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From the Human Neurochemical Pathology Laboratory (Drs. Furukawa and Kish, and L. DiStefano, L. Chang, and K. Price), Centre for Addiction and Mental Health, The Clarke Division, Toronto, Ontario, Canada; the Department of Neuroscience (Dr. Nygaard), UMDNJ-New Jersey Medical School, Newark, NJ; Technische Universität München (Dr. Gütlich), Institut für Organische Chemie und Biochemie, Lehrstuhl III, Garching, Germany; the Division of Neurology (Dr. Rajput), University of Saskatchewan, Saskatoon, Saskatchewan, Canada; the Institute of Biochemical Pharmacology (Drs. Pifl and Hornykiewicz), University of Vienna, Austria; the Department of Genetics (Dr. Shimadzu), Mitsubishi Kagaku Bio-Clinical Laboratories, Inc., Tokyo, Japan; and the Department of Biochemistry and Molecular Biology (Dr. Haycock), Louisiana State University, Medical Center, New Orleans, LA.
Address correspondence and reprint requests to Dr. Yoshiaki Furukawa, Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, The Clarke Division, 250 College Street, Toronto, Ontario M5T 1R8, Canada.
OBJECTIVE: To determine the mechanism leading to striatal dopamine (DA) loss in dopa-responsive dystonia (DRD).
BACKGROUND: Although mutations in the gene GCH1, coding for the tetrahydrobiopterin (BH4) biosynthetic enzyme guanosine triphosphate–cyclohydrolase I, have been identified in some patients with DRD, the actual status of brain BH4 (the cofactor for tyrosine hydroxylase [TH]) is unknown.
METHODS: The authors sequenced GCH1 and measured levels of total biopterin (BP) and total neopterin (NP), TH, and dopa decarboxylase (DDC) proteins, and the DA and vesicular monoamine transporters (DAT, VMAT2) in autopsied brain of two patients with typical DRD.
RESULTS: Patient 1 had two GCH1 mutations but Patient 2 had no mutation in the coding region of this gene. Striatal BP levels were markedly reduced (<20% of control subjects) in both patients and were also low in two conditions characterized by degeneration of nigrostriatal DA neurons (PD and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated primate), whereas brain NP concentrations were selectively decreased (<45%) in the DRD patients. In the putamen, both DRD patients had severely reduced (<3%) TH protein levels but had normal concentrations of DDC protein, DAT, and VMAT2.
CONCLUSIONS: The data suggest that 1) brain BH4 is decreased substantially in dopa-responsive dystonia, 2) dopa-responsive dystonia can be distinguished from degenerative nigrostriatal dopamine deficiency disorders by the presence of reduced brain neopterin, and 3) the striatal dopamine reduction in dopa-responsive dystonia is caused by decreased TH activity due to low cofactor concentration and to actual loss of TH protein. This reduction of TH protein, which might be explained by reduced enzyme stability/expression consequent to congenital BH4 deficiency, can be expected to limit the efficacy of acute BH4 administration on dopamine biosynthesis in dopa-responsive dystonia.
Key words: Dopa-responsive dystonia—GTP-cyclohydrolase I—Tetrahydrobiopterin—Neopterin—Tyrosine hydroxylase.
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