title: Upregulation of Glutaredoxin-1 Activates Microglia and Promotes Neurodegeneration: Implications for Parkinson's Disease.
abstract: Neuroinflammation and redox dysfunction are recognized factors in Parkinson's disease (PD) pathogenesis, and diabetes is implicated as a potentially predisposing condition. Remarkably, upregulation of glutaredoxin-1 (Grx1) is implicated in regulation of inflammatory responses in various disease contexts, including diabetes. In this study, we investigated the potential impact of Grx1 upregulation in the central nervous system on dopaminergic (DA) viability.
  
  
  
  Increased GLRX copy number in PD patients was associated with earlier PD onset, and Grx1 levels correlated with levels of proinflammatory tumor necrosis factor-alpha (TNF-α) in mouse and human brain samples, prompting mechanistic in vitro studies. Grx1 content/activity in microglia was upregulated by lipopolysaccharide (LPS), or TNF-α, treatment. Adenoviral overexpression of Grx1, matching the extent of induction by LPS, increased microglial activation; Grx1 silencing diminished activation. Selective inhibitors/probes of nuclear factor κB (NF-κB) activation revealed glrx1 induction to be mediated by the Nurr1/NF-κB axis. Upregulation of Grx1 in microglia corresponded to increased death of neuronal cells in coculture. With a mouse diabetes model of diet-induced insulin resistance, we found upregulation of Grx1 in brain was associated with DA loss (decreased tyrosine hydroxylase [TH]; diminished TH-positive striatal axonal terminals); these effects were not seen with Grx1-knockout mice.
  
  
  
  Our results indicate that Grx1 upregulation promotes neuroinflammation and consequent neuronal cell death in vitro, and synergizes with proinflammatory insults to promote DA loss in vivo. Our findings also suggest a genetic link between elevated Grx1 and PD development.
  
  
  
  In vitro and in vivo data suggest Grx1 upregulation promotes neurotoxic neuroinflammation, potentially contributing to PD. Antioxid. Redox Signal. 25, 967-982.
authors.affiliation: 1 Department of Pharmacology, School of Medicine, Case Western Reserve University , Cleveland, Ohio.
authors.forename: Olga
authors.initials: O
authors.lastname: Gorelenkova Miller
authors.affiliation: 2 Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine , Boston, Massachusetts.
authors.forename: Jessica Belle
authors.initials: JB
authors.lastname: Behring
authors.affiliation: 3 Department of Pathology, School of Medicine, Case Western Reserve University , Cleveland, Ohio.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Siedlak
authors.affiliation: 3 Department of Pathology, School of Medicine, Case Western Reserve University , Cleveland, Ohio.
authors.forename: Sirui
authors.initials: S
authors.lastname: Jiang
authors.affiliation: 2 Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine , Boston, Massachusetts.
authors.forename: Reiko
authors.initials: R
authors.lastname: Matsui
authors.affiliation: 2 Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine , Boston, Massachusetts.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Bachschmid
authors.affiliation: 3 Department of Pathology, School of Medicine, Case Western Reserve University , Cleveland, Ohio.
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: 1 Department of Pharmacology, School of Medicine, Case Western Reserve University , Cleveland, Ohio.|4 Louis Stokes Cleveland Veterans Administration Medical Research Center , Cleveland, Ohio.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mieyal
mesh_terms: D000818:Animals; D016923:Cell Death; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage; D015870:Gene Expression; D005786:Gene Expression Regulation; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D054477:Glutaredoxins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D016207:Cytokines; D054477:Glutaredoxins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D018808:Transcription Factor AP-1; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Parkinson's disease; diabetes; microglia; neuroinflammation glutaredoxin