title: Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia.
abstract: 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.
authors.affiliation: Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, The Clarke Division, Toronto, Ontario, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Furukawa
authors.forename: T G
authors.initials: TG
authors.lastname: Nygaard
authors.forename: M
authors.initials: M
authors.lastname: Gütlich
authors.forename: A H
authors.initials: AH
authors.lastname: Rajput
authors.forename: C
authors.initials: C
authors.lastname: Pifl
authors.forename: L
authors.initials: L
authors.lastname: DiStefano
authors.forename: L J
authors.initials: LJ
authors.lastname: Chang
authors.forename: K
authors.initials: K
authors.lastname: Price
authors.forename: M
authors.initials: M
authors.lastname: Shimadzu
authors.forename: O
authors.initials: O
authors.lastname: Hornykiewicz
authors.forename: J W
authors.initials: JW
authors.lastname: Haycock
authors.forename: S J
authors.initials: SJ
authors.lastname: Kish
mesh_terms: D000328:Adult; D000368:Aged; D001708:Biopterins / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000627:therapeutic use*; D004421:Dystonia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
chemical_list: D001708:Biopterins; D004295:Dihydroxyphenylalanine; D014446:Tyrosine 3-Monooxygenase