Advertisement

Metabolic Brain Disease

, Volume 22, Issue 1, pp 39–43 | Cite as

Role of Neuronal Nitric Oxide in the Dopamine Deficit of HPRT-Deficient Mice

  • Doug W. SmithEmail author
  • Hyder A. Jinnah
original paper

Abstract

Lesch-Nyhan disease is a debilitating disorder caused by a lack of purine salvage activity. Basal ganglia dopamine deficits manifest in both patients and hypoxanthine phosphoribosyltransferase (HPRT) mutant mice. We previously reported decreased activity in an oxidant sensitive enzyme in the brain of HPRT-deficient mice. In the present study, we have investigated whether one source of free radicals, neuronal nitric oxide synthase (NOS1), contributes to the dopamine deficit associated with HPRT deficiency. HPRT knockout and wild-type mice were bred, either to lack, or to have the full complement of NOS1 alleles. Double mutant mice had striatal dopamine and dopamine metabolite levels indistinguishable from the HPRT single mutant counterparts. These results indicate that NOS1 produced nitric oxide does not contribute to the dopamine deficit seen in HPRT deficiency.

Keywords

Inborn error in metabolism Dopaminergic system dysfunction Oxidative stress Mitochondrial aconitase Nitric oxide 

Notes

Acknowledgements

This work was supported by funding from the Lesch-Nyhan Children’s Research Foundation and NIH (NS44544-0IAI).

References

  1. Ara J, Przedborski S, Naini AB, Jackson-Lewis V, Trifiletti R, Horwitz J, Ischiropoulos H (1998) Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-mthyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Proc Natl Acad Sci USA 95(13):7659–7663PubMedCrossRefGoogle Scholar
  2. Ernst M, Zametkin AJ, Matochik JA, Pascualvaca D, Jons PH, Hardy K, Hankerson JG, Doudet DJ, Cohen RM (1996) Presynaptic dopaminergic deficits in Lesch-Nyhan disease. NEJM 334(24):1568–1572PubMedCrossRefGoogle Scholar
  3. Gardner P (2002) Aconitase: Sensitive target and measure of superoxide. Methods Enzymol 349:9–23PubMedGoogle Scholar
  4. Hantraye P, Brouillet E, Ferrante R, Palfi S, Dolan R, Matthews RT, Beal MF (1996) Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nat Med 2(3):1017–1021PubMedCrossRefGoogle Scholar
  5. He Y, Imam S, Dong Z, Jankovic J, Ali S, Appel S, Le W (2003) Role of nitric oxide in rotenone-induced nigro-striatal injury. J Neurochem 86(6):1338–1345PubMedCrossRefGoogle Scholar
  6. Huang P, Dawson T, Bredt D, Snyder S, Fishman M (1993) Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75(7):1273–1286PubMedCrossRefGoogle Scholar
  7. Hunot S, Hirsch E (2003) Neuroinflammatory processes in Parkinson’s disease. Ann Neurol 53(Suppl 3):S49–S60PubMedCrossRefGoogle Scholar
  8. Itzhak Y, Ali S (1996) The neuronal nitric oxide synthase inhibitor, 7-nitroindazole, protects against methamphetamine-induced neurotoxicity. J Neurochem 67(4):1770–1773PubMedCrossRefGoogle Scholar
  9. Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53(Suppl 3):S26–S38PubMedCrossRefGoogle Scholar
  10. Jinnah H, Friedmann T (2001) Lesch-Nyhan disease and its variants. In: Scriver C, Beaudet A, Valle D, Sly W (eds) The metabolic and molecular bases of inherited disease. McGraw Hill. II:2537–2570Google Scholar
  11. Jinnah H, Jones M, Wojcik B, Rothstein J, Hess E, Friedmann T, Breese G (1999) Influence of age and strain on striatal dopamine loss in a genetic mouse model of Lesch-Nyhan disease. J Neurochem 72:225–229PubMedCrossRefGoogle Scholar
  12. Jinnah HA, De Gregorio L, Harris JC, Nyhan WL, O’Neill JP (2000) The spectrum of inherited mujtations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res 463:309–326PubMedCrossRefGoogle Scholar
  13. Jinnah HA, Hess E, Wilson M, Gage F, Friedmann T (1992) Localization of hypoxanthine-guanine phosphoribosyltransferase mRNA in the mouse brain by in situ hybridization. Mol Cell Neurosci 3:64–78CrossRefPubMedGoogle Scholar
  14. Jinnah HA, Wojcik B, Hunt M, Narang N, Lee K, Goldstein M, Wamsley JK, Langlais P, Friedmann T (1994) Dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease. J Neurosci 14(3):1164–1175PubMedGoogle Scholar
  15. Lloyd K, Hornykiewicz O, Davidson L, Shannak K, Farley I, Goldstein M, Shibuya M, Kelley W, Fox I (1981) Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch-Nyhan syndrome. New Eng J Med 5:1106–1111CrossRefGoogle Scholar
  16. Przedborski S, Jackson-Lewis V, Yokoyama R, Shibata T, Dawson VL, Dawson KM (1996) Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc Natl Acad Sci, USA 93:4565–4571PubMedCrossRefGoogle Scholar
  17. Rosenbloom F, Henderson J, Caldwell L, Kelley W, Seegmiller J (1968) Biochemical basis of accelerated purine biosynthesis de novo in human fibroblasts lacking hypoxanthine-guanine phosphoribosyltransferase. J Biol Chem 243(6):1166–1173PubMedGoogle Scholar
  18. Visser JE, Smith DW, Moy SS, Breese GR, Friedmann T, Rothstein JD, Jinnah HA (2002) Oxidative stress and dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease. Dev Brain Res 133:127–139CrossRefGoogle Scholar
  19. Wong D, Harris JC, Naidu S, Yokoi F, Marenco S, Dannals R, Ravert H, Yaster M, Evans A, Rousset O, Bryan R, Gjedde A, Kuhar M, Breese G (1996) Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo. Proc Natl Acad Sci, USA 93:5539–5543PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Center for Molecular Genetics, Department of PediatricsUniversity of CaliforniaSan DiegoUSA
  2. 2.Neurology DepartmentJohns Hopkins UniversityBaltimoreUSA
  3. 3.Discipline of Anatomy, School of Biomedical SciencesUniversity of NewcastleCallaghanAustralia

Personalised recommendations