Molecular pathophysiology of amyotrophic lateral sclerosis

2021 Fiscal Year Annual Research Report

• Project/Area Number: 18K07537
• Research Institution: Tokyo Medical University
• Principal Investigator: 相澤 仁志 東京医科大学, 医学部, 主任教授 (10292103)
• Co-Investigator(Kenkyū-buntansha): 郭 伸 東京医科大学, 医学部, 特任教授 (40160981)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 孤発性筋萎縮性側索硬化症 / ADAR2 / Pin1

Outline of Annual Research Achievements

孤発性筋萎縮性側索症ではRNA編集酵素であるadenosine deaminase acting on RNA2(ADAR2)の酵素活性が疾患特異的、運動ニューロン特異的に低下し、病理学的には核内TDP-43が消失し、細胞内にTDP-43陽性核内封入体を生じ、同時に核膜の機能障害を起こすことを報告してきた。また、ADAR2のconditional knockout (AR2) miceでも筋萎縮性側索硬化症と同様の臨床症状と病理変化をきたすことから、このマウスは孤発性筋萎縮性側索硬化症の病態モデルであるとともに、ADAR2活性の低下が孤発性筋萎縮性側索硬化症の病態が関与していることを強く支持すると考えられる。
今年度は核内ADAR2活性を制御するnuclear isomerase Pin1の発現が細胞質内TDP-43封入体を有する病的運動ニューロンでPin1の発現が亢進している事を定量的に明らかにした。Pin1はADAR2活性の維持に必要であり、Pin1発現の亢進はADAR2活性の低下を補完する方向で作用し細胞保護的に働くものと考えられた。

Research Products

• [Journal Article] Prolyl isomerase Pin1 expression in the spinal motor neurons of patients with sporadic amyotrophic lateral sclerosis (2022)
  • Author(s): Haruhisa Kato, Makiko Naito, Tomoko Saito, Takuto Hideyama, Yasuhiro Suzuki, Takashi Kimura, Shin Kwak, Hitoshi Aizawa
  • Journal Title: J Clinical Neurology Volume: in press Pages: in press
  • Peer Reviewed
• [Journal Article] Nuclear pore destruction and loss of nuclear TDP-43 in FUS mutation-related amyotrophic lateral sclerosis motor neurons (2022)
  • Author(s): Aizawa Hitoshi、Teramoto Sayaka、Hideyama Takuto、Kato Haruhisa、Terashi Hiroo、Suzuki Yasuhiro、Kimura Takashi、Kwak Shin
  • Journal Title: Journal of the Neurological Sciences Volume: 436 Pages: 120187～120187
  • DOI: 10.1016/j.jns.2022.120187
  • Peer Reviewed
• [Journal Article] Low-dose statin therapy for intracranial artery stenosis: A single center preliminary study (2022)
  • Author(s): Aizawa Hitoshi、Taguchi Takeshi、Ido Nobuhiro、Kato Haruhisa、Terashi Hiroo
  • Journal Title: Journal of the Neurological Sciences Volume: 432 Pages: 120075～120075
  • DOI: 10.1016/j.jns.2021.120075
  • Peer Reviewed
• [Journal Article] Characteristics of sagittal spinopelvic alignment in patients with Parkinson's disease (2021)
  • Author(s): Terashi Hiroo、Endo Kenji、Kato Haruhisa、Ido Nobuhiro、Aizawa Hitoshi
  • Journal Title: Acta Neurologica Scandinavica Volume: 145 Pages: 53～62
  • DOI: 10.1111/ane.13521
  • Peer Reviewed
• [Journal Article] Relationship between 123I-FP-CIT-SPECT and motor severity in drug-naive patients with Parkinson's disease (2021)
  • Author(s): Terashi Hiroo、Taguchi Takeshi、Ueta Yuki、Mitoma Hiroshi、Aizawa Hitoshi
  • Journal Title: Journal of the Neurological Sciences Volume: 426 Pages: 117476～117476
  • DOI: 10.1016/j.jns.2021.117476
  • Peer Reviewed
• [Journal Article] Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis (2021)
  • Author(s): Aizawa H, Kato H, Oba K, Kawahara T, Okubo Y, Saito T, Naito M, Urushitani M, Tamaoka A, Nakamagoe K, Ishii K, Kanda T, Katsuno M, Atsuta N, Maeda Y, Nagai M, Nishiyama K, Ishiura H, Toda T, Kawata A, Abe K, Yabe I, Takahashi-Iwata I, Sasaki H, Warita H, Aoki M, Sobue G, Mizusawa H, Matsuyama Y, Haga T, Kwak S
  • Journal Title: Journal of Neurology Volume: 269 Pages: 885～896
  • DOI: 10.1007/s00415-021-10670-y
  • Peer Reviewed
• [Journal Article] Persistent Hemichorea as a Preceding Symptom of Cerebral Infarction Due to Middle Cerebral Artery Stenosis (2021)
  • Author(s): Ueta Yuki、Kato Haruhisa、Naito Makiko、Taguchi Takeshi、Terashi Hiroo、Aizawa Hitoshi
  • Journal Title: Internal Medicine Volume: 60 Pages: 3805～3808
  • DOI: 10.2169/internalmedicine.7191-21
  • Peer Reviewed