Propagation of prion-like proteins and cellular responses

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15H02356
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: 長谷川 成人 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
• Keywords: αシヌクレイン / プリオン / 伝播 / 不活性化 / MSA / DLB

Outline of Annual Research Achievements

合成αSyn fibrilsについて、ヒトαシヌクレインを一過性に発現するSH-SY5Y培養細胞モデルと野生型マウスで、プリオン様活性を示す最小量を決定した。次に実際の患者脳におけるαSynについてのプリオン様seeding活性を検討するため、MSA患者剖検脳から調製した不溶性αSynとDLB患者剖検脳から調製したαSynについて検討をした結果、Prusinerらの報告にあるように、その活性に大きな違いが認められた。また、MSAとDLBの不溶性αSynについて、WBとImmunoEMで検討したところ、バンドパターンに違いがあり、形態的にも違いが観察された。患者脳由来の不溶性αSynを培養細胞に導入し、細胞内で形成されるリン酸化αSynの量を定量した結果、MSAはDLBより強いシード活性をもち、その活性は合成αSynとほぼ同じかそれ以上であった。さらにマウスに接種しそのin vivoでのプリオン様シーディング活性も調べた結果、DLB由来のαSynは接種後3ヶ月ではほとんど病変が検出されなかったのに対し、MSA患者由来のαSynはレビー小体様の病変が認められた。最後に不活性化について検討し、合成synとMSA synについて培養細胞とマウスで検討し、その不活性化には1~2%SDS中でのオートクレーブ処理、あるいは134℃でのオートクレーブ処理が必要であることが示された。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Unusual tau pathology of the cerebellum in patients with amyotrophic lateral sclerosis/parkinsonism-dementia complex from the Kii Peninsula, Japan. (2018)
  • 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: 28 Pages: 287-291
  • DOI: 10.1111/bpa.12500.
  • Peer Reviewed
• [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: Exp Anim Volume: 67 Pages: 63-70
  • DOI: 10.1538/expanim.17-0060.
  • Peer Reviewed
• [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 Pages: 819
  • DOI: 10.1038/s41598-018-19198-0.
  • Peer Reviewed / Open Access
• [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 Pages: 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, Kondo H, Serrano GE, Beach TG, Robinson AC, Mann DM, Akiyama H, Hasegawa M, Arai T
  • Journal Title: Sci Rep Volume: 7 Pages: 1513
  • DOI: 10.1038/s41598-017-01587-6.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes. 5.発行年 2017年 3.雑誌名 (2017)
  • Author(s): Tanaka Y, Suzuki G, Matsuwaki T, Hosokawa M, Serrano G, Beach TG, Yamanouchi K, Hasegawa M, Nishihara M.
  • Journal Title: Hum Mol Genet Volume: 26 Pages: 969-988
  • DOI: 10.1093/hmg/ddx011.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 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): Shimozawa A, Ono M, Takahara D, Tarutani A, Imura S, Masuda-Suzukake M, Higuchi M, Yanai K, Hisanaga SI, Hasegawa M
  • Journal Title: Acta Neuropathol Commun Volume: 5 Pages: 12
  • DOI: 10.1186/s40478-017-0413-0.
  • Peer Reviewed / Open Access
• [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 Pages: 7709
  • DOI: 10.1038/s41598-017-06953-y.
  • Peer Reviewed / Open Access
• [Journal Article] Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease. (2017)
  • Author(s): Mano T, Nagata K, Nonaka T, Tarutani A, Imamura T, Hashimoto T, Bannai T, Koshi-Mano K, Tsuchida T, Ohtomo R, Takahashi-Fujigasaki J, Yamashita S, Ohyagi Y, Yamasaki R, Tsuji S, Tamaoka A, Ikeuchi T, Saido TC, Iwatsubo T, Ushijima T, Murayama S, Hasegawa M, Iwata A.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114 Pages: E9645-E9654.
  • DOI: 10.1073/pnas.1707151114.
  • Peer Reviewed / Open Access
• [Journal Article] Isoform-independent and -dependent phosphorylation of microtubule-associated protein tau in mouse brain during postnatal development. (2017)
  • Author(s): Tuerde D, Kimura T, Miyasaka T, Furusawa K, Shimozawa A, Hasegawa M, Ando K, Hisanaga SI.
  • Journal Title: J Biol Chem Volume: 293 Pages: 1781-1793
  • DOI: 10.1074/jbc.M117.798918.
  • Peer Reviewed / Open Access
• [Journal Article] Desulfation of Heparan Sulfate by Sulf1 and Sulf2 Is Required for Corticospinal Tract Formation. (2017)
  • Author(s): Okada T, Keino-Masu K, Nagamine S, Kametani F, Ohto T, Hasegawa M, van Kuppevelt T, Kunita S, Takahashi S, and Masu M
  • Journal Title: Sci Rep Volume: 7 Pages: 13847
  • DOI: 10.1038/s41598-017-14185-3.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pathological endogenous α-synuclein accumulation in oligodendrocyte precursor cells potentially induces inclusions in multiple system atrophy. (2017)
  • Author(s): Kaji S, Maki T, Kinoshita H, Uemura N, Ayaki T, Kawamoto Y, Furuta T, Urushitani M, Hasegawa M, Ono Y, Kinoshita Y, Mao X, Quach TH, Dawson VL, Dawson TM, Takahashi R.
  • Journal Title: Stem Cell Rep Volume: 10 Pages: 30530-1
  • DOI: 10.1016/j.stemcr.2017.12.001.
  • Peer Reviewed / Open Access / Int'l Joint Research