Protection of dopaminergic cells by urate requires its accumulation in astrocytes.
Urate is the end product of purine metabolism and a major antioxidant circulating in humans. Recent data link higher levels of urate with a reduced risk of developing Parkinson's disease and with a slower rate of its progression. In this study, we investigated the role of astrocytes in urate-induced protection of dopaminergic cells in a cellular model of Parkinson's disease. In mixed cultures of dopaminergic cells and astrocytes oxidative stress-induced cell death and protein damage were reduced by urate. By contrast, urate was not protective in pure dopaminergic cell cultures. Physical contact between dopaminergic cells and astrocytes was not required for astrocyte-dependent rescue as shown by conditioned medium experiments. Urate accumulation in dopaminergic cells and astrocytes was blocked by pharmacological inhibitors of urate transporters expressed differentially in these cells. The ability of a urate transport blocker to prevent urate accumulation into astroglial (but not dopaminergic) cells predicted its ability to prevent dopaminergic cell death. Transgenic expression of uricase reduced urate accumulation in astrocytes and attenuated the protective influence of urate on dopaminergic cells. These data indicate that urate might act within astrocytes to trigger release of molecule(s) that are protective for dopaminergic cells.
Molecular Neurobiology Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA 02129, USA. pattona80@hotmail.com
Sara
S
Cipriani
Cody A
CA
Desjardins
Thomas C
TC
Burdett
Yuehang
Y
Xu
Kui
K
Xu
Michael A
MA
Schwarzschild
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology*; D001253:Astrocytes / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006861:Hydrogen Peroxide / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009573:Nitrites / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity; D050050:Protein Carbonylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014503:Urate Oxidase / Q000235:genetics; D014527:Uric Acid / Q000378:metabolism* / Q000494:pharmacology*
D000975:Antioxidants; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D009573:Nitrites; D016877:Oxidants; D017382:Reactive Oxygen Species; D014527:Uric Acid; D006861:Hydrogen Peroxide; D014503:Urate Oxidase