Age-related decreases in GTP-cyclohydrolase-I immunoreactive neurons in the monkey and human substantia nigra

Er Yun Chen, Eric Kallwitz, Stuart E. Leff, Elizabeth J. Cochran, Elliott J. Mufson, Jeffrey H. Kordower, Ronald J. Mandel

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30 Scopus citations


Guanosine triphosphate cyclohydrolase I (GTPCHI) is a critical enzyme in catecholamine function and is rate limiting for the synthesis of the catecholamine co-factor tetrahydrobiopterin. The present study assessed the distribution of GTPCHI immunoreactivity (-ir) within the monkey and human ventral midbrain and determined whether its expression is altered as a function of age. Light and confocal microscopic analyses revealed that young monkeys and humans displayed GTPCHI-ir within melanin-containing and tyrosine-hydroxylase-ir neurons in primate substantia nigra. Stereological counts revealed that there was a 67.4% reduction in GTPCHI-ir neuronal number, a 63.5% reduction in GTPCHI-ir neuronal density, and a 37.6% reduction in neuronal volume in aged monkeys relative to young cohorts. Similar age-related changes were seen in humans, in whom there were significant reductions in the number of GTPCHI-ir nigral neurons in middle age (58.4%) and aged (81.5%) cases relative to young cohorts. The density of GTPCHI-ir neurons within the nigra was similarly reduced in middle-aged (63.0%) and aged (81.8%) cases. In contrast to monkeys, aged humans did not display shrinkage in the volume of GTPCHI-ir nigral neurons. The presence of numerous melanin-positive, but GTPCHI-ir immunonegative, neurons in the aged monkey and human nigra indicates that these decreases represent an age-related phenotypic downregulation of this enzyme and not a loss of neurons per se. These data indicate that there is a dramatic decrease in GTPCHI-ir in nonhuman primates and humans as a function of age and that loss of this enzyme may be partly responsible for the age-related decrease in dopaminergic tone within nigrostriatal systems. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)534-548
Number of pages15
JournalJournal of Comparative Neurology
Issue number4
StatePublished - 2000
Externally publishedYes


  • Aging
  • Human
  • Monkeys
  • Parkinson's disease
  • Substantia nigra

ASJC Scopus subject areas

  • Neuroscience(all)


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