DJ-1 inhibits glutathione degradation by downregulating CHAC1 expression in astrocytes. (November 2022)

• Record Type: Journal Article
• Authors: Ge, Yuan; Zheng, Xinlei; Mao, Shiyu; Zhang, Qingyu; Hu, Gang; Wei, Yao
• Is Part Of: Neuroscience research. Volume 184(2022)
• Page Start: 62
• Page End: 69
• Publication Date: 2022-11
• Subjects: DJ-1 -- ChaC glutathione-specific gamma-glutamylcyclotransferase 1 -- Activating transcription factor 3 -- Glutathione metabolism -- Astrocyte; Neurosciences -- Research -- Periodicals; Neurosciences -- Research -- Japan -- Periodicals; Neurology -- Periodicals; Neurosciences -- Periodicals; Neurosciences -- Recherche -- Périodiques; Neurosciences -- Recherche -- Japon -- Périodiques; Neurosciences -- Research; Japan; Periodicals; 612.8
• DOI: 10.1016/j.neures.2022.08.006
• Languages: English
• ISSNs: 0168-0102

Abstract

Abstract: The PARK7 gene, which encodes DJ-1 protein, is the causative gene of autosomal recessive early-onset Parkinson's disease. DJ-1 has many biological functions, including regulating glutathione (GSH) levels. However, the molecular mechanism by which DJ-1 regulates GSH levels in astrocytes remains unclear. With high throughput sequencing, we discovered that DJ-1 knockout could significantly upregulate the expression of ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1). We demonstrate that DJ-1 can bind with the basic leucine zipper domain of activating transcription factor 3 (ATF3) through bimolecular fluorescence complementation. Besides, DJ-1 inhibits ATF3 binding to the CHAC1 promoter and downregulates the expression of CHAC1 to reduce GSH degradation. Our research suggests that the loss of DJ-1 in astrocytes promotes the degradation of GSH, leading neurons more vulnerable to oxidative damage. It provides a theoretical basis for developing drugs targeting DJ-1 and GSH in the brain. Highlights: DJ-1 in astrocytes can regulate glutathione levels. CHAC1 expression is elevated in DJ-1 knockout cells. DJ-1 binds to the basic leucine zipper domain of ATF3 to inhibit its binding to the CHAC1 promoter. DJ-1 inhibits glutathione degradation by downregulating CHAC1 expression.