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Genes for human catecholamine-synthesizing enzymes.

T Nagatsu1

  • 1Institute for Comprehensive Medical Science, School of Medicine, Fujita Health University, Aichi, Japan.

Neuroscience Research
|October 1, 1991
PubMed
Summary
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Researchers cloned human catecholamine-synthesizing enzyme genes, discovering multiple tyrosine hydroxylase (TH) messenger RNAs (mRNAs) in primates. Aging reduced TH mRNA, while transgenic mice showed increased TH expression but normal catecholamine levels, suggesting complex regulation.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Catecholamine neurotransmitters (dopamine, noradrenaline, adrenaline) are synthesized via four key enzymes: tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT).
  • Understanding the genetic regulation of these enzymes is crucial for comprehending catecholamine synthesis and related neurological functions.

Purpose of the Study:

  • To clone and sequence full-length complementary DNAs (cDNAs) and genomic DNAs of human catecholamine-synthesizing enzymes (TH, AADC, DBH, PNMT).
  • To investigate the diversity of messenger RNAs (mRNAs) for these enzymes, particularly TH, and their regulation.
  • To explore the functional implications of human TH gene expression in transgenic mouse models.

Main Methods:

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  • Cloning and sequencing of human TH, AADC, DBH, and PNMT cDNAs and genomic DNAs.
  • Analysis of alternative mRNA splicing to identify different mRNA variants.
  • Generation and analysis of transgenic mice expressing multiple copies of the human TH gene.
  • In situ hybridization, Western blot analysis, and enzyme activity assays in transgenic mice.
  • Measurement of catecholamine levels in transgenic and non-transgenic mice.

Main Results:

  • Multiple mRNA forms of human TH, DBH, and PNMT were discovered, with four distinct TH mRNA types arising from alternative splicing.
  • The multiplicity of TH mRNA was found to be primate-specific, with aging associated with reduced TH mRNA levels in the human brain.
  • Transgenic mice exhibited significantly elevated human TH mRNA and protein levels in the brain, particularly in the substantia nigra and ventral tegmental area, but showed no significant changes in overall catecholamine levels.

Conclusions:

  • The alternative splicing of TH mRNA provides a mechanism for additional regulatory control over human TH enzyme activity, potentially impacting catecholamine synthesis.
  • Aging-related decline in TH mRNA suggests a link to age-associated changes in catecholamine neurotransmission.
  • The findings in transgenic mice indicate complex regulatory mechanisms governing human TH gene expression and catecholamine homeostasis, even with substantial increases in TH levels.