, Volume 14, Issue 1, pp 148–153 | Cite as

Urate as a Marker of Risk and Progression of Neurodegenerative Disease



Urate is a naturally occurring antioxidant whose levels are associated with reduced risk of developing Parkinson’s disease (PD) and Alzheimer’s disease. Urate levels are also associated with favorable progression in PD, amyotrophic lateral sclerosis, Huntington’s disease, and multisystem atrophy. These epidemiological data are consistent with laboratory studies showing that urate exhibits neuroprotective effects by virtue of its antioxidant properties in several preclinical models. This body of evidence supports the hypothesis that urate may represent a shared pathophysiologic mechanism across neurodegenerative diseases. Most importantly, beyond its role as a molecular predictor of disease risk and progression, urate may constitute a novel therapeutic target. Indeed, clinical trials of urate elevation in PD and amyotrophic lateral sclerosis are testing the impact of raising peripheral urate levels on disease outcomes. These studies will contribute to unraveling the neuroprotective potential of urate in human pathology. In parallel, preclinical experiments are deepening our understanding of the molecular pathways that underpin urate’s activities. Altogether, these efforts will bring about new insights into the translational potential of urate, its determinants, and its targets and their relevance to neurodegeneration.


Biomarker Risk Prognosis Inosine Oxidative stress 

Supplementary material

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  1. 1.
    D'Amico E, Factor-Litvak P, Santella RM, Mitsumoto H. Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis. Free Radic Biol Med 2013;65:509–527.CrossRefPubMedGoogle Scholar
  2. 2.
    Henchcliffe C, Beal MF. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 2008;4:600–609.CrossRefPubMedGoogle Scholar
  3. 3.
    Proctor P. Similar functions of uric acid and ascorbate in man? Nature 1970;228:868.CrossRefPubMedGoogle Scholar
  4. 4.
    Yeum KJ, Russell RM, Krinsky NI, Aldini G. Biomarkers of antioxidant capacity in the hydrophilic and lipophilic compartments of human plasma. Arch Biochem Biophys 2004;430:97–103.CrossRefPubMedGoogle Scholar
  5. 5.
    Fabbrini E, Serafini M, Colic Baric I, Hazen SL, Klein S. Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects. Diabetes 2014;63:976–981.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Johnson RJ, Titte S, Cade JR, Rideout BA, Oliver WJ. Uric acid, evolution and primitive cultures. Semin Nephrol 2005;25:3–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Cipriani S, Chen X, Schwarzschild MA. Urate: a novel biomarker of Parkinson's disease risk, diagnosis and prognosis. Biomark Med 2010;4:701–712.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Torralba KD, De Jesus E, Rachabattula S. The interplay between diet, urate transporters and the risk for gout and hyperuricemia: current and future directions. Int J Rheum Dis 2012;15:499–506.CrossRefPubMedGoogle Scholar
  9. 9.
    Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008;40:437–442.CrossRefPubMedGoogle Scholar
  10. 10.
    Schwarzschild MA, Ascherio A, Beal MF, et al. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol 2014;71:141–150.CrossRefPubMedGoogle Scholar
  11. 11.
    Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 1981;78:6858–6862.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Church WH, Ward VL. Uric acid is reduced in the substantia nigra in Parkinson's disease: effect on dopamine oxidation. Brain Res Bull 1994;33:419–425.CrossRefPubMedGoogle Scholar
  13. 13.
    Davis JW, Grandinetti A, Waslien CI, Ross GW, White LR, Morens DM. Observations on serum uric acid levels and the risk of idiopathic Parkinson's disease. Am J Epidemiol 1996;144:480–484.CrossRefPubMedGoogle Scholar
  14. 14.
    Weisskopf MG, O'Reilly E, Chen H, Schwarzschild MA, Ascherio A. Plasma urate and risk of Parkinson's disease. Am J Epidemiol 2007;166:561–567.Google Scholar
  15. 15.
    Chen H, Mosley TH, Alonso A, Huang X. Plasma urate and Parkinson's disease in the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2009;169:1064–1069Google Scholar
  16. 16.
    de Lau LM, Koudstaal PJ, Hofman A, Breteler MM. Serum uric acid levels and the risk of Parkinson disease. Ann Neurol 2005;58:797–800.Google Scholar
  17. 17.
    Uribe-San Martin R, Venegas Francke P, Lopez Illanes F, et al. Plasma urate in REM sleep behavior disorder. Mov Disord 2013;28:1150–1151.Google Scholar
  18. 18.
    Gao X, Chen H, Choi HK, Curhan G, SchwarzschildMA, Ascherio A. Diet, urate, and Parkinson's disease risk in men. Am J Epidemiol 2008;167:831–838.Google Scholar
  19. 19.
    Facheris MF, Hicks AA, Minelli C, et al. Variation in the uric acid transporter gene SLC2A9 and its association with AAO of Parkinson's disease. J Mol Neurosci 2011;43:246–250.Google Scholar
  20. 20.
    Gonzalez-Aramburu I, Sanchez-Juan P, Jesus S, et al. Genetic variability related to serum uric acid concentration and risk of Parkinson's disease. Mov Disord 2013;28:1737–1740.Google Scholar
  21. 21.
    Lu N, DubreuilM, Zhang Y, et al. Gout and the risk of Alzheimer's disease: a population-based, BMI-matched cohort study. Ann Rheum Dis 2016;75:547–551.Google Scholar
  22. 22.
    Schwarzschild MA, Schwid SR, Marek K, et al. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch Neurol 2008;65:716–723.Google Scholar
  23. 23.
    Ascherio A, LeWitt PA, Xu K, et al. Urate as a predictor of the rate of clinical decline in Parkinson disease. Arch Neurol 2009;66:1460–1468.Google Scholar
  24. 24.
    Simon KC, Eberly S, Gao X, et al. Mendelian randomization of serum urate and parkinson disease progression. Ann Neurol 2014;76:862–868.Google Scholar
  25. 25.
    Paganoni S, Zhang M, Quiroz Zarate A, et al. Uric acid levels predict survival in men with amyotrophic lateral sclerosis. J Neurol 2012;259:1923–1928.Google Scholar
  26. 26.
    Abraham A, Drory VE. Influence of serum uric acid levels on prognosis and survival in amyotrophic lateral sclerosis: a metaanalysis. J Neurol 2014;261:1133–1138.Google Scholar
  27. 27.
    Atassi N, Berry J, Shui A, et al. The PRO-ACT database: design, initial analyses, and predictive features. Neurology 2014;83:1719–1725.Google Scholar
  28. 28.
    Kuffner R, Zach N, Norel R, et al. Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression. Nat Biotechnol 2015;33:51–57.Google Scholar
  29. 29.
    Zheng Z, Guo X, Wei Q, et al. Serum uric acid level is associated with the prevalence but not with survival of amyotrophic lateral sclerosis in a Chinese population. Metab Brain Dis 2014;29:771–775.Google Scholar
  30. 30.
    Chio A, Calvo A, Bovio G, et al. Amyotrophic lateral sclerosis outcome measures and the role of albumin and creatinine: a population-based study. JAMA Neurol 2014;71:1134–1142.Google Scholar
  31. 31.
    Auinger P, Kieburtz K, McDermott MP. The relationship between uric acid levels and Huntington's disease progression. Mov Disord 2010;25:224–228.Google Scholar
  32. 32.
    Irizarry MC, Raman R, Schwarzschild MA, et al. Plasma urate and progression of mild cognitive impairment. Neurodegener Dis 2009;6:23–28.Google Scholar
  33. 33.
    Lee JE, Song SK, SohnYH, Lee PH.Uric acid as a potential disease modifier in patients with multiple system atrophy. Mov Disord 2011;26:1533–1536.Google Scholar
  34. 34.
    Cipriani S, Desjardins CA, Burdett TC, Xu Y, Xu K, Schwarzschild MA. Urate and its transgenic depletion modulate neuronal vulnerability in a cellular model of Parkinson's disease. PLOS ONE 2012;7:e37331.Google Scholar
  35. 35.
    ChenX, Burdett TC, Desjardins CA, et al. Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration. Proc Natl Acad Sci U S A 2013;110:300–305.Google Scholar
  36. 36.
    Cipriani S, Desjardins CA, Burdett TC, Xu Y, Xu K, Schwarzschild MA. Protection of dopaminergic cells by urate requires its accumulation in astrocytes. J Neurochem 2012;123:172–181.Google Scholar
  37. 37.
    Du Y, Chen CP, Tseng CY, Eisenberg Y, Firestein BL. Astrogliamediated effects of uric acid to protect spinal cord neurons from glutamate toxicity. Glia 2007;55:463–472.Google Scholar
  38. 38.
    Yu ZF, Bruce-Keller AJ, Goodman Y, Mattson MP. Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res 1998;53:613–625.Google Scholar
  39. 39.
    Scott GS, Cuzzocrea S, Genovese T, Koprowski H, Hooper DC. Uric acid protects against secondary damage after spinal cord injury. Proc Natl Acad Sci U S A 2005;102:3483–3488.Google Scholar
  40. 40.
    Romanos E, Planas AM, Amaro S, Chamorro A. Uric acid reduces brain damage and improves the benefits of rt-PA in a rat model of thromboembolic stroke. J Cereb Blood FlowMetab 2007;27:14–20.Google Scholar
  41. 41.
    Kean RB, Spitsin SV, Mikheeva T, Scott GS, Hooper DC. The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity. J Immunol 2000;165:6511–6518.Google Scholar
  42. 42.
    Chamorro A, Amaro S, CastellanosM, et al. Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial. Lancet Neurol 2014;13:453–460.Google Scholar
  43. 43.
    Llull L, Laredo C, Renu A, et al. Uric acid therapy improves clinical outcome in women with acute ischemic stroke. Stroke 2015;46: 2162–2167.Google Scholar
  44. 44.
    Annanmaki T, Muuronen A,Murros K. Low plasma uric acid level in Parkinson's disease. Mov Disord 2007;22:1133–1137.Google Scholar
  45. 45.
    BogdanovM,MatsonWR,Wang L, et al.Metabolomic profiling to develop blood biomarkers for Parkinson's disease. Brain 2008;131:389–396.Google Scholar
  46. 46.
    Lawton KA, Brown MV, Alexander D, et al. Plasma metabolomic biomarker panel to distinguish patients with amyotrophic lateral sclerosis from disease mimics. Amyotroph Lateral Scler Frontotemporal Degener 2014;15:362–370.Google Scholar
  47. 47.
    Keizman D, Ish-ShalomM, Berliner S, et al. Low uric acid levels in serum of patients with ALS: further evidence for oxidative stress? J Neurol Sci 2009;285:95–99.Google Scholar
  48. 48.
    Alonso A, Rodriguez LA, Logroscino G, Hernan MA. Gout and risk of Parkinson disease: a prospective study. Neurology 2007;69:1696–1700.Google Scholar
  49. 49.
    Gong L, Zhang QL, Zhang N, et al. Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson's disease: linking to Akt/ GSK3beta signaling pathway. J Neurochem 2012;123:876–885.Google Scholar
  50. 50.
    Jones DC, Gunasekar PG, Borowitz JL, Isom GE. Dopamineinduced apoptosis is mediated by oxidative stress and Is enhanced by cyanide in differentiated PC12 cells. J Neurochem 2000;74:2296–2304.Google Scholar
  51. 51.
    Zhu TG, Wang XX, Luo WF, et al. Protective effects of urate against 6-OHDA-induced cell injury in PC12 cells through antioxidant action. Neurosci Lett 2012;506:175–179.Google Scholar
  52. 52.
    Duan W, Ladenheim B, Cutler RG, Kruman, II, Cadet JL, Mattson MP. Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease. J Neurochem 2002;80:101–110.Google Scholar
  53. 53.
    Guerreiro S, Ponceau A, Toulorge D, et al. Protection of midbrain dopaminergic neurons by the end-product of purine metabolism uric acid: potentiation by low-level depolarization. J Neurochem 2009;109:1118–1128.Google Scholar
  54. 54.
    Bakshi R, Zhang H, Logan R, et al. Neuroprotective effects of urate are mediated by augmenting astrocytic glutathione synthesis and release. Neurobiol Dis 2015;82:574–579.Google Scholar
  55. 55.
    Zhang N, Shu HY, Huang T, et al. Nrf2 signaling contributes to the neuroprotective effects of urate against 6-OHDA toxicity. PLOS ONE 2014;9:e100286.Google Scholar
  56. 56.
    Onetti Y, Dantas AP, Perez B, et al. Middle cerebral artery remodeling following transient brain ischemia is linked to early postischemic hyperemia: a target of uric acid treatment. Am J Physiol Heart Circ Physiol 2015;308:H862–H874.Google Scholar
  57. 57.
    Johnson RJ. Why focus on uric acid? Curr Med Res Opin 2015;31(Suppl. 2):3–7.Google Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2016

Authors and Affiliations

  1. 1.Harvard Medical School, Department of NeurologyMassachusetts General HospitalBostonUSA
  2. 2.Department of Physical Medicine and RehabilitationSpaulding Rehabilitation HospitalBostonUSA
  3. 3.VA Boston Healthcare SystemBostonUSA
  4. 4.MassGeneral Institute for Neurodegenerative Disease (MIND)BostonUSA

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