STXBP1 haploinsufficiency impairs membrane trafficking and dendrite growth
| Project/Area Number |
20K16898
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
Tozawa Takenori 京都府立医科大学, 医学(系)研究科(研究院), 助教 (30804950)
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | STXBP1脳症 / Munc18-1 / Syntaxin1A / MyosinVa / 細胞内輸送障害 / STX1A / syntaxin1A / 膜輸送障害 / 蛋白質異常凝集 / 神経変性 / 発達性てんかん性脳症 / Myosin-Va |
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| Outline of Research at the Start |
STXBP1脳症は、乳児期早期に難治性てんかんに加え重度の精神発達遅滞を呈する発達性てんかん性脳症である。STXBP1の遺伝子産物Munc18-1は、Syntaxin-1Aのシャペロン分子としてシナプス開口放出に関わるが、STXBP1脳症の病態は不明な点が多い。申請者は、Munc18-1の未知の機能を予測するため、新規相互作用因子解析を行い、中枢神経に発現するモータータンパク質Myosin-Vaを同定した。本研究の目的は、STXBP1 脳症の病態は、膜に必要なタンパク質を輸送できない細胞内輸送障害であると仮説を立て、患者由来iPS細胞から誘導した神経細胞を用いてその病態を解明することである。
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| Outline of Final Research Achievements |
STXBP1 encephalopathy (STXBP1-E) is one of the early infantile onset developmental epileptic encephalopathy. Munc18-1, the gene encoding STXBP1, has a role in regulation of exocytosis as a chaperone protein of STX1A. However, there is little knowledge about another binding partner associated with STXBP1-E pathology. In this study, we found a novel interacting partner of Munc18-1, MyosinVa, by using affinity purification coupled to mass spectrometry. We revealed that Munc18-1, MyosinVa and STX1A are co-immunoprecipitated in mouse brain synaptosomes and colocalized in primary hippocampal culture neuron. Furthermore, RNAi- mediated gene knockdown in neuro2a cell demonstrate that the interaction between Munc18-1 and MyosinVa is required for membrane trafficking STX1A.
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| Academic Significance and Societal Importance of the Research Achievements |
これまでSTXBP1がコードするMunc18-1のSTX1A以外のbinding partnerの知見が少なかったため、Munc18-1のシナプス開口放出の調整以外の機能は不明であった。本研究において、Munc18-1がモーター蛋白質MyosinVaとの相互作用によってプレシナプス蛋白質を膜へ輸送する機能を持つことが分かったことは、STXBP1脳症の病態理解に役立つ点で学術的な意義が高い。
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Report
(3 results)
Research Products
(4 results)
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[Presentation] Functional and transcriptomic analysis of STXBP1 encephalopathy iPS-derived GABAergic neuron.2021
Author(s)
Eiske Ichise, Tomohiro Chiyonobu, Mitsuru Ishikawa, Yasuyoshi Tanaka, Takenori Tozawa, Satoshi Yamashita, Michiko Yoshida, Norimichi Higurashi, Toshiyuki Yamamoto, Hideyuki Okano, Shinichi Hirose.
Organizer
第63回日本小児神経学会学術集会
Related Report
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[Presentation] Impaired activity and differential gene expression in STXBP1 encephalopathy patient iPS-derived GABAergic neurons.2021
Author(s)
Eiske Ichise, Tomohiro Chiyonobu, Mitsuru Ishikawa, Yasuyoshi Tanaka, Mami Shibata, Takenori Tozawa, Satoshi Yamashita, Michiko Yoshida, Masafumi Morimoto, Norimichi Higurashi, Toshiyuki Yamamoto, Hideyuki Okano, Shinichi Hirose.
Organizer
日本人類伝学会第66回大会 第28回日本遺伝子診療学会大会 合同開催
Related Report
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