Molecular pathophysiology of amyotrophic lateral sclerosis

• Project/Area Number: 18K07537
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Aizawa Hitoshi 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
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 筋萎縮性側索硬化症 / ADAR2 / Pin 1 / TDP-43 / 孤発性筋萎縮性側索硬化症 / Pin1 / nucleoporin / nuclear isomerase Pin1 / importin-α4

Outline of Final Research Achievements

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Selective deficiency of edited adenosine deaminase acting on RNA 2 (ADAR2), a key molecule in the acquisition of Ca2+ resistance in motor neurons has been reported in sporadic ALS (sALS) spinal motor neurons. ADAR2 activity is positively regulated by prolyl isomerase Pin1, a known phosphorylation-dependent peptidyl-prolyl cis/trans isomerase. In sALS, neurons expressing high Pin1 levels had TDP-43 inclusions, a pathological marker of ding motor neurons, more frequently than those without high Pin1 expression. These results suggest that the higher Pin1 expression in motor neurons with TDP-43 pathology from sALS patients may represent a compensatory mechanism.

Academic Significance and Societal Importance of the Research Achievements

孤発性筋萎縮性側索硬化症(ALS)は運動ニューロンの変性脱落により全身の筋力低下をきたし2－5年で呼吸不全に陥る疾患であるが、現在まで臨床的に効果的治療法は存在しない。孤発性ALSではRNA編集酵素であるadenosine deaminase acting on RNA2(ADAR2)の酵素活性の低下が運動ニューロン死の原因と考えられるが、ADAR2活性を制御する因子の解析がなされていなかった。本研究により病的運動ニューロンにおいてADAR2を制御するPin 1の発現が亢進していることを明らかにした。孤発性ALSの病態の解明に寄与するとともに新規治療薬に結び付く結果と考えられる。

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
  • 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] 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 Issue: 23 Pages: 3805-3808
  • DOI: 10.2169/internalmedicine.7191-21
  • NAID: 130008123591
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-12-01
  • 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 Issue: 1 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 Issue: 2 Pages: 885-896
  • DOI: 10.1007/s00415-021-10670-y
  • Peer Reviewed
• [Journal Article] The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1. (2021)
  • Author(s): Hayashida A, Li Y, Yoshino H, Daida K, Ikeda A, Ogaki K, Fuse A, Mori A, Takanashi M, Nakahara T, Yoritaka A, Tomizawa Y, Furukawa Y, Kanai K, Nakayama Y, Ito H, Ogino M, Hattori Y, Hattori T,Ichinose Y, Takiyama Y, Saito T, Kimura T, Aizawa H, et al.
  • Journal Title: Neurobiology in Aging Volume: 146
  • Peer Reviewed
• [Journal Article] Impact of the catechol-O-methyltransferase Val158Met polymorphism on the pharmacokinetics of l-dopa and its metabolite 3-O-methyldopa in combination with entacapone (2020)
  • Author(s): Yamamoto Joe、Omura Tomohiro、Kasamo Sachiko、Yamamoto Shota、Kawata Masayoshi、Yonezawa Atsushi、Taruno Yosuke、Endo Hisako、Aizawa Hitoshi、Sawamoto Nobukatsu、Matsubara Kazuo、Takahashi Ryosuke、Tasaki Yoshikazu
  • Journal Title: Journal of Neural Transmission Volume: 128 Issue: 1 Pages: 27-36
  • DOI: 10.1007/s00702-020-02267-y
  • Peer Reviewed
• [Journal Article] Analysis of non-invasive gait recording under free-living conditions in patients with Parkinson's disease: relationship with global cognitive function and motor abnormalities. (2020)
  • Author(s): Terashi H, Taguchi T, Ueta Y, Okubo Y, Mitoma H, Aizawa H.
  • Journal Title: BMC Neurol Volume: 20 Issue: 1 Pages: 161-161
  • DOI: 10.1186/s12883-020-01729-w
  • Peer Reviewed / Open Access
• [Journal Article] Assessment and Rating of Motor Cerebellar Ataxias With the Kinect v2 Depth Sensor: Extending Our Appraisal (2020)
  • Author(s): Honda Takeru、Mitoma Hiroshi、Yoshida Hirotaka、Bando Kyota、Terashi Hiroo、Taguchi Takeshi、Miyata Yohane、Kumada Satoko、Hanakawa Takashi、Aizawa Hitoshi、Yano Shiro、Kondo Toshiyuki、Mizusawa Hidehiro、Manto Mario、Kakei Shinji
  • Journal Title: Frontiers in Neurology Volume: 11 Pages: 1-14
  • DOI: 10.3389/fneur.2020.00179
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Suitable indications of eculizumab for patients with refractory generalized myasthenia gravis (2020)
  • Author(s): Oyama M, Okada K, Masuda M, Shimizu Y, Yokoyama K, Uzawa A, Kawaguchi N, Ikeguchi R, Hoshino Y, Hatano T, Ozawa Y, Nakahara J, Aizawa H, Kitagawa K, Hattori N, Kuwabara S, Murai H, Suzuki S
  • Journal Title: Therapeutic Advances in Neurological Disorders Volume: 13 Pages: 1-9
  • DOI: 10.1177/1756286420904207
  • Peer Reviewed / Open Access
• [Journal Article] Underlying embolic and pathologic differentiation by cerebral microbleeds in cryptogenic stroke (2020)
  • Author(s): Kikuno Muneaki、Ueno Yuji、Shimizu Takahiro、Kuriki Ayako、Tateishi Yohei、Doijiri Ryosuke、Shimada Yoshiaki、Takekawa Hidehiro、Yamaguchi Eriko、Koga Masatoshi、Kamiya Yuki、Ihara Masafumi、Tsujino Akira、Hirata Koichi、Toyoda Kazunori、Hasegawa Yasuhiro、Aizawa Hitoshi、Hattori Nobutaka、Urabe Takao
  • Journal Title: Journal of Neurology Volume: 267 Issue: 5 Pages: 1482-1490
  • DOI: 10.1007/s00415-020-09732-4
  • Peer Reviewed
• [Journal Article] 筋萎縮性側索硬化症への挑戦 (2020)
  • Author(s): 相澤 仁志
  • Journal Title: 東京都医師会雑誌 Volume: 73 Pages: 5-7
• [Journal Article] Association of daily physical activity with cognition and mood disorders in treatment-naive patients with early-stage Parkinson’s disease (2019)
  • Author(s): Terashi Hiroo、Taguchi Takeshi、Ueta Yuki、Mitoma Hiroshi、Aizawa Hitoshi
  • Journal Title: Journal of Neural Transmission Volume: 126 Issue: 12 Pages: 1617-1624
  • DOI: 10.1007/s00702-019-02085-x
  • Peer Reviewed
• [Journal Article] 孤発性ALSに対するペランパネル (2019)
  • Author(s): 相澤 仁志、郭 伸
  • Journal Title: Brain and Nerve Volume: 71 Pages: 1270-1278
• [Journal Article] Impaired Nucleoporins Are Present in Sporadic Amyotrophic Lateral Sclerosis Motor Neurons that Exhibit Mislocalization of the 43-kDa TAR DNA-Binding Protein. (2019)
  • Author(s): Aizawa H, Yamashita T, Kato H, Kimura T, Kwak S
  • Journal Title: J Clin Neurol. Volume: 15（1） Issue: 1 Pages: 62-67
  • DOI: 10.3988/jcn.2019.15.1.62
  • Peer Reviewed / Open Access
• [Presentation] A Phase II Clinical Trial of Perampanel for Sporadic Amyotrophic Lateral Sclerosis (2020)
  • 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, MD, Toda T, et al.
  • Organizer: 31th International symposium on ALS/MND
  • Int'l Joint Research
• [Presentation] PERAMPANEL FOR SPORADIC AMYOTROPHIC LATERAL SCLEROSIS (2020)
  • 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, MD, Toda T, et al.
  • Organizer: 2020 Annual Meeting of Neurology
  • Int'l Joint Research
• [Presentation] Disrupted nuclear pore complex with mislocalization of TDP-43 in sporadic amyotrophic lateral sclerosis motor neurons (2019)
  • Author(s): Aizawa H, Yamashita T, Kato H, Kimura T, Saito T, Teramoto S, Kwak S.
  • Organizer: 第60回日本神経病理学会