αシヌクレイン伝播に基づく新規パーキンソン病モデルマウスの作製と病態解析

• Project Area: Prevention of brain protein aging and dementia
• Project/Area Number: 17H05698
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: 高橋 良輔 京都大学, 医学研究科, 教授 (90216771)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: αシヌクレイン / フィブリル伝播 / パーキンソン病 / 遺伝子改変マウス / 多系統萎縮症 / アルファシヌクレイン / モデル動物 / 脳神経疾患

Outline of Annual Research Achievements

PDレビー病理の進展におけるBraak仮説によると、最初期レビー病理は消化管神経叢から脳幹に伝播し、その後上行するとされる。しかし、実験的にこの現象は検証されていなかった。本年度はマウス胃壁にαsynフィブリルを接種することで、脳幹にαsyn凝集病変が形成されることを示した。一側迷走神経を切断することで切断側の凝集病変は消失したため、迷走神経を介して凝集体が伝播したことが示された。一方、数カ月で形成されたαsyn凝集病変は8，12か月後には消退の一途を辿ったことから、この伝播は一過性であり、実験的にはBraak仮説による最初期レビー病理の脳幹からの上向・伝播は示すことができなかった。このことからは、迷走神経背側核からのさらなる病変進展には遺伝要因や環境要因が必要であることが推察された。（Uemura N et al. Mol Neurodegener. 2018）。また、α-Syn BAC(A53T) Tgマウスの線条体にα-Synフィブリルを接種すると、1カ月で中脳黒質のドパミン神経細胞にαsyn凝集病変が形成され、2か月後には約40％の黒質神経細胞死を認めた。本モデルは、急速なαsyn凝集体形成とドパミン神経細胞死をきたす新規のモデルとして前臨床モデルとしての有用性が極めて高いと考えられる（Okuda S et al. in prep）。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Role of Perivascular Oligodendrocyte Precursor Cells in Angiogenesis After Brain Ischemia (2019)
  • Author(s): Kishida Natsue、Maki Takakuni、Takagi Yasushi、Yasuda Ken、Kinoshita Hisanori、Ayaki Takashi、Noro Takayuki、Kinoshita Yusuke、Ono Yuichi、Kataoka Hiroharu、Yoshida Kazumichi、Lo Eng H.、Arai Ken、Miyamoto Susumu、Takahashi Ryosuke
  • Journal Title: Journal of the American Heart Association Volume: 8 Issue: 9
  • DOI: 10.1161/jaha.118.011824
  • NAID: 120006980544
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylated NF-κB subunit p65 aggregates in granulovacuolar degeneration and neurites in neurodegenerative diseases with tauopathy (2019)
  • Author(s): Yamaguchi Yuko、Ayaki Takashi、Li Fangzhou、Tsujimura Atsushi、Kamada Masaki、Ito Hidefumi、Maki Takakuni、Sawamoto Nobukatsu、Urushitani Makoto、Takahashi Ryosuke
  • Journal Title: Neuroscience Letters Volume: 704 Pages: 229-235
  • DOI: 10.1016/j.neulet.2019.03.036
  • Peer Reviewed
• [Journal Article] GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson’s disease (2019)
  • Author(s): Ikuno Masashi、Yamakado Hodaka、Akiyama Hisako、Parajuli Laxmi Kumar、Taguchi Katsutoshi、Hara Junko、Uemura Norihito、Hatanaka Yusuke、Higaki Katsumi、Ohno Kousaku、Tanaka Masaki、Koike Masato、Hirabayashi Yoshio、Takahashi Ryosuke
  • Journal Title: Human Molecular Genetics Volume: 印刷中 Issue: 11 Pages: 1894-1904
  • DOI: 10.1093/hmg/ddz030
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Long-term, open-label, phase 3 study of rasagiline in Japanese patients with early Parkinson’s disease (2019)
  • Author(s): Hattori Nobutaka、Takeda Atsushi、Takeda Shinichi、Nishimura Akira、Kitagawa Tadayuki、Mochizuki Hideki、Nagai Masahiro、Takahashi Ryosuke
  • Journal Title: Journal of Neural Transmission Volume: 126 Issue: 3 Pages: 299-308
  • DOI: 10.1007/s00702-018-1964-3
  • Peer Reviewed / Open Access
• [Journal Article] Long-term safety and efficacy of adjunctive rasagiline in levodopa-treated Japanese patients with Parkinson’s disease (2019)
  • Author(s): Hattori Nobutaka、Takeda Atsushi、Takeda Shinichi、Nishimura Akira、Nakaya Ryou、Mochizuki Hideki、Nagai Masahiro、Takahashi Ryosuke
  • Journal Title: Journal of Neural Transmission Volume: 126 Issue: 3 Pages: 289-297
  • DOI: 10.1007/s00702-018-1962-5
  • Peer Reviewed / Open Access
• [Journal Article] Visually-Rated Medial Temporal Lobe Atrophy with Lower Educational History as a Quick Indicator of Amnestic Cognitive Impairment after Stroke (2019)
  • Author(s): Takahashi Yukako、Saito Satoshi、Yamamoto Yumi、Uehara Toshiyuki、Yokota Chiaki、Sakai Go、Nishida Norifumi、Takahashi Ryosuke、Kalaria Raj N.、Toyoda Kazunori、Nagatsuka Kazuyuki、Ihara Masafumi
  • Journal Title: Journal of Alzheimer's Disease Volume: 67 Issue: 2 Pages: 621-629
  • DOI: 10.3233/jad-180976
  • Peer Reviewed
• [Journal Article] TDP-43 levels are higher in platelets from patients with sporadic amyotrophic lateral sclerosis than in healthy controls (2019)
  • Author(s): Hishizawa Miki、Yamashita Hirofumi、Akizuki Mayumi、Urushitani Makoto、Takahashi Ryosuke
  • Journal Title: Neurochemistry International Volume: 124 Pages: 41-45
  • DOI: 10.1016/j.neuint.2018.12.009
  • Peer Reviewed
• [Journal Article] Amyotrophic Lateral Sclerosis after Receiving the Human Papilloma Virus Vaccine: A Case Report of a 15-year-old Girl (2018)
  • Author(s): Hikiami Ryota、Yamakado Hodaka、Tatsumi Shinsui、Ayaki Takashi、Hashi Yuichiro、Yamashita Hirofumi、Sawamoto Nobukatsu、Tsuji Teruyuki、Urushitani Makoto、Takahashi Ryosuke
  • Journal Title: Internal Medicine Volume: 57 Issue: 13 Pages: 1917-1919
  • DOI: 10.2169/internalmedicine.0285-17
  • NAID: 130007387154
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-07-01
  • Peer Reviewed / Open Access
• [Journal Article] Homozygous 31 trinucleotide repeats in the SCA2 allele are pathogenic for cerebellar ataxia (2018)
  • Author(s): Tojima Maya、Murakami Gaku、Hikawa Rie、Yamakado Hodaka、Yamashita Hirofumi、Takahashi Ryosuke、Matsui Masaru
  • Journal Title: Neurology Genetics Volume: 4 Issue: 6
  • DOI: 10.1212/nxg.0000000000000283
  • Peer Reviewed / Open Access
• [Journal Article] NLRP3 Inflammasome-Related Proteins Are Upregulated in the Putamen of Patients With Multiple System Atrophy (2018)
  • Author(s): Li Fangzhou、Ayaki Takashi、Maki Takakuni、Sawamoto Nobukatsu、Takahashi Ryosuke
  • Journal Title: Journal of Neuropathology & Experimental Neurology Volume: 77 Issue: 11 Pages: 1055-1065
  • DOI: 10.1093/jnen/nly090
  • Peer Reviewed
• [Journal Article] Ser46-Phosphorylated MARCKS Is a Marker of Neurite Degeneration at the Pre-aggregation Stage in PD/DLB Pathology (2018)
  • Author(s): Fujita Kyota、Homma Hidenori、Kondo Kanoh、Ikuno Masashi、Yamakado Hodaka、Tagawa Kazuhiko、Murayama Shigeo、Takahashi Ryosuke、Okazawa Hitoshi
  • Journal Title: eneuro Volume: 5 Issue: 4 Pages: 0217-18
  • DOI: 10.1523/eneuro.0217-18.2018
  • Peer Reviewed / Open Access
• [Journal Article] Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve (2018)
  • Author(s): Uemura Norihito、Yagi Hisashi、Uemura Maiko T.、Hatanaka Yusuke、Yamakado Hodaka、Takahashi Ryosuke
  • Journal Title: Molecular Neurodegeneration Volume: 13 Issue: 1 Pages: 21-21
  • DOI: 10.1186/s13024-018-0257-5
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of adjunctive rasagiline in Japanese Parkinson's disease patients with wearing-off phenomena: A phase 2/3, randomized, double-blind, placebo-controlled, multicenter study (2018)
  • Author(s): Hattori Nobutaka、Takeda Atsushi、Takeda Shinichi、Nishimura Akira、Kato Masafumi、Mochizuki Hideki、Nagai Masahiro、Takahashi Ryosuke
  • Journal Title: Parkinsonism & Related Disorders Volume: 53 Pages: 21-27
  • DOI: 10.1016/j.parkreldis.2018.04.025
  • Peer Reviewed / Open Access
• [Journal Article] Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes (2018)
  • Author(s): Komine Okiru、Yamashita Hirofumi、Fujimori-Tonou Noriko、Koike Masato、Jin Shijie、Moriwaki Yasuhiro、Endo Fumito、Watanabe Seiji、Uematsu Satoshi、Akira Shizuo、Uchiyama Yasuo、Takahashi Ryosuke、Misawa Hidemi、Yamanaka Koji
  • Journal Title: Cell Death & Differentiation Volume: 印刷中 Issue: 12 Pages: 2130-2146
  • DOI: 10.1038/s41418-018-0098-3
  • Peer Reviewed / Open Access
• [Journal Article] Japanese multicenter database of healthy controls for [123I]FP-CIT SPECT (2018)
  • Author(s): Matsuda H, Murata M, Mukai Y, Sako K, Ono H, Toyama H, Inui Y, Taki Y, Shimomura H, Nagayama H, Tateno A, Ono K, Murakami H, Kono A, Hirano S, Kuwabara S, Maikusa N, Ogawa M, Imabayashi E, Sato N, Takano H, Hatazawa J, Takahashi R
  • Journal Title: Eur J Nucl Med Mol Imaging Volume: 45 Issue: 8 Pages: 1405-1416
  • DOI: 10.1007/s00259-018-3976-5
  • Peer Reviewed / Open Access
• [Journal Article] Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy (2018)
  • Author(s): Kaji Seiji、Maki Takakuni、Kinoshita Hisanori、Uemura Norihito、Ayaki Takashi、Kawamoto Yasuhiro、Furuta Takahiro、Urushitani Makoto、Hasegawa Masato、Kinoshita Yusuke、Ono Yuichi、Mao Xiaobo、Quach Tran H.、Iwai Kazuhiro、Dawson Valina L.、Dawson Ted M.、Takahashi Ryosuke
  • Journal Title: Stem Cell Rep Volume: 10 Issue: 2 Pages: 356-365
  • DOI: 10.1016/j.stemcr.2017.12.001
  • NAID: 120006414715
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pericyte-derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion (2017)
  • Author(s): Uemura Maiko T.、Ihara Masafumi、Maki Takakuni、Nakagomi Takayuki、Kaji Seiji、Uemura Kengo、Matsuyama Tomohiro、Kalaria Raj N.、Kinoshita Ayae、Takahashi Ryosuke
  • Journal Title: Brain Pathology Volume: 31 May Issue: 4 Pages: 1-15
  • DOI: 10.1111/bpa.12523
  • NAID: 120006305874
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Zonisamide inhibits monoamine oxidase and enhances motor performance and social activity (2017)
  • Author(s): Uemura Maiko T.、Asano Takeshi、Hikawa Rie、Yamakado Hodaka、Takahashi Ryosuke
  • Journal Title: Neuroscience Research Volume: 124 Pages: 25-32
  • DOI: 10.1016/j.neures.2017.05.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model (2017)
  • Author(s): Kikuchi Tetsuhiro、Morizane Asuka、Doi Daisuke、Magotani Hiroaki、Onoe Hirotaka、Hayashi Takuya、Mizuma Hiroshi、Takara Sayuki、Takahashi Ryosuke、Inoue Haruhisa、Morita Satoshi、Yamamoto Michio、Okita Keisuke、Nakagawa Masato、Parmar Malin、Takahashi Jun
  • Journal Title: Nature Volume: 548 Issue: 7669 Pages: 592-596
  • DOI: 10.1038/nature23664
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] αシヌクレインの凝集・伝播と細胞死 (2017)
  • Author(s): 澤村正典、上村紀仁、高橋良輔
  • Journal Title: 医学のあゆみ Volume: 262 Pages: 585-589
• [Presentation] GBA haploinsufficiency accelerated alpha synuclein pathology with altered lipid metabolism in a premotor model of Parkinson’s disease (2018)
  • Author(s): H. Yamakado, M. Ikuno, H. Akiyama, L. Parajuli, K. Taguchi, J. Hara, N. Uemura, Y. Hatanaka, K. Higaki, M. Tanaka, M. Koike, Y. Hirabayashi, R. Takahashi
  • Organizer: MDS2018, Hongkong
  • Int'l Joint Research
• [Presentation] α-synuclein propagation in brains via olfactory pathway in non-human primate model. (2018)
  • Author(s): 澤村 正典, 尾上浩隆, 上村紀仁, 伊佐正, 高橋良輔
  • Organizer: MDS2018, Hongkong
  • Int'l Joint Research
• [Presentation] Deletion of GBA2 in neuronopathic Gaucher's disease medaka couldn’t rescue the phenotype. (2018)
  • Author(s): Etsuro Nakanishi, Norihito Uemura, Hisako Akiyama, Masato Kinoshita, Hodaka Yamakado, Shunichi Takeda, Yoshio Hirabayashi, Ryosuke Takahashi
  • Organizer: MDS2018, Hongkong
  • Int'l Joint Research
• [Presentation] GBA2 a new modifier for Gauchers’s disease and GBA1-related Parkinson’s disease? (2018)
  • Author(s): Etsuro Nakanishi, Norihito Uemura, Hisako Akiyama, Masato Kinoshita, Hodaka Yamakado, Shunichi Takeda, Yoshio Hirabayashi, Ryosuke Takahashi
  • Organizer: AOCN2018, Seoul
  • Int'l Joint Research
• [Presentation] Inoculation of alpha-synuclein fibrils into the mouse gastrointestinal tract induces Lewy-like pathology in the brain via the vagal nerve (2017)
  • Author(s): 上村紀仁、八木寿梓、髙橋良輔
  • Organizer: 第40回神経科学学会
• [Presentation] The Possible Pathological Interaction Between Oligodendrocyte Precursor Cells and Multiple System Atrophy (2017)
  • Author(s): 梶 誠兒、眞木崇州、上村紀仁、高橋良輔
  • Organizer: 第40回神経科学学会
• [Presentation] Lewy pathology is accelerated in α-Synuclein fibril inoculated α-Synuclein BAC transgenic mice (2017)
  • Author(s): 奥田 真也、上村紀仁、山門穂高、高橋良輔
  • Organizer: 第40回神経科学学会
• [Presentation] αシヌクレイントランスジェニックマウスへのフィブリル脳内接種によるパーキンソン病モデル作製 (2017)
  • Author(s): 奥田 真也、上村紀仁、上村麻衣子、山門穂高、高橋良輔
  • Organizer: 第11回パーキンソン病・運動障害疾患コングレス
• [Presentation] αシヌクレインの消化管から脳幹への伝播について (2017)
  • Author(s): 上村紀仁、髙橋良輔
  • Organizer: 第70回日本自律神経学会総会（JSNR 2017）
• [Presentation] Inoculation of alpha-synuclein fibrils into the mouse gastrointestinal tract induces Lewy-like pathology in the brain via the vagal nerve (2017)
  • Author(s): Norihito Uemura, Maiko T Uemura, Hisashi Yagi, Ryosuke Takahashi
  • Organizer: WCN2017
  • Int'l Joint Research
• [Presentation] A NOVEL MICE MODEL FOR PARKINSON’S DISEASE: FIBRIL-INOCULATED MUTANT α-SYNUCLEIN BAC TRANSGENIC MICE (2017)
  • Author(s): Shinya Okuda, Norihito Uemura, Maiko T Uemura, Hodaka Yamakado, Ryosuke Takahashi
  • Organizer: WCN2017
  • Int'l Joint Research
• [Presentation] 遺伝子改変とαシヌクレイン接種による新規パーキンソン病モデルマウスの開発 (2017)
  • Author(s): 上村紀仁
  • Organizer: ConBio2017
• [Presentation] ΑLPHA-SYNUCLEIN-INDUCED PATHOLOGY OF OLIGODENDROCYTES AND MULTIPLE SYSTEM ATROPHY (2017)
  • Author(s): Seiji Kaji, Takakuni Maki, Norihito Uemura, Ryosuke Takahashi
  • Organizer: The 2nd International Taiwanese Congress of Neurology
  • Int'l Joint Research
• [Presentation] α-Synuclein Preformed Fibrils Induce Disruption of Myelin Basic Protein Expression in Primary Oligodendrocyte Culture Deciphering Glial Pathology in Multiple System Atrophy (2017)
  • Author(s): Seiji Kaji, Takakuni Maki, Norihito Uemura, Ryosuke Takahashi
  • Organizer: International Congress of Parkinson’s Disease and Movement Disorders
  • Int'l Joint Research
• [Presentation] ELUCIDATING ALPHA-SYNUCLEIN PATHOLOGY OF MULTIPLE SYSTEM ATROPHY USING PRIMARY OLIGODENDROCYTE CULTURE (2017)
  • Author(s): Seiji Kaji, Takakuni Maki, Norihito Uemura, Ryosuke Takahashi
  • Organizer: WCN2017
  • Int'l Joint Research