
  • Peer Reviewed
• [Journal Article] Lysosomal storage and advanced senescence in the brain of LAMP-2-deficient Danon disease (2013)
  • Author(s): Furuta A, Wakabayashi K, Haratake J, Kikuchi H, Kabuta T, Mori F, Tokonami F, Katsumi Y, Tanioka F, Uchiyama Y, Nishino I, Wada K
  • Journal Title: Acta Neuropathol. Volume: 125 Pages: 459-461
  • DOI: 10.1007/s00401-012-1075-4
  • Peer Reviewed
• [Journal Article] Valosin-containing protein immunoreactivity in tauopathies, synucleinopathies, polyglutamine diseases and intranuclear inclusion body disease (2013)
  • Author(s): Mori F, Tanji K, Toyoshima Y, Sasaki H, Yoshida M, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Neuropathology Volume: 33 Pages: 637-644
  • DOI: 10.1111/neup.12050
  • Peer Reviewed
• [Journal Article] An autopsy case of preclinical multiple system atrophy (MSA-C) (2013)
  • Author(s): Kon T, Mori F, Tanji K, Miki Y, Wakabayashi K
  • Journal Title: Neuropathology Volume: 33 Pages: 667-672
  • DOI: 10.1111/neup.12037
  • Peer Reviewed
• [Journal Article] Brain expression level and activity of HDAC6 protein in neurodegenerative dementia. (2013)
  • Author(s): Odagiri S, Tanji K, Mori F, Miki Y, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 430 Pages: 394-399
  • DOI: 10.1016/j.bbrc.2012.11.034
  • Peer Reviewed
• [Journal Article] Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases (2013)
  • Author(s): Tanji K, Maruyama A, Odagiri S, Mori F, Itoh K, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Journal of Neuropathology & Experimental Neurology Volume: 72 Pages: 18-28
  • DOI: 10.1097/nen.0b013e31827b5713
  • Peer Reviewed
• [Journal Article] Ubiquilin immunoreactivity in cytoplasmic and nuclear inclusions in synucleinopathies, polyglutamine diseases and intranuclear inclusion body disease (2012)
  • Author(s): Mori F, Tanji K, Odagiri S, Toyoshima Y, Yoshida M, Ikeda T, Sasaki H, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: ActaNeuropathol Volume: 124 Pages: 149-151
  • DOI: 10.1007/s00401-012-0999-z
  • Peer Reviewed
• [Journal Article] Endosomal sorting related protein CHMP2B is localized in Lewy bodies and glial cytoplasmic inclusions in alpha-synucleinopathy (2012)
  • Author(s): Tanikawa S, Mori F, Tanji K, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Neurosci Lett Volume: 527 Pages: 16-21
  • DOI: 10.1016/j.neulet.2012.08.035
  • Peer Reviewed
• [Journal Article] Alteration of autophagosomal proteins in the brain of multiple system atrophy (2012)
  • Author(s): Tanji K, Odagiri S, Maruyama A, Mori F, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Neurobiology of Disease Volume: 49C Pages: 190-198
  • DOI: 10.1016/j.nbd.2012.08.017
  • Peer Reviewed
• [Presentation] ポリグルタミン病ならびに核内封入体病におけるGタンパク質共役受容体GPR26の局在 (2015)
  • Author(s): 森 文秋、丹治邦和、三木康生、豊島靖子、吉田眞理、柿田明美、高橋 均、内海 潤、佐々木秀直、若林孝一
  • Organizer: 第56回日本神経病理学会総会学術研究会
  • Place of Presentation: 九州大学医学部百年講堂（福岡県・福岡市）
  • Year and Date: 2015-06-03
• [Presentation] オートファジー関連タンパク質（ULK1、ULK2、VPS34、AMBRA1）はレビー小体の形成過程に関与している (2015)
  • Author(s): 三木康生、丹治邦和、森文秋、柿田明美、高橋均、内海潤、佐々木秀直、若林孝一
  • Organizer: 第56回日本神経病理学会総会学術研究会
  • Place of Presentation: 九州大学医学部百年講堂（福岡県・福岡市）
  • Year and Date: 2015-06-03
• [Presentation] Neuron derived orphan receptor-1はシヌクレイノパチーの封入体に局在する (2015)
  • Author(s): 今 智矢、三木康生、丹治邦和、森 文秋、冨山誠彦、豊島靖子、柿田明美、高橋 均、内海 潤、佐々木秀直、若林孝一
  • Organizer: 第56回日本神経病理学会総会学術研究会
  • Place of Presentation: 九州大学医学部百年講堂（福岡県・福岡市）
  • Year and Date: 2015-06-03
• [Presentation] Schwann細胞にリン酸化αシヌクレインの蓄積を認めた多系統萎縮症の1剖検例 (2015)
  • Author(s): 中村桂子、森文秋、今智矢、丹治邦和、三木康生、冨山誠彦、黒滝日出一、山田正仁、柿田明美、高橋均、若林孝一
  • Organizer: 第56回日本神経病理学会総会学術研究会
  • Place of Presentation: 九州大学医学部百年講堂（福岡県・福岡市）
  • Year and Date: 2015-06-03
• [Presentation] Sigma-1 receptorの蓄積は種々の神経変性疾患の核内封入体に共通する (2014)
  • Author(s): 三木康生、森文秋、今智矢、丹治邦和、豊島靖子、吉田眞理、佐々木秀直、柿田明美、高橋均、若林孝一
  • Organizer: 第55回日本神経病理学会
  • Place of Presentation: 学術総合センター（東京）
  • Year and Date: 2014-06-05 – 2014-06-07
• [Presentation] オートファジー/ストレス顆粒関連蛋白陽性のエオジン好性封入体 (2014)
  • Author(s): 森文秋、渡辺柚香、三木康生、丹治邦和、小田桐紗織、衛藤光明、若林孝一
  • Organizer: 第55回日本神経病理学会
  • Place of Presentation: 学術総合センター（東京）
  • Year and Date: 2014-06-05 – 2014-06-07
• [Presentation] MSAとオートファジー (2014)
  • Author(s): 若林孝一
  • Organizer: 第55回日本神経学会
  • Place of Presentation: 福岡国際会議場（福岡市）
  • Year and Date: 2014-05-21 – 2014-05-24
  • Invited
• [Presentation] FIG4は、ピック小体、レヴィ小体およびポリグルタミン病と核内封入体病における核内封入体に局在する (2014)
  • Author(s): 今智矢、森文秋、丹治邦和、三木康生、豊島靖子、柿田明美、吉田眞理、佐々木秀直、高橋均、若林孝一
  • Organizer: 第55回日本神経学会
  • Place of Presentation: 福岡国際会議場（福岡市）
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] 神経変性疾患におけるユビキリンの免疫組織化学的検討 (2013)
  • Author(s): 森文秋、丹治邦和、豊島靖子、佐々木秀直、吉田眞理、柿田明美、高橋均、若林孝一
  • Organizer: 第54回日本神経病理学会
  • Place of Presentation: タワーホール船橋（東京都）
• [Presentation] 神経変性疾患におけるvalosin-containing proteinの免疫組織化学的検討 (2013)
  • Author(s): 森文秋、丹治邦和、豊島靖子、佐々木秀直、吉田眞理、柿田明美、高橋均、若林孝一
  • Organizer: 第54回日本神経病理学会
  • Place of Presentation: タワーホール船橋（東京都）
• [Presentation] 神経変性疾患脳におけるユビキチンリガーゼKeap1の解析 (2013)
  • Author(s): 丹治邦和、丸山敦史、小田桐紗織、森文秋、伊東健、柿田明美、高橋均、若林孝一
  • Organizer: 第54回日本神経病理学会
  • Place of Presentation: タワーホール船橋（東京都）
• [Presentation] 発症前の多系統萎縮症（MSA-C）の１剖検例 (2013)
  • Author(s): 今智矢、森文秋、丹治邦和、三木康生、若林孝一
  • Organizer: 第54回日本神経病理学会
  • Place of Presentation: タワーホール船橋（東京都）
• [Presentation] レビー小体型認知症における病変の拡大進展機構 (2012)
  • Author(s): 若林孝一
  • Organizer: 第31回日本認知症学会
  • Place of Presentation: つくば国際会議場(つくば市)(招待講演)
  • Year and Date: 2012-10-26
• [Presentation] 神経変性疾患におけるautophagic adapter protein (NBRl)の関与 (2012)
  • Author(s): 小田桐紗織, ほか
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 朱鷺メッセ(新潟市)
  • Year and Date: 2012-06-30
• [Presentation] レビー小体病おけるオートファゴソーム関連タンパク質の変化 (2012)
  • Author(s): 丹治邦和, ほか
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 朱鷺メッセ(新潟市)
  • Year and Date: 2012-06-29
• [Presentation] 多系統萎縮症におけるオートファゴソーム関連タンパク質の変化 (2012)
  • Author(s): 丹治邦和, ほか
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 朱鷺メッセ(新潟市)
  • Year and Date: 2012-06-29
• [Book] Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging (2014)
  • Author(s): Tanji K, Mori F, Wakabayashi K
  • Total Pages: 398
  • Publisher: Elsevier
• [Patent(Industrial Property Rights)] オートファジーを調節するマイクロRNA (2014)
  • Inventor(s): 若林孝一、佐々木秀直、内海潤
  • Industrial Property Rights Holder: 若林孝一、佐々木秀直、内海潤
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-09-11
  • Acquisition Date: 2015-03-19
  • Overseas
• [Patent(Industrial Property Rights)] オートファジーを調節するマイクロRNA (2013)
  • Inventor(s): 佐々木秀直、内海潤、若林孝一
  • Industrial Property Rights Holder: 佐々木秀直、内海潤、若林孝一
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-09-11