Neuroprotective mechanisms mediated by PKC phosphorylation in spinocerebellar degeneration and their application to novel therapies.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06801
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Kobe University
• Principal Investigator: Shirafuji Toshihiko 神戸大学, 医学研究科, 特命講師 (30595765)
• Co-Investigator(Kenkyū-buntansha): 上山 健彦 神戸大学, バイオシグナル総合研究センター, 教授 (80346254)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: PKC / SCA / 脊髄小脳変性症 / リン酸化 / VCP / PLEKHG4

Outline of Final Research Achievements

Previous reports suggest that increased PKC activity is a common neuroprotective mechanism in cerebellar Purkinje cells in SCA.
In the present study, we identified VCP and PLEKHG4 as PKC substrates in cerebellar Purkinje cells, with PKC phosphorylation sites at Ser770 and Ser27, Ser677 respectively.
The interaction of PLEKHG4 phosphorylation mutants with RAC1 and CDC42 was analysed and phosphorylation was critical for the interaction, suggesting that PLEKHG4 S27 and S677 phosphorylation exerts cerebellar Purkinje cell protection via RAC1 and CDC42 function. In contrast, no data were obtained on the involvement of VCP S770 phosphorylation in cell death.

Free Research Field

病態神経学

Academic Significance and Societal Importance of the Research Achievements

小脳プルキンエ細胞にPLEKHG4, VCPともに発現するので、小脳プルキンエ細胞保護作用のあるPKC活性化の基質が解明された。また、PLEKHG4については、RAC1/CDC42との結合がリン酸化で調整されることが解明された。
これらのことは小脳プルキンエ細胞でのPKCリン酸化シグナルの一端が解明されたことになり、SCAの病態解明、治療法開発に資するものである。