各種プリオンによる末梢からの感染力評価法の樹立

2018 Fiscal Year Annual Research Report

• Project/Area Number: 18H02738
• Research Institution: Tohoku University
• Principal Investigator: 北本 哲之 東北大学, 医学系研究科, 教授 (20192560)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: プリオン / 末梢ルート / FDC / 腹腔内投与

Outline of Annual Research Achievements

本研究の発想は、同じヨーロッパの孤発性ＣＪＤを感染源とする硬膜移植後ＣＪＤと成長ホルモン製剤投与後のＣＪＤにおいて感染したプリオンの比率が大きく異なるのは何に由来するのかを追及することであった。具体的には、ヨーロッパの孤発性ＣＪＤではＭ１プリオンが７０％、Ｖ２プリオンが３０％の比率で認められる。一方、その孤発性ＣＪＤから採取された硬膜を用いた医原性プリオン病はＭ１プリオンが７０％、Ｖ２プリオンが３０％とほとんどその比率で感染が成立していた。一方、成長ホルモン製剤投与後のＣＪＤでは、この比率は全く異なり、Ｍ１プリオンの感染は５～１０％に満たないもので、ほとんどがＶ２プリオン感染であった。この違いを明らかにすることが、本研究の主な目的である。
本年度は、頭蓋内投与される硬膜移植と末梢投与である成長ホルモン製剤との感染の成立頻度に差が存在するのかを検討するために、ヒト化マウスを用いて感染実験を行った。頭蓋内投与では、Ｍ１プリオンもＶ２プリオンもヒト型プリオン蛋白ノックインマウスではどの遺伝子型のマウスでも１００％の頻度で感染が成立した。一方、腹腔内投与では、Ｍ１プリオンはKi-129Met/Metでは０/１０、Ki-129Val/Valでは３/８の頻度の成功率であった。一方、Ｖ２プリオンはそれぞれ、８/１５と１５/１６という頻度で感染が成立することが明らかとなった。つまり、当初予想したように、末梢ルート感染では、Ｖ２プリオンの感染性に較べてＭ１プリオンの感染の成立率は著しく低いという新しい結果が得られたのである。この研究をさらにＭ１プリオンとＶ２プリオンの症例数を増やし、また他のプリオンでも頭蓋内投与と末梢投与で差がでてくるのかを進める予定である。研究は、予定以上のスピードで進んでいる。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

当初考えていたメカニズムとして末梢ルートによる感染性の違いを初年度で明らかにすることができた。

Strategy for Future Research Activity

それぞれ感染性の差を確かなものにするために、Ｍ１プリオン、Ｖ２プリオンの感染材料を増やす予定である。さらに、日常的に感染する機会があると考えられる他のプリオンに関しても感染実験を行う。

Research Products

• [Journal Article] An autopsied case of MM1-type sporadic Creutzfeldt- Jakob disease with pathology of Wernicke encephalopathy (2019)
  • Author(s): Iwasaki Y, Hashimoto R, Saito Y, Aiba I, Inukai A, Akagi A, Mimuro M, Miyahara H, Kitamoto T, Yoshida M
  • Journal Title: Prion Volume: 13(1) Pages: 13-20
  • DOI: 10.1080/19336896. 2018.1545525. Epub 2018 Nov 14
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intermolecular crosslinking of abnormal prion protein is efficiently induced by a primuline-sensitized photoreaction (2019)
  • Author(s): Teruya K, Nishizawa K, Oguma A, Sakasegawa Y, Kitamoto T, Doh-Ura K
  • Journal Title: Biochim Biophys Acta Gen Subj Volume: 1863(2) Pages: 384-394
  • DOI: 10.1016/ j.bbagen. 2018.11.008.Epub 2018 Nov 14
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ganglioside synthase knock-out reduces prion disease incubation time in mouse models (2019)
  • Author(s): Kobayashi A, Qi Z, Shimazaki T, Munesue Y, Miyamoto T, Isoda N, Sawa H, Aoshima K, Kimura T, Mohri S, Kitamoto T, Yamashita T, Miyoshi I
  • Journal Title: Am J Pathol Volume: 189(3) Pages: 677-686
  • DOI: 10.1016/j.ajpath.2018.11.009.Epub 2018 Dec 13
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In Vitro Seeding Activity of Glycoform-Deficient Prions from Variably Protease-Sensitive Prionopathy and Familial CJD Associated with PrPV180I Mutation (2019)
  • Author(s): Wang Z, Yuan J, Shen P, Abskharon R, Lang Y, Dang J, Adornato A, Xu L, Chen J, Feng J, Moudjou M, Kitamoto T, Langeveld J, Appleby B, Ma J, Kong Q, Petersen RB, Zou WQ, Cui L
  • Journal Title: Mol Neurobiol Volume: - Pages: -
  • DOI: 10.1007/s12035-018-1459-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pathological progression of genetic Creutzfeldt-Jakob disease with a PrP V180I mutation (2018)
  • Author(s): Akagi A, Iwasaki Y, Mimuro M, Kitamoto T, Yamada M, Yoshida M
  • Journal Title: Prion Volume: 12(1) Pages: 54-62
  • DOI: 10.1080/19336896. 2017.1414130.Epub 2018 Jan 31
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study (2018)
  • Author(s): Cali I, Cohen ML, Haik S, Parchi P, Giaccone G, Collins SJ, Kofskey D, Wang H, McLean CA, Brandel JP, Privat N, Sazdovitch V, Duyckaerts C, Kitamoto T, Belay ED, Maddox RA, Tagliavini F, Pocchiari M, Leschek E, Appleby BS, Safar JG, Schonberger LB, Gambetti P
  • Journal Title: Acta Neuropathol Commun Volume: 6(1) Pages: 5
  • DOI: 10.1186/s40478-017-0503-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development of a quick bioassay for the evaluation of transmission properties of acquired prion diseases (2018)
  • Author(s): Munesue Y, Shimazaki T, Qi Z, Isoda N, Sawa H, Aoshima K, Kimura T, Mohri S, Kitamoto T, Kobayashi A
  • Journal Title: Neurosci Lett Volume: 668 Pages: 43-47
  • DOI: 10.1016/j.neulet. 2018.01.014.Epub 2018 Jan 9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Biochemical features of genetic Creutzfeldt-Jakob disease with valine-to-isoleucine substitution at codon 180 on the prion protein gene (2018)
  • Author(s): Ito Y, Sanjo N, Hizume M, Kobayashi A, Ohgami T, Satoh K, Hamaguchi T, Yamada M, Kitamoto T, Mizusawa H, Yokota T
  • Journal Title: Biochem Biophys Res Commun Volume: 496(4) Pages: 1055-1061
  • DOI: 10.1016/j.bbrc. 2018.01.119.Epub 2018 Jan 31
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] An autopsy report of three kindred in a Gerstmann-Sträussler-Scheinker disease P105L family with a special reference to prion protein, tau, and beta-amyloid (2018)
  • Author(s): Ishizawa K, Mitsufuji T, Shioda K, Kobayashi A, Komori T, Nakazato Y, Kitamoto T, Araki N, Yamamoto T, Sasaki A
  • Journal Title: Brain Behav Volume: 8(10) Pages: e01117
  • DOI: 10.1002/brb3.1117.Epub 2018 Sep 21
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Autopsy case of V180I genetic Creutzfeldt-Jakob disease presenting with early disease pathology (2018)
  • Author(s): Iwasaki Y, Kato H, Ando T, Akagi A, Mimuro M, Miyahara H, Kitamoto T, Yoshida M
  • Journal Title: Neuropathology Volume: 38(6) Pages: 638-645
  • DOI: 10.1111/neup.12516.Epub 2018 Sep 14
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] PrPres deposition in the retina is a common finding of sporadic, familial and iatrogenic Creutzfeldt-Jakob diseases(CJD) (2018)
  • Author(s): Takao M, Kimura H, Kitamoto T, Mihara B
  • Journal Title: Acta Neuropathol Commun Volume: 6(1) Pages: 78
  • DOI: 10.1186/s40478- 018-0582-5.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Autopsied case of non-plaque-type dura mater graft-associated Creutzfeldt-Jakob disease presenting with extensive amyloid-β deposition (2018)
  • Author(s): Iwasaki Y, Imamura K, Iwai K, Kobayashi Y, Akagi A, Mimuro M, Miyahara H, Kitamoto T, Yoshida M
  • Journal Title: Neuropathology Volume: 38(5) Pages: 549-556
  • DOI: 10.1111/neup.12503. Epub 2018 Aug 6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Creutzfeldt-Jakob disease with Alzheimer pathology, presenting with status epilepticus following repeated partial seizures: a case report and literature review (2018)
  • Author(s): Miyake K, Hara T, Oshima E, Kawada K, Ishizu H, Yamauchi Y, Satoh K, Kitamoto T, Takenoshita S, Terada S, Yamada N
  • Journal Title: BMC Neurol Volume: 18(1) Pages: 54
  • DOI: 10.1186/s12883-018-1055-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Iatrogenic Creutzfeldt-Jakob disease (2018)
  • Author(s): Kobayashi A, Kitamoto T, Mizusawa H
  • Journal Title: Handb Clin Neurol Volume: 153 Pages: 207-218
  • DOI: 10.1016/B978-0-444-63945-5.00012-X
  • Int'l Joint Research
• [Journal Article] Neuroimaging- pathological correlations of [18F]THK5351 PET in progressive supranuclear palsy (2018)
  • Author(s): Ishiki A, Harada R, Kai H, Sato N, Totsune T, Tomita N, Watanuki S, Hiraoka K, Ishikawa Y, Funaki Y, Iwata R, Furumoto S, Tashiro M, Sasano H, Kitamoto T, Kudo Y, Yanai K, Furukawa K, Okamura N, Arai H
  • Journal Title: Acta Neuropathol Commun Volume: 6(1) Pages: 53
  • DOI: 10.1186/s40478-018-0556-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Specific amyloid-β42 deposition in the brain of a Gerstmann-Straussler-Scheinker disease patient with a P105L mutation on the prion protein gene (2018)
  • Author(s): Furukawa F, Sanjo N, Kobayashi A, Hamaguchi T, Yamada M, Kitamoto T, Mizusawa H, Yokota T
  • Journal Title: Prion Volume: 12(5-6) Pages: 315-319
  • DOI: 10.1080/19336896. 2018.1541689.Epub 2018 Nov 13
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A domain responsible for spontaneous conversion of bank vole prion protein (2018)
  • Author(s): Kobayashi A, Matsuura Y, Takeuchi A, Yamada M, Miyoshi I, Mohri S, Kitamoto T
  • Journal Title: Brain Pathol Volume: 29(2) Pages: 155-163
  • DOI: 10.1111/bpa.12638. Epub 2018 Oct 29
  • Peer Reviewed / Int'l Joint Research