• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Development of Therapeutics for Mitochondrial Impairment in Autism Spectrum Disorders

Research Project

Project/Area Number 19H03406
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 48030:Pharmacology-related
Research InstitutionTohoku University

Principal Investigator

Fukunaga Kohji  東北大学, 薬学研究科, 名誉教授 (90136721)

Co-Investigator(Kenkyū-buntansha) 松崎 秀夫  福井大学, 子どものこころの発達研究センター, 教授 (00334970)
川畑 伊知郎  東北大学, 薬学研究科, 特任准教授 (30579743)
篠田 康晴  東北大学, 薬学研究科, 助教 (70806405)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywords難治性希少疾患 / 自閉スペクトラム症 / ミトコンドリア障害 / アミノレブリン酸 / オキシトシン / 酸化ストレス / 海馬 / 記憶 / 自閉スペクトラム障害 / 遺伝子発現 / ミトコンドリア異常 / ミトコンドリア / バルプロ酸 / 社会性行動 / バルプロ酸暴露マウス / バルプロ酸暴露ラット / ミトコンドリア機能障害 / 自閉症 / トレースアミン関連受容体 / 5-アミノレブリン酸 / 自閉症モデルマウス
Outline of Research at the Start

自閉症スペクトラム症(ASD)の頻度は約1%で、男性有意に発症する難治性小児疾患である。対症療法以外に根本的治療法はない。病因の一つにミトコンドリア機能異常が知られており、ミトコンドリア関連遺伝子の変異も明らかにされている。本研究では(A)ミトコンドリア機能改善薬5-アミノレブリン酸(5-ALA)のASDマウスにおけるミトコンドリア機能および社会性行動改善の機序を明らかにする。(B) TAAR1受容体アゴニストのASDマウスの社会性行動改善作用とその機序を解明する。(C) 自閉症者リンパ球のミトコンドリア機能がバイオマーカーになるか検証する。

Outline of Final Research Achievements

We used autism spectrum disorder (ASD) rats by exposure to prenatal valproic acid (VPA; 600 mg/kg, p.o.) on embryonic day (E) 12.5. The oxidative stress was increased in the hippocampus after birth. This was accompanied by aberrant enzymatic activity in the mitochondrial electron transport chain. ASD behaviors were rescued by chronic oral administration of 5-aminolevulinic acid and intranasal administration of oxytocin. 5-ALA but not OXT treatment ameliorated oxidative stress and mitochondrial dysfunction in ASD rats. Microarray analyses revealed that VPA exposure altered gene expression, a part of which is involved in key features including memory. OXT partly improved the expression of these genes, which were predicted to interact with those involved in social behaviors and hippocampal-dependent memory. Collectively, the present study documented molecular profiling in neurotransmission related to ASD and support the mechanism improved by chronic treatments with 5-ALA or OXT.

Academic Significance and Societal Importance of the Research Achievements

自閉スペクトラム症(ASD)の頻度は約1%で、男性有意に発症する難治性小児疾患である。私達は ASDモデルである胎児期バルプロ酸暴露ラット(VPA暴露ラット)を用いて、脳内酸化ストレスの亢進の機序を明らかにした。天然アミノ酸であるアミノレブリン酸が酸化ストレス、ミトコンドリア障害を改善することを実証した。一方、臨床試験が実施されているオキシトシンの作用機序を遺伝子マイクロアレイ解析により明らかにした。アミノレブリン酸は天然アミノ酸であり、安全なサプリメントとして新しい改善方法を提唱した。さらに、オキシトシンの作用機序を明らかにすることで、ASDの治療法の開発に貢献した。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (26 results)

All 2022 2021 2020 Other

All Journal Article (20 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 20 results,  Open Access: 19 results) Presentation (5 results) (of which Int'l Joint Research: 4 results) Remarks (1 results)

  • [Journal Article] Transcriptome analysis in hippocampus of rats prenatally exposed to valproic acid and effects of intranasal treatment of oxytosin2022

    • Author(s)
      Kazuya Matsuo, Yasuharu Shinoda, Nona Abolhassani, Yusaku Nakabeppu, Kohji Fukunaga
    • Journal Title

      Frontiers in Psychiatry

      Volume: 13

    • DOI

      10.3389/fpsyt.2022.859198

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel fatty acid-binding protein 5 and 7 inhibitor ameliorates oligodendrocyte injury in multiple sclerosis mouse models2021

    • Author(s)
      Cheng An、Jia Wenbin、Kawahata Ichiro、Fukunaga Kohji
    • Journal Title

      eBioMedicine

      Volume: 72 Pages: 103582-103582

    • DOI

      10.1016/j.ebiom.2021.103582

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] T-Type Ca2+ Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model2021

    • Author(s)
      Xu Jing、Kawahata Ichiro、Izumi Hisanao、Fukunaga Kohji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 12 Pages: 6185-6185

    • DOI

      10.3390/ijms22126185

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fatty Acid-Binding Proteins Aggravate Cerebral Ischemia-Reperfusion Injury in Mice2021

    • Author(s)
      Guo Qingyun、Kawahata Ichiro、Degawa Tomohide、Ikeda-Matsuo Yuri、Sun Meiling、Han Feng、Fukunaga Kohji
    • Journal Title

      Biomedicines

      Volume: 9 Issue: 5 Pages: 529-529

    • DOI

      10.3390/biomedicines9050529

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Impact of Fatty Acid-Binding Proteins in α-Synuclein-Induced Mitochondrial Injury in Synucleinopathy2021

    • Author(s)
      Cheng An、Jia Wenbin、Kawahata Ichiro、Fukunaga Kohji
    • Journal Title

      Biomedicines

      Volume: 9 Issue: 5 Pages: 560-560

    • DOI

      10.3390/biomedicines9050560

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fatty acid-binding protein 7 triggers α-synuclein oligomerization in glial cells and oligodendrocytes associated with oxidative stress2021

    • Author(s)
      Cheng An、Wang Yi-fei、Shinoda Yasuharu、Kawahata Ichiro、Yamamoto Tetsunori、Jia Wen-bin、Yamamoto Hanae、Mizobata Tomohiro、Kawata Yasushi、Fukunaga Kohji
    • Journal Title

      Acta Pharmacologica Sinica

      Volume: 43 Issue: 3 Pages: 552-562

    • DOI

      10.1038/s41401-021-00675-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] T-type Ca2+ channel enhancer SAK3 administration improves the BPSD-like behaviors in AppNL?G-F/NL?G-F knock-in mice2021

    • Author(s)
      Degawa Tomohide、Kawahata Ichiro、Izumi Hisanao、Shinoda Yasuharu、Fukunaga Kohji
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 146 Issue: 1 Pages: 1-9

    • DOI

      10.1016/j.jphs.2021.02.006

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] An α-synuclein decoy peptide prevents cytotoxic α-synuclein aggregation caused by fatty acid binding protein 3.2021

    • Author(s)
      Fukui N, Yamamoto H, Miyabe M, Aoyama Y, Hongo K, Mizobata T, Kawahata I, Yabuki Y, Shinoda Y, Fukunaga K, Kawata Y.
    • Journal Title

      J Biol Chem.

      Volume: Apr 13 Pages: 100663-100663

    • DOI

      10.1016/j.jbc.2021.100663

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characterization of design grammar of peptides for regulating liquid droplets and aggregates of FUS2021

    • Author(s)
      Kamagata Kiyoto、Chiba Rika、Kawahata Ichiro、Iwaki Nanako、Kanbayashi Saori、Maeda Kana、Takahashi Hiroto、Hirano Atsushi、Fukunaga Koji、Ikeda Keisuke、Kameda Tomoshi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 6643-6643

    • DOI

      10.1038/s41598-021-86098-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Role of CaMKII and ERK Signaling in Addiction2021

    • Author(s)
      Jia Wenbin、Kawahata Ichiro、Cheng An、Fukunaga Kohji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 6 Pages: 3189-3189

    • DOI

      10.3390/ijms22063189

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Suppression of α-synuclein propagation after intrastriatal injection in FABP3 null mice2021

    • Author(s)
      Matsuo Kazuya、Kawahata Ichiro、Melki Ronald、Bousset Luc、Owada Yuji、Fukunaga Kohji
    • Journal Title

      Brain Research

      Volume: 1760 Pages: 147383-147383

    • DOI

      10.1016/j.brainres.2021.147383

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Epidermal Fatty Acid-Binding Protein 5 (FABP5) Involvement in Alpha-Synuclein-Induced Mitochondrial Injury under Oxidative Stress2021

    • Author(s)
      Wang Yifei、Shinoda Yasuharu、Cheng An、Kawahata Ichiro、Fukunaga Kohji
    • Journal Title

      Biomedicines

      Volume: 9 Issue: 2 Pages: 110-110

    • DOI

      10.3390/biomedicines9020110

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice2021

    • Author(s)
      Yuan Dian、Cheng An、Kawahata Ichiro、Izumi Hisanao、Xu Jing、Fukunaga Kohji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 2 Pages: 741-741

    • DOI

      10.3390/ijms22020741

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dopamine D2 Long Receptors Are Critical for Caveolae-Mediated α-Synuclein Uptake in Cultured Dopaminergic Neurons2021

    • Author(s)
      Kawahata Ichiro、Sekimori Tomoki、Wang Haoyang、Wang Yanyan、Sasaoka Toshikuni、Bousset Luc、Melki Ronald、Mizobata Tomohiro、Kawata Yasushi、Fukunaga Kohji
    • Journal Title

      Biomedicines

      Volume: 9 Issue: 1 Pages: 49-49

    • DOI

      10.3390/biomedicines9010049

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Impaired Acquisition of Nicotine-Induced Conditioned Place Preference in Fatty Acid-Binding Protein 3 Null Mice2021

    • Author(s)
      Jia Wenbin、Wilar Gofarana、Kawahata Ichiro、Cheng An、Fukunaga Kohji
    • Journal Title

      Molecular Neurobiology

      Volume: 58 Issue: 5 Pages: 2030-2045

    • DOI

      10.1007/s12035-020-02228-2

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fatty Acid Binding Protein 5 Mediates Cell Death by Psychosine Exposure through Mitochondrial Macropores Formation in Oligodendrocytes2020

    • Author(s)
      Cheng An、Kawahata Ichiro、Fukunaga Kohji
    • Journal Title

      Biomedicines

      Volume: 8 Issue: 12 Pages: 635-635

    • DOI

      10.3390/biomedicines8120635

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Intranasal Administration of Conditioned Medium from Cultured Mesenchymal Stem Cells Improves Cognitive Impairment in Olfactory Bulbectomized Mice2020

    • Author(s)
      Kojima Kazuhiro、Kawahata Ichiro、Izumi Hisanao、Yoshihara Sei-ichi、Oki Katsuyuki、Fukunaga Kohji
    • Journal Title

      Advances in Alzheimer's Disease

      Volume: 09 Issue: 03 Pages: 47-56

    • DOI

      10.4236/aad.2020.93004

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anti-Epileptic Effects of FABP3 Ligand MF1 through the Benzodiazepine Recognition Site of the GABAA Receptor2020

    • Author(s)
      Yabuki Yasushi、Liu Jiaqi、Kawahata Ichiro、Izumi Hisanao、Shinoda Yasuharu、Koga Kohei、Ueno Shinya、Shioda Norifumi、Fukunaga Kohji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 15 Pages: 5525-5525

    • DOI

      10.3390/ijms21155525

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] SAK3 Administration Improves Spine Abnormalities and Cognitive Deficits in AppNL-G-F/NL-G-F Knock-in Mice by Increasing Proteasome Activity through CaMKII/Rpt6 Signaling2020

    • Author(s)
      Izumi Hisanao、Kawahata Ichiro、Shinoda Yasuharu、Helmstetter Fred J.、Fukunaga Kohji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 11 Pages: 3833-3833

    • DOI

      10.3390/ijms21113833

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 5-aminolevulinic acid inhibits oxidative stress and ameliorates autistic-like behaviors in prenatal valproic acid-exposed rats2020

    • Author(s)
      Kazuya Matsuo, Yasushi Yabuki, Kohji Fukunaga
    • Journal Title

      Neuropharmacology

      Volume: 168 Pages: 107975-107992

    • DOI

      10.1016/j.neuropharm.2020.107975

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] Alzheimer disease-related memory deficits are associated with the deceased proteasome activity by impaired CaMKII/Rpt6 signaling2020

    • Author(s)
      Kohji Fukunaga
    • Organizer
      第14回プロテインホスファターゼ国際カンファレンス
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Alzheimer disease-related memory deficits are associated with the deceased proteasome activity by impaired CaMKII/Rpt6 signaling2020

    • Author(s)
      Kohji Fukunaga, Ichiro Kawahata
    • Organizer
      第14回プロテインホスファターゼ国際カンファレンス
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Novel therapeutic targets for Parkinson’s disease and movement disorders.2020

    • Author(s)
      Kawahata I, Hoshino K, Hasegawa K, Ichinose H, Kobayashi K and Fukunaga K
    • Organizer
      AAT-AD/PD 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Novel regulatory mechanism for tyrosine hydroxylase gene expression and its ubiquitin-proteasomal degradation.2020

    • Author(s)
      Kawahata I and Fukunaga K
    • Organizer
      第14回プロテインホスファターゼ国際カンファレンス
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 自閉スペクトラム症ラットにおける脳内酸化ストレスと自閉症様行動の関連性2020

    • Author(s)
      松尾 和哉、篠田 康晴、福永 浩司
    • Organizer
      第93回 日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Remarks] 先進脳創薬講座・研究概要と成果

    • URL

      http://www.pharm.tohoku.ac.jp/~brain/index-j.html

    • Related Report
      2021 Annual Research Report

URL: 

Published: 2019-04-18   Modified: 2023-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi