title: Urate and its transgenic depletion modulate neuronal vulnerability in a cellular model of Parkinson's disease.
abstract: Urate is a major antioxidant as well as the enzymatic end product of purine metabolism in humans. Higher levels correlate with a reduced risk of developing Parkinson's disease (PD) and with a slower rate of PD progression. In this study we investigated the effects of modulating intracellular urate concentration on 1-methyl-4-phenyl-pyridinium (MPP(+))-induced degeneration of dopaminergic neurons in cultures of mouse ventral mesencephalon prepared to contain low (neuron-enriched cultures) or high (neuron-glial cultures) percentage of astrocytes. Urate, added to the cultures 24 hours before and during treatment with MPP(+), attenuated the loss of dopaminergic neurons in neuron-enriched cultures and fully prevented their loss and atrophy in neuron-astrocyte cultures. Exogenous urate was found to increase intracellular urate content in cortical neuronal cultures. To assess the effect of reducing cellular urate content on MPP(+)-induced toxicity, mesencephalic neurons were prepared from mice over-expressing urate oxidase (UOx). Transgenic UOx expression decreased endogenous urate content both in neurons and astrocytes. Dopaminergic neurons expressing UOx were more susceptible to MPP(+) in mesencephalic neuron-enriched cultures and to a greater extent in mesencephalic neuron-astrocyte cultures. Our findings correlate intracellular urate content in dopaminergic neurons with their toxin resistance in a cellular model of PD and suggest a facilitative role for astrocytes in the neuroprotective effect of urate.
authors.affiliation: Neurology Department, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, Massachusetts, United States of America. scipriani@partners.org
authors.forename: Sara
authors.initials: S
authors.lastname: Cipriani
authors.forename: Cody A
authors.initials: CA
authors.lastname: Desjardins
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Burdett
authors.forename: Yuehang
authors.initials: Y
authors.lastname: Xu
authors.forename: Kui
authors.initials: K
authors.lastname: Xu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schwarzschild
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques; D014503:Urate Oxidase / Q000235:genetics / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D011994:Recombinant Proteins; D014527:Uric Acid; D014503:Urate Oxidase; D015655:1-Methyl-4-phenylpyridinium