Impaired membrane trafficking in STXBP1 encephalopathy

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15724
• 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): 2018-04-01 – 2020-03-31
• Keywords: STXBP1 encephalopathy / 発達性てんかん性脳症 / Munc18-1 / Myosin-Va / 軸索輸送障害 / 神経変性 / 細胞死

Outline of Final Research Achievements

To elucidate the pathology of STXBP1 encephalopathy, we tried to identify novel protein complex partners of Munc18-1 expressed in brain. By way of affinity purification coupled to mass spectrometry using PC12 cells, Myosin-Va which has a role of trafficking proteins required synapse formation in brain was identified as a candidate novel complex partner of Munc18-1. We confirmed co-immunoprecipitation of Munc18-1 short isofroms, not Munc18-1 long isoforms, with Myosin-Va and colocalization of two proteins in primary culture of mouse hippocampal neurons. Now, we are going to validate how Myosin-Va correlate with impairment of membrane trafficking in STXBP1 encephalopathy using the patient derived iPS neurons.

Free Research Field

小児神経学

Academic Significance and Societal Importance of the Research Achievements

STXBP1脳症は比較的頻度の多い発達性てんかん性脳症であるが、今回明らかになった新規相互作用因子Myosin-Vaに関連した細胞内輸送障害の病態を明らかにできれば、従来の抗てんかん薬のような対症療法のみならず、より病態に基づいた治療薬の開発につながると思われる。またSTXBP1脳症で起こると予想される細胞内輸送障害は、シナプス結合の異常や細胞死も引き起こす可能性があり、本疾患の病態解明はその他の発達性てんかん性脳症のみならず成人領域の神経変性疾患の分子病態の理解を深めることにもつながると思われる。