Regulation of neural circuit by Fragile X Mental Retardation Protein - its relation to ubiquitination and local translation

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07061
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Yokohama City University
• Principal Investigator: Yukio Sasaki 横浜市立大学, 生命医科学研究科, 准教授 (10295511)
• Research Collaborator: Ito Hidenori
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 横浜市 / 神経生物学 / 脆弱X症候群 / ユビキチン / セマフォリン

Outline of Final Research Achievements

The role of fragile X mental retardation protein (FMRP) in axon guidance and synapse formation during neural circuit formation was examined in relation to ubiquitination and local translation. Our results suggest that after stimulation with the axon guidance molecule Sema3A, FMRP was degraded in growth cones by the ubiquitin-proteasome system, followed by that local translation was triggered to induce a morphological change of growth cones. We also identified the ubiquitination related gene for FMRP, and found that the gene product induced disappearance of FMRP after granular accumulation of FMRP. FMRP-containing granules were also observed during synapse formation. Therefore, our findings suggested that ubiquitination of FMRP is involved in neural circuit formation through regulation of granule formation and local translation of FMRP.

Free Research Field

神経生物学

Academic Significance and Societal Importance of the Research Achievements

脆弱X症候群 (FXS)は遺伝性の発達障害としては最も頻度の高い疾患であり、知的障害、自閉症等の症状を示す。FXSの原因遺伝子産物であるFMRPは神経細胞において軸索、樹状突起における局所翻訳を制御し神経回路形成において重要な役割を担っているが、そのメカニズムは不明であった。我々が今回明らかにしたメカニズムは神経回路の発達にFMRPのユビキチン化が関与することを示唆する結果である。FXSに対する創薬は自閉症全般に応用できると考えられ、多くの製薬会社が参入しているが、まだ有効な薬剤は開発されていない。本研究の親展によりFXSの病態の一端が明らかになり、治療法の開発や創薬に結びつく可能性がある。