Neuronal glutathione loss leads to neuronal cell death accompanied by neuroinflammation

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16271
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Hashimoto ShokoShoko 国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (50632890)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: グルタチオン / 酸化ストレス / アルツハイマー病 / 神経変性疾患

Outline of Final Research Achievements

To defense against oxidative stress, organisms possess glutathione as an important antioxidant. However, glutathione level is decreased with ageing and progression of diseases including AD. Glutathione is synthesized through a reaction by Glutamyl-Cysteine ligase (GCL), which consists of catalytic subunit (GCLC) and modifier subunit (GCLM). We analyzed the brain pathologies of brain specific-conditional knockout mouse of GCLC (GCLC-cKO). In 3-month-old GCLC-cKO mice, we could see severe neuroinflammation. In 8-month-old, we observed significant brain atrophy caused by neuronal cell death. Moreover, we found significant increase in disease-associated microglia (DAM) and disease-associated astrocyte (DAA) markers, activation of C1q-mediated phagocytosis, and contribution of Gasdermine-mediated pyroptosis to neurodegeneration in GCLC-cKO. From our findings, we propose the mechanism by which a vicious cycle of oxidative stress and neuroinflammation facilitates neurodegenerative processes.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー病などの神経変性疾患における酸化ストレスの重要性を再確認することができた。さらに、酸化ストレスから神経変性までのメカニズムを明らかにしたことで、今後の酸化ストレス、神経炎症、神経変性疾患研究の促進につながる。また、酸化ストレスをターゲットとした神経変性疾患治療薬の開発にもつながる研究である。