Analysis of cellular, transgenic and human models of Huntington's disease reveals tyrosine hydroxylase alterations and substantia nigra neuropathology

George J. Yohrling IV, George C.T. Jiang, Molly M. DeJohn, David W. Miller, Anne B. Young, Kent E. Vrana, Jang Ho J. Cha

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder 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 β-hydroxylase (DβH) 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 neurotransmission in HD and may provide new insights into targets for pharmacotherapy.

Original languageEnglish (US)
Pages (from-to)28-36
Number of pages9
JournalMolecular Brain Research
Volume119
Issue number1
DOIs
StatePublished - Nov 6 2003

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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