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

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

Research output: Contribution to journalArticle

14 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)4519-4532
Number of pages14
JournalBiochemistry
Volume55
Issue number32
DOIs
StatePublished - Aug 16 2016

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry

Cite this

Johnson, W. M., Golczak, M., Choe, K., Curran, P. L., Miller, O. G., Yao, C., Wang, W., Lin, J., Milkovic, N. M., Ray, A., Ravindranath, V., Zhu, X., Wilson, M. A., Wilson-Delfosse, A. L., Chen, S. G., & Mieyal, J. J. (2016). Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson's Disease. Biochemistry, 55(32), 4519-4532. https://doi.org/10.1021/acs.biochem.5b01132