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Impaired ER-Golgi trafficking as a novel cellular pathology for Pelizaeus-Merzbacher disease

Research Project

Project/Area Number 16H05361
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionNational Center of Neurology and Psychiatry

Principal Investigator

INOUE KEN  国立研究開発法人国立精神・神経医療研究センター, 神経研究所 疾病研究第二部, 室長 (30392418)

Co-Investigator(Kenkyū-buntansha) 小坂 仁  自治医科大学, 医学部, 教授 (90426320)
Research Collaborator LI Heng  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2018: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Keywords細胞病態 / ペリツェウス・メルツバッハー病 / 小胞体 / 分泌経路 / 小胞体ストレス / 輸送障害 / 小児神経学 / ペリツェウス・メルツバッハ病
Outline of Final Research Achievements

The purpose of this study is to delineate the cellular pathogensis of a hypomyelnating leukodystrophy, Pelizaeus-Merzbacher disease caused by amino-acid substitution in the PLP1, which a myelin membrane protein in the central nervous system. In addition to the unfolded protein response, we identified that the mutant PLP1 disturb the transport of normal membrane and secretary proteins by impairing the formation of COPII vesicle that serve as transporting vehecles from ER to Golgi apparatus.

Academic Significance and Societal Importance of the Research Achievements

Pelizaeus-Merzbacher病は、生涯にわたって重度の障害を伴う小児の遺伝性神経難病であり、現在治療法はない。原因遺伝子であるPLP1のアミノ酸置換変異がオリゴデンドロサイトに引き起こす細胞毒性が著明な中枢神経系の髄鞘化不全を引き起こすことが疾患の本態と考えられているが、この細胞毒性の分子機序はこれまで不明であった。今回、ER-Golgi体輸送経路の障害が明らかになり、さらにCOPII小胞の形成が障害されることを明らかにしたので、今後これを分子標的とした治療法開発を行うことが可能になると期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (35 results)

All 2019 2018 2017 2016

All Journal Article (12 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 11 results,  Open Access: 6 results,  Acknowledgement Compliant: 2 results) Presentation (23 results) (of which Int'l Joint Research: 11 results,  Invited: 3 results)

  • [Journal Article] A novel intragenic deletion in OPHN1 in a Japanese patient with Dandy-Walker malformation.2019

    • Author(s)
      Iida A, Takeshita E, Kosugi S, Kamatani Y, Momozawa Y, Kubo M, Nakagawa E, Kurosawa K, Inoue K, Goto YI
    • Journal Title

      Human Genome Variation

      Volume: 6 Issue: 1 Pages: 1-4

    • DOI

      10.1038/s41439-018-0032-8

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing2019

    • Author(s)
      Iwama Kazuhiro、Mizuguchi Takeshi、Miyatake Satoko、Matsumoto Naomichi、et al
    • Journal Title

      Journal of Medical Genetics

      Volume: - Issue: 6 Pages: 396-407

    • DOI

      10.1136/jmedgenet-2018-105775

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Modelling Duchenne muscular dystrophy in MYOD1-converted urine-derived cells treated with 3-deazaneplanocin A hydrochloride2019

    • Author(s)
      Takizawa Hotake、Hara Yuko、Mizobe Yoshitaka、Ohno Taisuke、Suzuki Sadafumi、Inoue Ken、Takeshita Eri、Shimizu-Motohashi Yuko、Ishiyama Akihiko、Hoshino Mikio、Komaki Hirofumi、Takeda Shin’ichi、Aoki Yoshitsugu
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 3807-3807

    • DOI

      10.1038/s41598-019-40421-z

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP12019

    • Author(s)
      Yamamoto-Shimojima Keiko、Imaizumi Taichi、Aoki Yusuke、Inoue Ken、Kaname Tadashi、Okuno Yusuke、Muramatsu Hideki、Kato Kohji、Yamamoto Toshiyuki
    • Journal Title

      Journal of Human Genetics

      Volume: 未定 Issue: 7 Pages: 665-671

    • DOI

      10.1038/s10038-019-0600-x

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gene suppressing therapy for Pelizaeus-Merzbacher disease using artificial microRNA2019

    • Author(s)
      Li Heng、Okada Hironori、Suzuki Sadafumi、Sakai Kazuhisa、Izumi Hitomi、Matsushima Yukiko、Ichinohe Noritaka、Goto Yu-ichi、Okada Takashi、Inoue Ken
    • Journal Title

      JCI Insight

      Volume: 4 Issue: 10 Pages: 125052-125052

    • DOI

      10.1172/jci.insight.125052

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A patient with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and severe hypoganglionosis associated with a novel SOX10 mutation.2018

    • Author(s)
      Akutsu Y, Shirai K, Takei A, Goto Y, Aoyama T, Watanabe A, Imamura M, Enokizono T, Oto T, Hori T, Suzuki K, Hayashi M, Masumoto K, Inoue K.
    • Journal Title

      Am J Med Genet Part A.

      Volume: 176 Issue: 5 Pages: 1195-1199

    • DOI

      10.1002/ajmg.a.38657

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association of impaired neuronal migration with cognitive deficits in extremely preterm infants.2017

    • Author(s)
      Kubo, K.I., Deguchi, K., Nagai, T,, Ito, Y., Yoshida, K., Endo, T., Benner, S., Shan, W., Kitazawa, A., Aramaki, M., Ishii, K., Shin, M., Matsunaga, Y., Hayashi, K., Kakeyama, M., Tohyama, C., Tanaka, K.F., Tanaka, K., Takashima, S., Nakayama, M.
    • Journal Title

      JCI Insight.

      Volume: 2 Issue: 10 Pages: 88609-88609

    • DOI

      10.1172/jci.insight.88609

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cellular pathology of Pelizaeus-Merzbacher disease involving chaperones associated with endoplasmic reticulum stress.2017

    • Author(s)
      Inoue K.
    • Journal Title

      Front. Mol. Biosci.

      Volume: 4 Pages: 7-7

    • DOI

      10.3389/fmolb.2017.00007

    • Related Report
      2017 Annual Research Report
    • Open Access
  • [Journal Article] The magnetic resonance imaging spectrum of Pelizaeus-Merzbacher disease: A multicenter study of 19 patients.2016

    • Author(s)
      Sumida K, Inoue K, Takanashi JI, Sasaki M, Watanabe K, Suzuki M, Kurahashi H, Omata T, Tanaka M, Yokochi K, Iio J, Iyoda K, Kurokawa T, Matsuo M, Sato T, Iwaki A, Osaka H, Kurosawa K, Yamamoto T, Matsumoto N, Maikusa N, Mastuda H, Sato N
    • Journal Title

      Brain Dev

      Volume: in press Issue: 6 Pages: 571-80

    • DOI

      10.1016/j.braindev.2015.12.007

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A splicing mutation of proteolipid protein 1 in Pelizaeus-Merzbacher disease.2016

    • Author(s)
      Omata T, Nagai J, Shimbo H, Koizume S, Miyagi Y, Kurosawa K, Yamashita S, Osaka H, Inoue K.
    • Journal Title

      Brain & Development

      Volume: 38 Issue: 6 Pages: 581-584

    • DOI

      10.1016/j.braindev.2015.12.002

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Novel <i>SLC16A2</i> mutations in patients with Allan-Herndon-Dudley syndrome2016

    • Author(s)
      Shimojima K, Maruyama K, Kikuchi M, Imai A, Inoue K, Yamamoto T.
    • Journal Title

      Intractable & Rare Diseases Research

      Volume: 5 Issue: 3 Pages: 214-217

    • DOI

      10.5582/irdr.2016.01051

    • NAID

      130005410394

    • ISSN
      2186-361X, 2186-3644
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Brain atrophy in Pelizaeus-Merzbacher disease.2016

    • Author(s)
      Inoue K
    • Journal Title

      Dev Med Child Neurol.

      Volume: 58 Issue: 7 Pages: 653-653

    • DOI

      10.1111/dmcn.13077

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Presentation] To understand and fix the problems of hypomyelinating leukodystrophy2019

    • Author(s)
      Inoue K.
    • Organizer
      Glial Section Annual Meeting of the Korean Society for Brain and Neural Sciences
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 先天性大脳白質形成不全症の診断サポートのためのコンサルテーションボード2018

    • Author(s)
      井上 健、黒澤健司、才津浩智、山本俊至、小坂 仁、高梨潤一
    • Organizer
      第60回日本小児神経学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 線維芽細胞から神経細胞へのdirect conversionによる疾患原因遺伝子変異の機能解析2018

    • Author(s)
      植松有里佳、植松貢、佐藤亮、井上 健、呉繁夫
    • Organizer
      第60回日本小児神経学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] TUBB4A関連白質変性症7例のMR spectroscopyによる検討2018

    • Author(s)
      佐野賢太郎、室伏佑香、森山陽子、安藤直樹、池野充、井上 健、小坂仁、後藤知英、佐々木征行、萩野谷和裕、森本昌史、和田敬仁、髙梨潤一
    • Organizer
      第60回日本小児神経学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Neuronal network damage in mouse model of extremely preterm infants with brain injury.2018

    • Author(s)
      K. Deguchi, K. Kubo, K. Inoue, K. Nakajima.
    • Organizer
      ISDN 2018: 22nd Biennial Meeting of the International Society of Developmental Neuroscience
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Development of AAV enabling oligodendrocyte-specific gene suppression: implication for the treatment of Pelizaeus-Merzbacher disease.2018

    • Author(s)
      Inoue K, Li, H Okada H, Goto Y, Okada T
    • Organizer
      11th FENS, Forum of Neuroscience.
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Aritificial miRNAシステムを用いたAAV遺伝子発現抑制治療法の開発:Pelizaeus-Merzbacher病の治療法開発を目指して2018

    • Author(s)
      井上健、李コウ、岡田浩典、後藤雄一、岡田尚巳
    • Organizer
      第63回日本人類遺伝学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] AAV gene therapy with artificial miRNA-mediated oligodendrocyte-specific gene suppression: implication for the treatment of Pelizaeus-Merzbacher disease with PLP1 duplication.2018

    • Author(s)
      Inoue K, Li H, Okada H, Goto Y, Okada T.
    • Organizer
      The American Society of Human Genetics Annual Meeting 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Clinical and genomic characterization of seven novel PLP1 deletion cases reveals large-deletion syndrome specific to female cases.2018

    • Author(s)
      H. Hijazi, G.M. Hobson, L. Bernardini, S.S. Mar, M.A. Manning, A. Hanson-Kahn, C. Gonzaga-Jauregui, P. Simons, K. Sperle, F.S. Coelho, J.A. Lee, P. Fang, S.W. Cheung, K. Inoue, D. Pehlivan, J.R. Lupski, C.M.B Carvalho
    • Organizer
      The American Society of Human Genetics Annual Meeting 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Chemical chaperone screening for Pelizaeus-Merzbacher disease.2018

    • Author(s)
      T. Kouga, S. Koizume, E. Jimbo, T. Yamagata, K. Inoue, H. Osaka.
    • Organizer
      The American Society of Human Genetics Annual Meeting 2018.
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] elizaeus-Merzbacher病におけるPLP1遺伝子重複を標的としたAAVによるartificial miRNA遺伝子治療2018

    • Author(s)
      李 コウ、岡田 浩典、境 和久、岡田 尚巳、一戸 紀孝、後藤 雄一、井上 健
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Development of treatment for Pelizaeus-Merzbacher disease: drug-repositioning approach targeting a novel cellular pathology.2017

    • Author(s)
      K Inoue, H Li, Y Numata, H Saya, Y Goto.
    • Organizer
      12th European Pediatric Neurology Society Congress.
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 統合脳画像収集システムIBISSを利用したPelizaeus-Merzbcher病の臨床画像解析と疾患レジストリへの展開2017

    • Author(s)
      井上 健、住田 薫、高梨潤一、松田博史、佐々木征行、佐藤典子
    • Organizer
      第59回日本小児神経学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 急性散在性脳脊髄炎(ADEM)を発症したPolIII関連白質ジストロフィーの一例2017

    • Author(s)
      松岡剛司, 比屋根真彦, 大府正治, 山本俊至, 小坂仁, 高梨潤一, 才津浩智, 井上健.
    • Organizer
      第59回日本小児神経学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 遺伝性白質疾患の診断・治療・研究システムの構築2017

    • Author(s)
      小坂 仁,井上 健,三重野 牧子,吉田 誠克,久保田 雅也,佐々木 征行、松井 大,才津 浩智,髙梨 潤一,黒澤 健司,山本 俊至
    • Organizer
      第59回日本小児神経学会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 大脳白質形成不全を呈する疾患原因の解明Congenital cerebral hypomyelination.2017

    • Author(s)
      小坂 仁,井上 健
    • Organizer
      第59回日本小児神経学会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Genetic, clinical, and imaging study of Pelizaeus-Merzbacher disease using the Integrative Brain Imaging Support System (IBISS).2017

    • Author(s)
      Inoue K, Sumida K, Takanashi J, Matsuda H, Sasaki M, Sato N.
    • Organizer
      The American Society of Human Genetics Annual Meeting 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 小胞体-ゴルジ体輸送障害:Pelizaeus-Merzbacher病の新規細胞分子病態2017

    • Author(s)
      井上 健、李コウ、植松有里佳、後藤雄一
    • Organizer
      第62回日本人類遺伝学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 超早産児脳障害のモデルマウス脳における組織構築の解析2017

    • Author(s)
      久保 健一郎、出口 貴美子、北澤 彩子、石井 一裕、シン ミンギョン、高嶋 幸男、中山 雅弘、伊藤 雅之、井上 健、仲嶋 一範
    • Organizer
      第122回日本解剖学会総会
    • Related Report
      2016 Annual Research Report
  • [Presentation] ER-Golgi transport may serve as a novel drug target for Pelizaeus-Merzbacher disease caused by PLP1 amino acid substitutions.2016

    • Author(s)
      K Inoue, H Li, P.R. Mangalika, A Nishizawa, Y Numata, S Nakamura, T Morimura, H Saya, Y Goto.
    • Organizer
      13th International Congress of Human Genetics.
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Additive dominant effect of a SOX10 mutation underlying the complex phenotypes of PCWH.2016

    • Author(s)
      K. Inoue, Y. Ito, N. Inoue, Y.U. Inoue, S. Nakamura, Y. Matsuda, M. Inagaki, T. Ohkubo, J. Asami, Y.W. Terakawa, S. Kohsaka, Y. Goto, C. Akazawa, T. Inoue.
    • Organizer
      21st Biennial Meeting of the International Society for Developmental Neuroscience.
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 新規細胞病態を標的としたPelizaeus-Merzbacher病の治療薬の探索2016

    • Author(s)
      井上 健、マンガリイ・プリアンティ、西澤絢子、李コウ、中村祥子、佐谷秀行、後藤雄一
    • Organizer
      第58回日本小児神経学会
    • Related Report
      2016 Annual Research Report
  • [Presentation] Impaired ER-Golgi trafficking as a novel therapeutic target for Pelizaeus-Merzbacher disease caused by PLP1 amino acid substitutions.2016

    • Author(s)
      K Inoue, H Li, P.R. Mangalika, A Nishizawa, H Saya, Y Goto.
    • Organizer
      The American Society of Human Genetics Annual Meeting 2016
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research

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Published: 2016-04-21   Modified: 2020-03-30  

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