Proteinopathyとしての認知症疾患の病態解明をめざした実験的研究

2010 Fiscal Year Annual Research Report

• Project/Area Number: 21591536
• Research Institution: Tokyo Metropolitan Organization for Medical Research
• Principal Investigator: 秋山 治彦 財団法人東京都医学研究機構, 東京都精神医学総合研究所, 参事研究員 (20231839)
• Keywords: プロテイノパチー / グラニュリン / アルツハイマー病 / タウ / FUS / 前頭側頭葉変性症 / TDP-43

Research Abstract

遺伝子改変マウスの交配
APP Tg2576,tau(P301L),APP-Tg2576/tau(P301L),TDP-43(G298S)の各トランスジェニック(Tg)マウス,およびグラニュリン(GRN)ノックアウト(KO)マウスの系統維持と繁殖を行い,相互にかけあわせて加齢させる実験を進めている.APP-TgあるいはAPP/tau-TgとGRN-KOとを交配して重複遺伝子異常を持つマウスを選別し加齢を待ったが,単独TgにおいてAβやtauの異常蓄積が生じるよりはるかに若い月齢での死亡が相次いだため解析を行うに至っていない.TDP-43(G298S)-Tgマウスは後肢麻痺という症状は発現するもののTDP-43異常蓄積がきわめて乏しい(皆無ではない)系統であるが,ヒト家族性FTLD-TDPの遺伝的異常であるGRN-KOをかけあわせても病変の加速は認められなかった.GRN-KOとtau(P301L)との交配系(tau(P301L)GRN(+/-))もヒト変性疾患に相当する加齢期間を得るのが難しく,現状では若齢マウスのみの解析が可能であるが,tau(P301L)単独マウスよりも脳可溶化区分の異常リン酸化tauが増加する傾向が見られた
ヒト剖検脳の解析
本研究を立案した後,tau陰性TDP-43陰性前頭側頭葉変性症(FTLD)に異常蓄積する蛋白質としてFUSが同定された.そこで当研究室に所蔵されている全66例のFTLD剖検脳を再解析したところ,9例のFUS陽性FTLDを確認した.FUSはTDP-43と類似のRNA結合蛋白質であり,やはり家族性ALSの原因遺伝子となるなど,両者の病態の共通性が推測される.そこでまずFTLD-FUS剖検脳の免疫組織化学的解析を進め,核に局在する正常なFUSと細胞質に異常蓄積したFUSとの間に蛋白質の構造に違いにもとづく反応性の違いを見いだした

Research Products

• [Journal Article] Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy (2010)
  • Author(s): Arai T, Hasegawa M, Nonoka T, Kametani F, Yamashita M, Hosokawa M, Niizato K, Tsuchiya K, Kobayashi Z, Ikeda K, Yoshida M, Nonaya M, Fujishiro H, Akiyama H
  • Journal Title: Neuropathology Volume: 30 Pages: 170-181
  • DOI: doi:10.1111/j.1440-1789.2009.01089.x
  • Peer Reviewed
• [Journal Article] Argyrophilic grain disease with delusions and hallucinations : a pathological study (2010)
  • Author(s): Asaoka T, Tsuchiya K, Fujishiro H, Arai T, Hasegawa M, Akiyama H, Iseki E, Oda T, Onaya M, Tominaga I
  • Journal Title: Psychogeriatrics Volume: 10 Pages: 69-76
  • Peer Reviewed
• [Journal Article] Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease (2010)
  • Author(s): Coomaraswamy J, Kilger E, Wolfing H, Schafer C, Kaeser SA, Wegenast-Braun BM, Hefendehl JK, Wolburg H, Mazzella M, Ghiso J, Goedert M, Akiyama H, et al.[12番目/16名]
  • Journal Title: Proc Natl Acad Sci USA Volume: 107 Pages: 7969-7974
  • DOI: doi:10.1073/pnas.1001056107
  • Peer Reviewed
• [Journal Article] Pseudopolyneuritic form of ALS revisited : clinical and pathological heterogeneity (2010)
  • Author(s): Kobayashi Z, Tsuchiya K, Arai T, Yokota O, Watabiki S, Ishizu H, Akiyama H, Mizusawa H
  • Journal Title: Neuropathology Volume: 30 Pages: 372-380
  • DOI: doi:10.1111/j.1440-1789.2009.01084.x
  • Peer Reviewed
• [Journal Article] Clinicopathological characteristics of FTLD-TDP showing corticospinal tract degeneration but lacking lower motor neuron loss (2010)
  • Author(s): Kobayashi Z, Tsuchiya K, Arai T, Yokota O, Yoshida M, Shimomura Y, Kondo H, Haga C, Asaoka T, Onaya M, Ishizu H, Akiyama H, Mizusawa H
  • Journal Title: J Neurol Sci Volume: 298 Pages: 70-77
  • DOI: doi:10.1016/j.jns.2010.08.013
  • Peer Reviewed
• [Journal Article] Frontotemporal lobar degeneration with motor neuron disease showing severe and circumscribed atrophy of anterior temporal lobes (2010)
  • Author(s): Kuwahara H, Tsuchiya K, Saito Y, Kobayashi Z, Miyazaki H, Izumiyama Y, Akiyama H, Arai T, Mizusawa H
  • Journal Title: J Neurol Sci Volume: 297 Pages: 92-96
  • DOI: doi:10.1016/j.jns.2010.07.004
  • Peer Reviewed
• [Journal Article] Familial ALS with G298S mutation in TARDBP : a comparison of CSF tau protein levels with those in sporadic ALS (2010)
  • Author(s): Nozaki I, Arai M, Takahashi K, Hamaguchi T, Yoshikawa H, Muroishi T, Noguchi-Shinohara M, Ito H, Itokawa M, Akiyama H, Kawata A, Yamada M
  • Journal Title: Intern Med Volume: 49 Pages: 1209-1212
  • DOI: doi:10.2169/internalmedicine.49.3300
  • Peer Reviewed
• [Journal Article] TDP-43 M337V mutation in familial amyotrophic lateral sclerosis in Japan (2010)
  • Author(s): Tamaoka A, Arai M, Itokawa M, Arai T, Hasegawa M, Tsuchiya K, Takuma H, Tsuji H, Ishii A, Watanabe M, Takahashi Y, Goto J, Tsuji S, Akiyama H
  • Journal Title: Intern Med Volume: 49 Pages: 331-334
  • DOI: doi:10.2169/internalmedicine.49.2915
  • Peer Reviewed
• [Journal Article] Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders (2010)
  • Author(s): Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, Akiyama H, et al.[8番目/12名]
  • Journal Title: Acta Neuropathol Volume: 119 Pages: 689-702
  • DOI: doi:10.1007/s00401-010-0664-3
  • Peer Reviewed
• [Journal Article] Phosphorylated TDP-43 pathology and hippocampal sclerosis in progressive supranuclear palsy (2010)
  • Author(s): Yokota O, Davidson Y, Bigio EH, Ishizu H, Terada S, Arai T, Hasegawa M, Akiyama H, Sikkink S, Pickering-Brown S, Mann DM
  • Journal Title: Acta Neuropathol Volume: 120 Pages: 55-66
  • DOI: doi:10.1007/s00401-010-0702-1
  • Peer Reviewed
• [Journal Article] Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration : an update (2010)
  • Author(s): Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJ, Kumar-Singh S, Akiyama H, et al.[16番目/21名]
  • Journal Title: Acta Neuropathol Volume: 119 Pages: 1-4
  • DOI: doi:10.1007/s00401-009-0612-2
  • Peer Reviewed
• [Journal Article] Occurrence of basophilic inclusions and FUS-immunoreactive neuronal and glial inclusions in a case of familial amyotrophic lateral sclerosis (2010)
  • Author(s): Kobayashi Z, et al.
  • Journal Title: J Neurol Sci Volume: 293 Pages: 6-11
  • Peer Reviewed
• [Journal Article] Effect of topographical distribution of α-synuclein pathology on TDP-43 accumulation in Lewy body disease (2010)
  • Author(s): Yokota O, et al.
  • Journal Title: Acta Neuropathol Volume: 120 Pages: 789-801
  • Peer Reviewed
• [Presentation] Screening for FUS proteinopathy in the institutional brain collection (2010)
  • Author(s): Akiyama H, Kobayashi Z, Arai T, Hosokawa M, Tsuchiya K, Yokota O, Shimomura Y, Kondo H, Haga C, Hasegawa M
  • Organizer: The 7th International Conference on Frontotemporal Dementias
  • Place of Presentation: Indianapolis, USA
  • Year and Date: 2010-10-06