Mechanisms of epigenetic regulation of glod-4/GLO1 gene in C. elegans

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07842
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Kanazawa University
• Principal Investigator: Shin-ichi Harada 金沢大学, 医学系, 准教授 (90272955)
• Co-Investigator(Kenkyū-buntansha): 原島 愛 金沢大学, 医学系, 助教 (50705522)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: Glyoxlase

Outline of Final Research Achievements

Mutations in the glyoxalase gene, GLO1 which encode a methylglyoxal metabolizing enzyme, have been reported in some patients with schizophrenia. To understand the transcriptional mechanisms of GLO1, we analyzed the transcriptional regulatory regions of the glad-4 gene, which encodes the human GLO1 gene homolog in the nematode C. elegans. As a result, multiple highly homologous regions were found in the upstream regulatory regions of both the GLO1 / glod-4 gene, but it was not possible to identify the binding activity of SKN-1/Nrf2, which is one of the transcription factor, that binds the ARE motif identified in the upstream region of GLO1 gene.
In addition, we found the compound X, which is presumed to be involved in the life extension of the glod-4 mutant by using the screening of the drug library.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

生体内では糖質が代謝されることによりグリオキサール(GO)やメチルグリオキサール(MG)などの中間体が生成する。これら中間体の細胞毒性は非常に強く、加齢や糖尿病状態により蓄積することで糖尿病合併症の発症・進展に関与するだけでなく、神経変性疾患などの多様な疾患にも深くかかわっている。これら代謝物は、解毒酵素と呼ばれるGlyoxalase(GLO1)により酵素的に代謝され反応性の低い乳糖に変換される。
近年、MGによる精神疾患への関与が指摘され、MGの代謝、解毒に関与するGLO1とさまざまな精神疾患との関連や、GLO1遺伝子の分子基盤をを明らかにすることは精神疾患治療薬開発にも極めて重要である。