| RRC ID |
53237
|
| 著者 |
Johnson WM, Golczak M, Choe K, Curran PL, Miller OG, Yao C, Wang W, Lin J, Milkovic NM, Ray A, Ravindranath V, Zhu X, Wilson MA, Wilson-Delfosse AL, Chen SG, Mieyal JJ.
|
| タイトル |
Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson's Disease.
|
| ジャーナル |
Biochemistry
|
| 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.
|
| 巻・号 |
55(32)
|
| ページ |
4519-32
|
| 公開日 |
2016-8-16
|
| DOI |
10.1021/acs.biochem.5b01132
|
| PMID |
26894491
|
| PMC |
PMC4987251
|
| MeSH |
Amino Acid Sequence
Animals
Caenorhabditis elegans
Cell Line, Tumor
Cysteine / metabolism
Glutaredoxins / metabolism*
Glutathione / metabolism
Humans
Mice
Parkinson Disease / metabolism*
Protein Deglycase DJ-1 / chemistry
Protein Deglycase DJ-1 / deficiency
Protein Deglycase DJ-1 / metabolism*
Protein Processing, Post-Translational
|
| IF |
2.865
|
| 引用数 |
16
|
| リソース情報 |
| 線虫 |
tm1346
tm4634 |
