Control of neurite development by a novel SUMOylation-regulating mechanism

2022 Fiscal Year Final Research Report

• Project/Area Number: 18K06491
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Waseda University
• Principal Investigator: Akiyama Hiroki 早稲田大学, 人間科学学術院, その他(招聘研究員) (40568854)
• Co-Investigator(Kenkyū-buntansha): 榊原 伸一 早稲田大学, 人間科学学術院, 教授 (70337369)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Keywords: SUMO / SENP5 / 神経細胞 / 大脳発生 / ミトコンドリア

Outline of Final Research Achievements

Drp1, a key molecule in the mitochondrial fission machinery, undergoes various post-translational modifications including conjugation to the small ubiquitin-like modifier (SUMO). However, the functional significance of SUMOylation/deSUMOylation on Drp1 remains controversial. SUMO-specific protease 5 (Senp5L) catalyzes the deSUMOylation of Drp1.We revealed that a splicing variant of Senp5L, Senp5S, which lacks peptidase activity, prevents deSUMOylation of Drp1 by competing against other Senps. The altered SUMOylation level of Drp1 induced by Senp5L/5S affects mitochondrial morphology. A dynamic SUMOylation/deSUMOylation balance controls neuronal polarization and migration during the development of the cerebral cortex. These findings suggest a novel role of post-translational modification, in which deSUMOylation enzyme isoforms competitively regulate mitochondrial dynamics via Drp1 SUMOylation levels, in a tightly controlled process of neuronal differentiation and corticogenesis.

Free Research Field

神経細胞生物学

Academic Significance and Societal Importance of the Research Achievements

これまで不明であった，『神経系発生過程におけるSUMO化の機能的役割とは何か』という問いに答えをだせた本研究により，翻訳後修飾の生理機能，神経系の発生機構の理解が大きく進んだ。特筆すべきは，同一分子（SENP5）のアイソフォーム間の競合的なSUMO化制御という新しいメカニズムを発見し，この新規メカニズムによる制御をうけ，神経系発生過程へ関与する分子を同定したことである。
大脳皮質発生の異常は様々な疾患との関連が示されており，本研究から得られた知見はこれらの疾患の病因解明の一助となると考えられる。