Volume 76, Issue 1 pp. 95-107
Research Article

Loss of dopamine phenotype among midbrain neurons in Lesch–Nyhan disease

Martin Göttle PhD

Martin Göttle PhD

Department of Neurology, Emory University, Atlanta, GA

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Cecilia N. Prudente PhD

Cecilia N. Prudente PhD

Department of Neurology, Emory University, Atlanta, GA

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Rong Fu PhD

Rong Fu PhD

Department of Neurology, Emory University, Atlanta, GA

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Diane Sutcliffe MS

Diane Sutcliffe MS

Department of Neurology, Emory University, Atlanta, GA

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Hong Pang

Hong Pang

Department of Neurology, Emory University, Atlanta, GA

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Deborah Cooper

Deborah Cooper

Department of Pathology, Emory University, Atlanta, GA

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Emir Veledar PhD

Emir Veledar PhD

Department of Cardiology and Rollins School of Public Health, Emory University, Atlanta, GA

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Jonathan D. Glass MD, PhD

Jonathan D. Glass MD, PhD

Department of Neurology, Emory University, Atlanta, GA

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Marla Gearing PhD

Marla Gearing PhD

Department of Pathology, Emory University, Atlanta, GA

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Jasper E. Visser MD, PhD

Jasper 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

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H. A. Jinnah MD, PhD

Corresponding 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 author
First published: 03 June 2014
Citations: 43

Abstract

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

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