Propagation of prion-like proteins and cellular responses

• Project/Area Number: 15H02356
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: HASEGAWA Masato 公益財団法人東京都医学総合研究所, 認知症・高次脳機能研究分野, 分野長 (10251232)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥43,680,000 (Direct Cost: ¥33,600,000、Indirect Cost: ¥10,080,000); Fiscal Year 2017: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000); Fiscal Year 2016: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000); Fiscal Year 2015: ¥22,100,000 (Direct Cost: ¥17,000,000、Indirect Cost: ¥5,100,000)
• Keywords: タウ / αシヌクレイン / TDP-43 / 伝播 / プリオン / 不活性化 / MSA / DLB / 神経変性疾患 / アミロイド / 脳神経疾患 / APP / C9ORF72

Outline of Final Research Achievements

We analyzed pathological tau in various neurodegenerative diseases and found that the C-terminal banding pattern of the insoluble tau is distinct for each disease, suggesting that the band patterns reflect different conformations of tau molecular species. We also showed that extracellular region of APP is involved in uptake of tau fibrils into cells, raising the possibility that APP influences cell-to-cell spreading of tau pathologies in AD. In addition, we identified that residues 274-353 are responsible for the conversion of TDP-43 to amyloid-like fibrils and that templated aggregation of TDP-43 by seeding with different peptides induces various types of TDP-43 pathologies. Regarding alpha-synuclein, we showed that fragmented amyloid-like aggregates of short alpha-synunclein fibrils are the key pathogenic seeds that trigger prion-like conversion, and that the propagation is recapitulated in wild-type marmoset by inoculation of sonicated mouse alpha-synculein fibrils.

Research Products

• [Int'l Joint Research] Seoul National University/Yonsei University/Konkuk University(韓国)
• [Int'l Joint Research] University of California/Weill Cornell Medical College(米国)
• [Int'l Joint Research] Neuroscience Research Australia/University of New South Wales/University of Sydney(Australia)
• [Int'l Joint Research] University of Cambridge(United Kingdom)
• [Int'l Joint Research] Manchester University(英国)
• [Int'l Joint Research] UNSW Medicine(Australia)
• [Journal Article] Progranulin haploinsufficiency reduces amyloid beta deposition in Alzheimer’s disease model mice (2018)
  • Author(s): Hosokawa M, Tanaka Y, Arai T, Kondo H, Akiyama H, Hasegawa M
  • Journal Title: Experimental Animals Volume: 67 Issue: 1 Pages: 63-70
  • DOI: 10.1538/expanim.17-0060
  • NAID: 130006339997
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Isoform-independent and -dependent phosphorylation of microtubule-associated protein tau in mouse brain during postnatal development. (2018)
  • Author(s): Tuerde, D., Kimura, T., Miyasaka, T., Furusawa, K., Shimozawa, A., Hasegawa, M., Ando, A., Hisanaga, S.
  • Journal Title: J. Biol, Chem. Volume: 293 Issue: 5 Pages: 1781-1793
  • DOI: 10.1074/jbc.m117.798918
  • Peer Reviewed / Open Access
• [Journal Article] Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome (2018)
  • Author(s): Yabe I, Yaguchi H, Kato Y, Miki Y, Takahashi H, Tanikawa S, Shirai S, Takahashi I, Kimura M, Hama Y, Matsushima M, Fujioka S, Kano T, Watanabe M, Nakagawa S, Kunieda Y, Ikeda Y, Hasegawa M, Nishihara H, Ohtsuka T, Tanaka S, Tsuboi Y, Hatakeyama S, Wakabayashi K, Sasaki H
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 819-819
  • DOI: 10.1038/s41598-018-19198-0
  • NAID: 120006377499
  • 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] otent prion-like behaviors of pathogenic α-synuclein and evaluation of inactivation methods. (2018)
  • Author(s): Tarutani A, Arai T, Murayama S, Hisanaga SI, Hasegawa M
  • Journal Title: Acta Neuropathol Commun Volume: 6 Issue: 1 Pages: 29-29
  • DOI: 10.1186/s40478-018-0532-2
  • Peer Reviewed / Open Access
• [Journal Article] Accumulation of multiple neurodegenerative disease-related proteins in familial frontotemporal lobar degeneration associated with granulin mutation (2017)
  • Author(s): Hosokawa M, Arai T. Kondo H. Serrano GE. Beach TG. Robinson AC. Mann DM. Akiyama H. Haesgawa M
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 1513-1513
  • DOI: 10.1038/s41598-017-01587-6
  • NAID: 120007129118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes. (2017)
  • Author(s): Tanaka Y, Suzuki G, Matsuwaki T, Hosokawa M, Serrano G, Beach TG, Yamanouchi K, Hasegawa M, Nishihara M.
  • Journal Title: Human Molecular Genetics Volume: 26 Pages: 969-988
  • DOI: 10.1093/hmg/ddx011
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Wild-type monomeric α-synuclein can impair vesicle endocytosis and synaptic fidelity via tubulin polymerization at the calyx of Held. (2017)
  • Author(s): Eguchi K, Taoufiq Z, Thorn-Seshold O, Trauner D, Hasegawa M, Takahashi T
  • Journal Title: J Neurosci Volume: 37 Issue: 25 Pages: 6043-6052
  • DOI: 10.1523/jneurosci.0179-17.2017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Propagation of pathological α-synuclein in marmoset brain (2017)
  • Author(s): Aki Shimozawa, Maiko Ono, Daisuke Takahara, Airi Tarutani, Sei Imura, Masami Masuda-Suzukake, Makoto Higuchi, Kazuhiko Yanai, Shin-ichi Hisanaga, Masato Hasegawa
  • Journal Title: Acta Neuropathologica Communications Volume: 5 Issue: 1 Pages: 12-14
  • DOI: 10.1186/s40478-017-0413-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TDP-43 stabilises the processing intermediates of mitochondrial transcripts. (2017)
  • Author(s): Izumikawa K, Nobe Y, Yoshikawa H, Ishikawa H, Miura Y, Nakayama H, Nonaka T, Hasegawa M, Egawa N, Inoue H, Nishikawa K, Yamano K, Simpson RJ, Taoka M, Yamauchi Y, Isobe T, Takahashi N
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 7709-7709
  • DOI: 10.1038/s41598-017-06953-y
  • NAID: 120006364102
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Unusual tau pathology of the cerebellum in patients with amyotrophic lateral sclerosis/parkinsonism-dementia complex from the kii peninsula, Japan. (2017)
  • Author(s): Morimoto S, Hatsuta H, Kokubo Y, Nakano Y, Hasegawa M, Yoneda M, Hirokawa Y, Kuzuhara S, Shiraishi T, Murayama S.
  • Journal Title: Brain Pathol. Volume: - Issue: 2 Pages: 287-291
  • DOI: 10.1111/bpa.12500
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer’s disease (2017)
  • Author(s): Mano Tatsuo、Nagata Kenichi、Nonaka Takashi、Tarutani Airi、Imamura Tomohiro、Hashimoto Tadafumi、Bannai Taro、Koshi-Mano Kagari、Tsuchida Takeyuki、Ohtomo Ryo、Takahashi-Fujigasaki Junko、Yamashita Satoshi、Ohyagi Yasumasa、Yamasaki Ryo、Tsuji Shoji、Tamaoka Akira、et al.
  • Journal Title: Proc Natl Acad Sci U.S.A. Volume: 114 Issue: 45
  • DOI: 10.1073/pnas.1707151114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Desulfation of Heparan Sulfate by Sulf1 and Sulf2 Is Required for Corticospinal Tract Formation (2017)
  • Author(s): Okada Takuya、Keino-Masu Kazuko、Nagamine Satoshi、Kametani Fuyuki、Ohto Tatsuyuki、Hasegawa Masato、van Kuppevelt Toin H.、Kunita Satoshi、Takahashi Satoru、Masu Masayuki
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 13847-13847
  • DOI: 10.1038/s41598-017-14185-3
  • NAID: 120007134746
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exposure to bacterial endotoxin generates a distinct strain of α-synuclein fibril. (2016)
  • Author(s): Kim C, Lv G, Lee JS, Jung BC, Masuda-Suzukake M, Hong CS, Valera E, Lee HJ, Paik SR, Hasegawa M, Masliah E, Eliezer D, Lee SJ.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 30891-30891
  • DOI: 10.1038/srep30891
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] α-Synuclein: Experimental Pathology. (2016)
  • Author(s): Hasegawa M, Nonaka T, Masuda-Suzukake M.
  • Journal Title: Cold Spring Harb Perspect Med. Volume: 6 Issue: 9 Pages: a024273-a024273
  • DOI: 10.1101/cshperspect.a024273
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effect of Fragmented Pathogenic α-Synuclein Seeds on Prion-like Propagation. (2016)
  • Author(s): Tarutani A, Suzuki G, Shimozawa A, Nonaka T, Akiyama H, Hisanaga S, and Hasegawa M.
  • Journal Title: J. Biol. Chem., J. Biol. Chem. Volume: 291 Issue: 36 Pages: 18675-18688
  • DOI: 10.1074/jbc.m116.734707
  • Peer Reviewed / Open Access
• [Journal Article] α-Synuclein fibrils exhibit gain-of-toxic-function, promoting tau aggregation and inhibiting microtubule assembly. (2016)
  • Author(s): Oikawa T, Nonaka T, Hisanaga S, Hasegawa M.
  • Journal Title: J Biol Chem. Volume: 291 Issue: 29 Pages: 15046-15056
  • DOI: 10.1074/jbc.m116.736355
  • Peer Reviewed / Open Access
• [Journal Article] Gain-of-function profilin 1 mutations linked to familial amyotrophic lateral sclerosis cause seed-dependent intracellular TDP-43 aggregation. (2016)
  • Author(s): Tanaka Y, Nonaka T, Suzuki G, Kametani F, Hasegawa M.
  • Journal Title: Human Molecular Genetics Volume: 25 Issue: 7 Pages: 1420-33
  • DOI: 10.1093/hmg/ddw024
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phosphorylation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Truncated Casein Kinase 1δ Triggers Mislocalization and Accumulation of TDP-43. (2016)
  • Author(s): Nonaka T, Suzuki G, Tanaka Y, Kametani F, Hirai S, Okado H, Miyashita T, Saitoe M, Akiyama H, Masai H, Hasegawa M.
  • Journal Title: J Biol Chem Volume: 291 Issue: 17 Pages: 8896-907
  • DOI: 10.1074/jbc.m115.713552
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau. (2016)
  • Author(s): Taniguchi-Watanabe S, Arai T, Kametani F, Nonaka T, Masuda-Suzukake M, Tarutani A, Murayama S, Saito Y, Arima K, Yoshida M, Akiyama H, Robinson A, Mann DM, Iwatsubo T, Hasegawa M.
  • Journal Title: Acta Neuropathol. Volume: 131(2) Issue: 2 Pages: 267-280
  • DOI: 10.1007/s00401-015-1503-3
  • NAID: 120007128537
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interplay between TDP-43 and docosahexaenoic acid-treated processes in amyotrophic lateral sclerosis. (2016)
  • Author(s): Cacabelosa D, Ayalaa V, Belen Granado-Serranoa A, Jove M, Torresa P, Boadaa J, Cabre R, Ramirez-Nuneza O, Gonzaloa H, Soler-Canterob A, Carlos Enrique Serranoa J, Josep Bellmunta M, Paz Romerob M, Jose Motilvab M, Nonaka T, Hasegawa M, Ferrerd I, Pamplonaa R, and Portero-Otin M.
  • Journal Title: Neurobiol. Dis. Volume: 88 Pages: 148-160
  • DOI: 10.1016/j.nbd.2016.01.007
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] .Cellebeller neuronal loss in ALS cases with ATXN2 intermediate repeat expansions. (2016)
  • Author(s): Tan R, Kril J, McGinley C, Hassani M, Suzukake M, Hasegawa M, Remika M, Kiernan M, Halliday G
  • Journal Title: Ann Neurol Volume: 79 Issue: 2 Pages: 295-305
  • DOI: 10.1002/ana.24565
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The Abundance of Nonphosphorylated Tau in Mouse and Human Tauopathy Brains Revealed by the Use of Phos-Tag Method (2016)
  • Author(s): Kimura T, Hatsuta H, Masuda-Suzukake M, Hosokawa M, Ishiguro K, Akiyama H, Murayama S, Hasegawa M, Hisanaga S
  • Journal Title: American Journal of Pathology Volume: 186 Issue: 2 Pages: 398-409
  • DOI: 10.1016/j.ajpath.2015.10.009
  • Peer Reviewed / Open Access
• [Journal Article] Neurodegeneration in Frontotemporal Lobar Degeneration and Motor Neurone Disease associated with expansions in C9orf72 is not associated with aggregated forms of dipeptide repeat proteins. (2016)
  • Author(s): Davidson Y, Robinson AC, Troakes C, Smith B, Al-Saraj S, Shaw C, Rollinson S, Masuda-Suzukake M, Suzuki G, Nonaka T, Pickering-Brown S, Snowden JS, Hasegawa M, Mann DMA.
  • Journal Title: Neuropathol Appl Neurobiol. Volume: 42 Issue: 3 Pages: 242-254
  • DOI: 10.1111/nan.12292
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Extracellular association of APP and tau fibrils induces intracellular aggregate formation of tau. (2015)
  • Author(s): Takahashi M, Miyata H, Kametani F, Nonaka T, Akiyama H, Hisanaga SI, Hasegawa M.
  • Journal Title: Acta Neuropathol. Volume: 129 Issue: 6 Pages: 895-907
  • DOI: 10.1007/s00401-015-1415-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The twenty-four KDa C-terminal tau fragment increases with aging in tauopathy mice: implications of prion-like properties. (2015)
  • Author(s): Matsumoto, S.E.;Motoi, Y.;Ishiguro, K.;Tabira, T.;Kametani, F.;Hasegawa, M.;Hattori, N.
  • Journal Title: Hum Mol Genet Volume: 24 Issue: 22 Pages: 6403-6416
  • DOI: 10.1093/hmg/ddv351
  • Peer Reviewed / Int'l Joint Research
• [Presentation] タンパク質の伝播から考える神経変性疾患治療の可能性 (2015)
  • Author(s): 長谷川成人
  • Organizer: 第33回 日本神経治療学会総会
  • Place of Presentation: 国際会議場（愛知県名古屋市）
  • Year and Date: 2015-11-28
  • Invited
• [Presentation] 神経変性疾患における異常タンパク質の伝播. (2015)
  • Author(s): 長谷川成人
  • Organizer: 第２０回日本神経感染症学会
  • Place of Presentation: ホテルメルパルク長野（長野県長野市）
  • Year and Date: 2015-10-23
  • Invited
• [Presentation] タウオパチーの生化学. (2015)
  • Author(s): 長谷川成人
  • Organizer: 第9回パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 品川プリンホテル（東京都品川区）
  • Year and Date: 2015-10-16
  • Invited
• [Presentation] Molecular analyses of pathological tau in tauopathy brains. (2015)
  • Author(s): Hasegawa M
  • Organizer: Brain Protein Aging and Dementia Control. 1st International Symposium. Molecular bases of brain protein aging.
  • Place of Presentation: 名古屋大学（愛知県名古屋市）
  • Year and Date: 2015-10-09
  • Int'l Joint Research / Invited
• [Presentation] 脳タンパク質老化と認知症制御. (2015)
  • Author(s): 長谷川成人
  • Organizer: 第15回日本蛋白質科学会年会.
  • Place of Presentation: あわぎんホール（徳島県徳島市）
  • Year and Date: 2015-06-26
  • Invited
• [Presentation] アルツハイマー病のタウ仮説. (2015)
  • Author(s): 長谷川成人
  • Organizer: 第111回日本精神神経学会学術総会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2015-06-05
  • Invited
• [Remarks] ALS患者脳中に異常蓄積したTDP-43を質量分析器を使いタンパク質化学的に解析した。
  • URL: http://www.igakuken.or.jp/topics/2016/0316.html
• [Remarks] リソソームにおけるプログラニュリンの機能的役割を解明
  • URL: http://www.igakuken.or.jp/topics/2017/0110.html
• [Remarks] パーキンソン病やレビー小体型認知症のマーモセットモデルの開発に成功
  • URL: http://www.igakuken.or.jp/topics/2017/0202.html