STXBP1 haploinsufficiency impairs membrane trafficking and dendrite growth

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16898
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Tozawa Takenori 京都府立医科大学, 医学(系)研究科(研究院), 助教 (30804950)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: STXBP1脳症 / Munc18-1 / Syntaxin1A / MyosinVa / 細胞内輸送障害

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.

Free Research Field

小児神経学

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。