Journal
MOLECULAR BRAIN RESEARCH
Volume 119, Issue 1, Pages 28-36Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.molbrainres.2003.08.009
Keywords
tyrosine hydroxylase; Huntingtin; substantia nigra; Huntington's disease; dopamine; mRNA
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Funding
- NIGMS NIH HHS [R01 GM-38931] Funding Source: Medline
- NIMH NIH HHS [MH/NS-31862] Funding Source: Medline
- NINDS NIH HHS [R01 NS-38106] Funding Source: Medline
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Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerativedisorder that is pathologically characterized by a striatal-specific degeneration. Aberrant dopamine neurotransmission has been proposed as a mechanism underlying the movement disorder of HD. We report that the enzymatic activity of tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine biosynthesis, is decreased in a transgenic mouse model of HD. In addition, mutant huntingtin was found to disrupt transcription of TH and dopamine beta-hydroxylase (DbetaH) promoter reporter constructs. In situ hybridization revealed extensive loss of TH mRNA and decreased dopaminergic cell size in human HD substantia nigra. TH-immunoreactive protein was reduced in human grade 4 HD substantia nigra by 32% compared to age-matched controls. These findings implicate abnormalities in dopamine neuro transmission in HD and may provide new insights into targets for pharmacotherapy. (C) 2003 Elsevier B.V. All rights reserved.
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