Regulation of DJ-1 by glutaredoxin 1 in vivo – implications for Parkinson’s disease

Authors

William M. Johnson, Case Western Reserve University
Marcin Golczak, Case Western Reserve University
Kyonghwan Choe, Case Western Reserve University
Pierce L. Curran, Case Western Reserve University
Olga Gorelenkova Miller, Case Western Reserve University
Chen Yao, Case Western Reserve University
Wenzhang Wang, Case Western Reserve University
Jiusheng Lin, University of Nebraska-LincolnFollow
Nicole M. Milkovic, University of Nebraska-Lincoln
Ajit Ray, Indian Institute of Science
Vijayalakshmi Ravindranath, Indian Institute of Science
Xiongwei Zhu, Case Western Reserve University
Mark A. Wilson, University of Nebraska-LincolnFollow
Amy L. Wilson-Delfosse, Case Western Reserve University
Shu G. Chen, Case Western Reserve UniversityFollow
John J. Mieyal, Case Western Reserve UniversityFollow

Document Type

Article

Date of this Version

2016

Citation

Biochemistry. 2016 August 16; 55(32): 4519–4532.

Comments

Copyright 2016 Johnson et al.

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 (Grx1) is the principal deglutathionylating enzyme within cells, and it has been reported to mediate protection of dopaminergic neurons in C. 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 evidence 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 homolog 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.