Age-related decreases in GTP-cyclohydrolase-I immunoreactive neurons in the monkey and human substantia nigra
Article first published online: 19 OCT 2000
Copyright © 2000 Wiley-Liss, Inc.
Journal of Comparative Neurology
Volume 426, Issue 4, pages 534–548, 30 October 2000
How to Cite
Chen, E.-Y., Kallwitz, E., Leff, S. E., Cochran, E. J., Mufson, E. J., Kordower, J. H. and Mandel, R. J. (2000), Age-related decreases in GTP-cyclohydrolase-I immunoreactive neurons in the monkey and human substantia nigra. J. Comp. Neurol., 426: 534–548. doi: 10.1002/1096-9861(20001030)426:4<534::AID-CNE3>3.0.CO;2-G
- Issue published online: 19 OCT 2000
- Article first published online: 19 OCT 2000
- Manuscript Revised: 11 JUL 2000
- Manuscript Accepted: 11 JUL 2000
- Manuscript Received: 13 MAR 2000
- NSAG. Grant Number: 16765
- substantia nigra;
- Parkinson's disease
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. J. Comp. Neurol. 426:534–548, 2000. © 2000 Wiley-Liss, Inc.