Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia

Objective: To determine the mechanism leading to striatal dopamine (DA) los s in dopa-responsive dystonia (DRD). Background: Although mutations in the gene GCH1, coding for the tetrahydrobiopterin (BH4) biosynthetic enzyme gua nosine triphosphate-cyclohydrolase I, have been identified in some patients with DRD, the actual status of brain BH4 (the cofactor for tyrosine hydrox ylase [TH]) is unknown, Methods: The authors sequenced GCH1 and measured le vels of total biopterin (BP) and total neopterin (NP), TH, and dopa decarbo xylase (DDC) proteins, and the DA and vesicular monoamine transporters (DAT , VMAT2) in autopsied brain of two patients with typical DRD, Results: Pati ent 1 had two GCH1 mutations but Patient 2 had no mutation in the coding re gion of this gene. Striatal BP levels were markedly reduced (<20% of contro l subjects) in both patients and were also low in two conditions characteri zed 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, bot h DRD patients had severely reduced (<3%) TH protein levels but had normal concentrations of DDC protein, DAT, and VMAT2. Conclusions: The data sugges t that 1) brain BH4 is decreased substantially in dopa-responsive dystonia, 2) dopa-responsive dystonia can be distinguished from degenerative nigrost riatal dopamine deficiency disorders by the presence of reduced brain neopt erin, and 3) the striatal dopamine reduction in dopa-responsive dystonia is caused by decreased TH activity due to low cofactor concentration and to a ctual loss of TH protein. This reduction of TH protein, which might be expl ained by reduced enzyme stability/expression consequent to congenital BH4 d eficiency, can be expected to limit the efficacy of acute BH4 administratio n on dopamine biosynthesis in dopa-responsive dystonia.