4.7 Article

Upregulation of Glutaredoxin-1 Activates Microglia and Promotes Neurodegeneration: Implications for Parkinson's Disease

期刊

ANTIOXIDANTS & REDOX SIGNALING
卷 25, 期 18, 页码 967-982

出版社

MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2015.6598

关键词

neuroinflammation glutaredoxin; Parkinson's disease; microglia; diabetes

资金

  1. Michael J. Fox Foundation for Parkinson's Research
  2. Abbvie
  3. Avid Radiopharmaceuticals
  4. Bristol-Myers Squibb
  5. Covance
  6. GE Healthcare
  7. Genentech
  8. GlaxoSmithKline
  9. Eli Lilly
  10. Lundbeck
  11. Merck
  12. Meso Scale Discovery
  13. Pfizer
  14. Piramal
  15. Roche
  16. Servier
  17. UCB
  18. NIH [NS085503, DK103750, HL133013, T32 NS077888]
  19. Department of Veterans Affairs Merit Review grant [BX000290]

向作者/读者索取更多资源

Aims: 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 glutaredoxin1 (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. Results: 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-alpha) in mouse and human brain samples, prompting mechanistic in vitro studies. Grx1 content/activity in microglia was upregulated by lipopolysaccharide (LPS), or TNF-alpha, 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 kappa B (NF-kappa B) activation revealed glrx1 induction to be mediated by the Nurr1/NF-kappa B 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. Innovation: 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. Conclusion: In vitro and in vivo data suggest Grx1 upregulation promotes neurotoxic neuroinflammation, potentially contributing to PD.

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