Altered phosphorylation of GAP-43 in epileptogenesis of the Hippocampal sclerosis

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17955
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Niigata University
• Principal Investigator: Okada Masayasu 新潟大学, 医歯学総合病院, 助教 (00626492)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 神経成長因子 / てんかん / 神経成長 / リン酸化 / リン酸化プロテオミクス

Outline of Final Research Achievements

We have recently discovered the phosphospecific mouse GAP-43 threonine 172 (pT172) antibody (Ab) as a growing axon marker. Mesial temporal lobe epilepsy (MTLE) caused by hippocampal sclerosis was reported that the neurons in the dentate hilus degenerated and that abnormal nerve sprouts occurred in granule cell layer (GCL) of the dentate gyrus (DG). However, there have been no previous reports on GAP-43 phosphorylation. Primate pT181 is corresponding to rodent pT172, and we tried applying this probe to human brain events and pathology, including MTLE. Using human iPS cell-derived neurons, we immunocytochemically identified pT181. We acquired the flavin fluorescence image at the GCL of DG in the living human hippocampal tissue of MTLE patients. The signal changes were correlated with the pT181-immunostaining intensity of GCL. The pT181 Ab was a marker probe to detect the growing axon in human development and the abnormal neuronal circuit.

Free Research Field

脳神経外科分野

Academic Significance and Societal Importance of the Research Achievements

本研究は、GAP-43という神経成長関連因子に関し、ヒトを含む正常神経細胞の成長や再生に関わるリン酸化部位とその制御キナーゼを初めて明らかにした。またその制御メカニズムが、難治性てんかんとして現在外科治療で治療されている内側側頭葉てんかんである海馬硬化症の海馬摘出標本においても認められ、後天的な異常神経回路形成においても、正常な神経発達のメカニズムが機能していることを明らかできた。今後こうした研究により、「てんかん」原生となる異常な神経回路形成そのものを抑制する治療法の開発が期待される。