title: Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson's Disease.
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.
authors.forename: William M
authors.initials: WM
authors.lastname: Johnson
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.forename: Kyonghwan
authors.initials: K
authors.lastname: Choe
authors.forename: Pierce L
authors.initials: PL
authors.lastname: Curran
authors.forename: Olga Gorelenkova
authors.initials: OG
authors.lastname: Miller
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.forename: Wenzhang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and the Redox Biology Center, University of Nebraska-Lincoln , Lincoln, Nebraska 68588, United States.
authors.forename: Jiusheng
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and the Redox Biology Center, University of Nebraska-Lincoln , Lincoln, Nebraska 68588, United States.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Milkovic
authors.affiliation: Centre for Neuroscience, Indian Institute of Science , C.V. Raman Avenue, Bangalore 560012, India.
authors.forename: Ajit
authors.initials: A
authors.lastname: Ray
authors.affiliation: Centre for Neuroscience, Indian Institute of Science , C.V. Raman Avenue, Bangalore 560012, India.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Ravindranath
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and the Redox Biology Center, University of Nebraska-Lincoln , Lincoln, Nebraska 68588, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wilson
authors.forename: Amy L
authors.initials: AL
authors.lastname: Wilson-Delfosse
authors.forename: Shu G
authors.initials: SG
authors.lastname: Chen
authors.affiliation: Louis B. Stokes Veterans Affairs Medical Research Center , Cleveland, Ohio 44106, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mieyal
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism; D054477:Glutaredoxins / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D010300:Parkinson Disease / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1 / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D054477:Glutaredoxins; D000071617:Protein Deglycase DJ-1; D005978:Glutathione; D003545:Cysteine