Loss of dopamine phenotype among midbrain neurons in Lesch–Nyhan disease
Martin Göttle PhD
Department of Neurology, Emory University, Atlanta, GA
Search for more papers by this authorCecilia N. Prudente PhD
Department of Neurology, Emory University, Atlanta, GA
Search for more papers by this authorRong Fu PhD
Department of Neurology, Emory University, Atlanta, GA
Search for more papers by this authorDiane Sutcliffe MS
Department of Neurology, Emory University, Atlanta, GA
Search for more papers by this authorHong Pang
Department of Neurology, Emory University, Atlanta, GA
Search for more papers by this authorDeborah Cooper
Department of Pathology, Emory University, Atlanta, GA
Search for more papers by this authorEmir Veledar PhD
Department of Cardiology and Rollins School of Public Health, Emory University, Atlanta, GA
Search for more papers by this authorJonathan D. Glass MD, PhD
Department of Neurology, Emory University, Atlanta, GA
Search for more papers by this authorMarla Gearing PhD
Department of Pathology, Emory University, Atlanta, GA
Search for more papers by this authorJasper E. Visser MD, PhD
Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands
Department of Neurology, Amphia Hospital, Breda, the Netherlands
Search for more papers by this authorCorresponding Author
H. A. Jinnah MD, PhD
Department of Neurology, Emory University, Atlanta, GA
Departments of Human Genetics, Emory University, Atlanta, GA
Departments of Pediatrics, Emory University, Atlanta, GA
Address correspondence to Dr Jinnah, 6300 Woodruff Memorial Research Building, Department of Neurology, Emory University, Atlanta, GA 30322. E-mail: [email protected]Search for more papers by this authorMartin Göttle PhD
Department of Neurology, Emory University, Atlanta, GA
Search for more papers by this authorCecilia N. Prudente PhD
Department of Neurology, Emory University, Atlanta, GA
Search for more papers by this authorRong Fu PhD
Department of Neurology, Emory University, Atlanta, GA
Search for more papers by this authorDiane Sutcliffe MS
Department of Neurology, Emory University, Atlanta, GA
Search for more papers by this authorHong Pang
Department of Neurology, Emory University, Atlanta, GA
Search for more papers by this authorDeborah Cooper
Department of Pathology, Emory University, Atlanta, GA
Search for more papers by this authorEmir Veledar PhD
Department of Cardiology and Rollins School of Public Health, Emory University, Atlanta, GA
Search for more papers by this authorJonathan D. Glass MD, PhD
Department of Neurology, Emory University, Atlanta, GA
Search for more papers by this authorMarla Gearing PhD
Department of Pathology, Emory University, Atlanta, GA
Search for more papers by this authorJasper E. Visser MD, PhD
Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands
Department of Neurology, Amphia Hospital, Breda, the Netherlands
Search for more papers by this authorCorresponding Author
H. A. Jinnah MD, PhD
Department of Neurology, Emory University, Atlanta, GA
Departments of Human Genetics, Emory University, Atlanta, GA
Departments of Pediatrics, Emory University, Atlanta, GA
Address correspondence to Dr Jinnah, 6300 Woodruff Memorial Research Building, Department of Neurology, Emory University, Atlanta, GA 30322. E-mail: [email protected]Search for more papers by this authorAbstract
Objective
Lesch–Nyhan disease (LND) is caused by congenital deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). Affected patients have a peculiar neurobehavioral syndrome linked with reductions of dopamine in the basal ganglia. The purpose of the current studies was to determine the anatomical basis for the reduced dopamine in human brain specimens collected at autopsy.
Methods
Histopathological studies were conducted using autopsy tissue from 5 LND cases and 6 controls. Specific findings were replicated in brain tissue from an HGprt-deficient knockout mouse using immunoblots, and in a cell model of HGprt deficiency by flow-activated cell sorting (FACS).
Results
Extensive histological studies of the LND brains revealed no signs suggestive of a degenerative process or other consistent abnormalities in any brain region. However, neurons of the substantia nigra from the LND cases showed reduced melanization and reduced immunoreactivity for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. In the HGprt-deficient mouse model, immunohistochemical stains for TH revealed no obvious loss of midbrain dopamine neurons, but quantitative immunoblots revealed reduced TH expression in the striatum. Finally, 10 independent HGprt-deficient mouse MN9D neuroblastoma lines showed no signs of impaired viability, but FACS revealed significantly reduced TH immunoreactivity compared to the control parent line.
Interpretation
These results reveal an unusual phenomenon in which the neurochemical phenotype of dopaminergic neurons is not linked with a degenerative process. They suggest an important relationship between purine recycling pathways and the neurochemical integrity of the dopaminergic phenotype. Ann Neurol 2014;76:95–107
References
- 1Jinnah HA, Visser JE, Harris JC, et al. Delineation of the motor disorder of Lesch-Nyhan disease. Brain 2006; 129: 1201–1217.
- 2Schretlen DS, Ward J, Meyer SM, et al. Behavioral aspects of Lesch-Nyhan disease and its variants. Dev Med Child Neurol 2005; 47: 673–677.
- 3Schretlen DS, Harris JC, Park KS, et al. Neurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthine-guanine phosphoribosyltransferase deficiency. J Int Neuropsychol Soc 2001; 7: 805–812.
- 4Jinnah HA, Friedmann T. Lesch-Nyhan disease and its variants. In: CR Scriver, AL Beaudet, WS Sly, D Valle, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York, NY: McGraw-Hill, 2001: 2537–2570.
- 5Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain 2014; 137(pt 5): 1282–1303.
- 6Jinnah HA, DeGregorio L, Harris JC, et al. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res 2000; 463: 309–326.
- 7Visser JE, Baer PR, Jinnah HA. Lesch-Nyhan syndrome and the basal ganglia. Brain Res Rev 2000; 32: 449–475.
- 8Baumeister AA, Frye GD. The biochemical basis of the behavioral disorder in the Lesch-Nyhan syndrome. Neurosci Biobehav Rev 1985; 9: 169–178.
- 9Lloyd KG, Hornykiewicz O, Davidson L, et al. Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch-Nyhan syndrome. N Engl J Med 1981; 305: 1106–1111.
- 10Saito Y, Takashima S. Neurotransmitter changes in the pathophysiology of Lesch-Nyhan syndrome. Brain Dev 2000; 22(suppl 1): S122–S131.
- 11Saito Y, Ito M, Hanaoka S, et al. Dopamine receptor upregulation in Lesch-Nyhan syndrome: a postmortem study. Neuropediatrics 1999; 30: 66–71.
- 12Wong DF, Harris JC, Naidu S, et al. Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo. Proc Natl Acad Sci U S A 1996; 93: 5539–5543.
- 13Ernst M, Zametkin AJ, Matochik JA, et al. Presynaptic dopaminergic deficits in Lesch-Nyhan disease. N Engl J Med 1996; 334: 1568–1572.
- 14Del Bigio MR, Halliday WC. Multifocal atrophy of cerebellar internal granular neurons in Lesch-Nyhan disease: case reports and review. J Neuropathol Exp Neurol 2007; 66: 346–353.
- 15Jinnah HA. Lesch-Nyhan disease: from mechanism to model and back again. Dis Model Mech 2009; 2: 116–121.
- 16Jinnah HA, Langlais PJ, Friedmann T. Functional analysis of brain dopamine systems in a genetic mouse model of Lesch-Nyhan syndrome. J Pharmacol Exp Ther 1992; 263: 596–607.
- 17Jinnah HA, Wojcik BE, Hunt MA, et al. Dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease. J Neurosci 1994; 14: 1164–1175.
- 18Jinnah HA, Jones MD, Wojcik BE, et al. Influence of age and strain on striatal dopamine loss in a genetic mouse model of Lesch-Nyhan disease. J Neurochem 1999; 72: 225–229.
- 19Egami K, Yitta S, Kasim S, et al. Basal ganglia dopamine loss due to defect in purine recycling. Neurobiol Dis 2007; 26: 396–407.
- 20Kang TH, Park Y, Bader JS, Friedmann T. The housekeeping gene hypoxanthine guanine phosphoribosyltransferase (HPRT) regulates multiple developmental and metabolic pathways of murine embryonic stem cell neuronal differentiation. PLoS One 2013; 8: e74967.
- 21Lewers JC, Ceballos-Picot I, Shirley TL, et al. Consequences of impaired purine recycling in dopaminergic neurons. Neuroscience 2008; 152: 761–772.
- 22Yeh J, Zheng S, Howard BD. Impaired differentiation of HPRT-deficient dopaminergic neurons: a possible mechanism underlying neuronal dysfunction in Lesch-Nyhan syndrome. J Neurosci Res 1998; 53: 78–85.
10.1002/(SICI)1097-4547(19980701)53:1<78::AID-JNR8>3.0.CO;2-G CAS PubMed Web of Science® Google Scholar
- 23Bitler CM, Howard BD. Dopamine metabolism in hypoxanthine-guanine phosphoribosyltransferase-deficient variants of PC12 cells. J Neurochem 1986; 47: 107–112.
- 24Goettle M, Burhenne H, Sutcliffe D, Jinnah HA. Purine metabolism during neuronal differentiation: the relevance of purine synthesis and recycling. J Neurochem 2013; 127: 805–818.
- 25Ceballos-Picot I, Mockel L, Potier MC, et al. Hypoxanthine-guanine phosphoribosyl transferase regulates early developmental programming of dopamine neurons: implications for Lesch-Nyhan disease pathogenesis. Hum Mol Genet 2009; 18: 2317–2327.
- 26Choi HK, Won LA, Kontur PJ, et al. Immortalization of embryonic mesencephalic dopaminergic neurons by somatic cell fusion. Brain Res 1991; 552: 67–76.
- 27Bazelon M, Fenichel GM, Randall J. Studies on neuromelanin. I. A melanin system in the human adult brainstem. Neurology 1967; 17: 512–519.
- 28Fenichel GM, Bazelon M. Studies on neuromelanin. II. Melanin in the brainstems of infants and children. Neurology 1968; 18: 817–820.
- 29Zecca L, Fariello R, Riederer P, et al. The absolute concentration of nigral neuromelanin, assayed by a new sensitive method, increases throughout the life and is dramatically decreased in Parkinson's disease. FEBS Lett 2002; 510: 216–220.
- 30Fedorow H, Halliday GM, Rickert CH, et al. Evidence for specific phases in the development of human neuromelanin. Neurobiol Aging 2006; 27: 506–512.
- 31Hyland K, Kasim S, Egami K, et al. Tetrahydrobiopterin and brain dopamine loss in a genetic mouse model of Lesch-Nyhan disease. J Inherit Metab Dis 2004; 27: 165–178.
- 32Fujimoto WY, Subak-Sharpe JH, Seegmiller JE. Hypoxanthine-guanine phosphoribosyltransferase deficiency: chemical agents selective for mutant or normal cultured fibroblasts in mixed and heterozygote cultures. Proc Natl Acad Sci U S A 1971; 68: 1516–1519.
- 33Nyhan WL. Dopamine function in Lesch-Nyhan disease. Environ Health Perspect 2000; 108: 409–411.
- 34Peterson DA, Sejnowski TJ, Poizner H. Convergent evidence for abnormal striatal synaptic plasticity in dystonia. Neurobiol Dis 2010; 37: 558–573.
- 35Perlmutter JS, Mink JW. Dysfunction of dopaminergic pathways in dystonia. Adv Neurol 2004; 94: 163–170.
- 36Moy SS, Criswell HE, Breese GR. Differential effects of bilateral dopamine depletion in neonatal and adult rats. Neurosci Biobehav Rev 1997; 21: 425–435.
- 37Breese GR, Criswell HE, Duncan GE, Mueller RA. Dopamine deficiency in self-injurious behavior. Psychopharmacol Bull 1989; 25: 353–357.
- 38Taira T, Kobayashi T, Hori T. Disappearance of self-mutilating behavior in a patient with Lesch-Nyhan syndrome after bilateral chronic stimulation of the globus pallidus interna. J Neurosurg 2003; 98: 414–416.
- 39Schretlen DJ, Varvaris M, Ho TE, et al. Cross-sectional analyses of regional brain volume abnormalities in Lesch-Nyhan disease and its variants. Lancet Neurol 2013; 12: 1151–1158.
- 40Visser JE, Schretlen DJ, Bloem BR, Jinnah HA. Levodopa is not a useful treatment for Lesch-Nyhan disease. Mov Disord 2011; 26: 746–749.
- 41Kang TH, Guibinga GH, Jinnah HA, Friedmann T. HPRT deficiency coordinately dysregulates canonical Wnt and presenilin-1 signaling: a neuro-developmental regulatory role for a housekeeping gene? PLoS One 2011; 6: e16572.
- 42Guibinga GH, Hrustanovic G, Bouic K, et al. MicroRNA-mediated dysregulation of neural developmental genes in HPRT deficiency: clues for Lesch-Nyhan disease? Hum Mol Genet 2011; 21: 609–622.
- 43Guibinga GH, Hsu S, Friedmann T. Deficiency of the housekeeping gene hypoxanthine-guanine phosphoribosyltransferase (HPRT) dysregulates neurogenesis. Mol Ther 2010; 18: 54–62.
- 44Money KM, Stanwood GD. Developmental origins of brain disorders: roles for dopamine. Front Cell Neurosci 2013; 7: 260.
- 45Hirsch E, Graybiel AM, Agid Y. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 1988; 334: 345–348.
- 46Alavian KN, Scholz C, Simon HH. Transcriptional regulation of mesencephalic dopaminergic neurons: the full circle of life and death. Mov Disord 2008; 23: 319–328.
- 47Jiang C, Wan X, He Y, et al. Age-dependent dopaminergic dysfunction in Nurr1 knockout mice. Exp Neurol 2005; 191: 154–162.
- 48Witta J, Baffi J, Palkovits M, et al. Nigrostriatal innervation is preserved in Nurr1-null mice, although dopaminergic neuron precursors are arrested from terminal differentiation. Mol Brain Res 2000; 84: 67–78.
- 49Furukawa Y, Nygaard TG, Gutlich M, et al. Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia. Neurology 1999; 53: 1032–1041.
- 50Furukawa Y, Kapatos G, Haycock JW, et al. Brain biopterin and tyrosine hydroxylase in asymptomatic dopa-responsive dystonia. Ann Neurol 2002; 51: 637–641.
- 51Grotzsch H, Pizzolato GP, Ghika J, et al. Neuropathology of a case of dopa-responsive dystonia associated with a new genetic locus, DYT14. Neurology 2002; 58: 1839–1842.
- 52Hyland K, Surtees RAH, Rodeck C, Clayton PT. Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 1992; 42: 1980–1988.