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

Johnson, William M and Golczak, Marcin and Choe, Kyonhwan and Curran, Pierce L and Miller, Olga Gorelenkova and Yao, Chen and Wang, Wenzhang and Lin, Jiusheng and Milkovic, Nicole M and Ray, Ajit and Ravindranath, Vijayalakshmi and Zhu, Xiongwei and Wilson, Mark A and Wilson-Delfosse, Amy L and Chen, Shu G and Mieyal, John J (2016) Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson's Disease. In: BIOCHEMISTRY, 55 (32). pp. 4519-4532.

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Abstract

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 (Grxl) 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 protection of dopaminergic Grxl in vivo remain unknown. Previously, DJ-1 protein content was shown to decrease concomitantly with diminution of Grxl protein content in cell culture of model neurons (SH-SYSY and Neuro-2A lines). In the current study we aimed to investigate the regulation of DJ-1 by Grxl in vivo and characterize its glutathionylation in vitro. Here, with Grx(-/-) mice we provide show that Grxl 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 Grxl 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.

Item Type:	Journal Article
Publication:	BIOCHEMISTRY
Additional Information:	Copy right for this article belongs to the AMER CHEMICAL SOC, 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
Department/Centre:	Division of Biological Sciences > Centre for Neuroscience
Date Deposited:	22 Oct 2016 09:22
Last Modified:	22 Oct 2016 09:22
URI:	http://eprints.iisc.ac.in/id/eprint/55021

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