Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson’s Disease

详细信息    查看全文

• 作者：William M. Johnson ; Marcin Golczak ; Kyonghwan Choe ; Pierce L. Curran ; Olga Gorelenkova Miller ; Chen Yao ; Wenzhang Wang ; Jiusheng Lin ; Nicole M. Milkovic ; Ajit Ray ; Vijayalakshmi Ravindranath ; Xiongwei Zhu ; Mark A. Wilson ; Amy L. Wilson-Delfosse ; Shu G. Chen ; John J. Mieyal
• 刊名：Biochemistry
• 出版年：2016
• 出版时间：August 16, 2016
• 年：2016
• 卷：55
• 期：32
• 页码：4519-4532
• 全文大小：652K
• 年卷期：0
• ISSN：1520-4995

文摘

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, caused by the degeneration of the dopaminergic neurons in the substantia nigra. Mutations in PARK7 (DJ-1) result in early onset autosomal recessive PD, and oxidative modification of DJ-1 has been reported to regulate the protective activity of DJ-1 in vitro. Glutathionylation is a prevalent redox modification of proteins resulting from the disulfide adduction of the glutathione moiety to a reactive cysteine-SH, and glutathionylation of specific proteins has been implicated in regulation of cell viability. Glutaredoxin 1 (Grx1) is the principal deglutathionylating enzyme within cells, and it has been reported to mediate protection of dopaminergic neurons in Caenorhabditis elegans; however many of the functional downstream targets of Grx1 in vivo remain unknown. Previously, DJ-1 protein content was shown to decrease concomitantly with diminution of Grx1 protein content in cell culture of model neurons (SH-SY5Y and Neuro-2A lines). In the current study we aimed to investigate the regulation of DJ-1 by Grx1 in vivo and characterize its glutathionylation in vitro. Here, with Grx^–/– mice we provide show that Grx1 regulates protein levels of DJ-1 in vivo. Furthermore, with model neuronal cells (SH-SY5Y) we observed decreased DJ-1 protein content in response to treatment with known glutathionylating agents, and with isolated DJ-1 we identified two distinct sites of glutathionylation. Finally, we found that overexpression of DJ-1 in the dopaminergic neurons partly compensates for the loss of the Grx1 homologue in a C. elegans in vivo model of PD. Therefore, our results reveal a novel redox modification of DJ-1 and suggest a novel regulatory mechanism for DJ-1 content in vivo.