title: Age-related decreases in GTP-cyclohydrolase-I immunoreactive neurons in the monkey and human substantia nigra.
abstract: 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.
authors.affiliation: Research Center for Brain Repair and Department of Neurological Sciences, Rush Presbyterian Medical Center, Chicago, Illinois 60612, USA.
authors.forename: E Y
authors.initials: EY
authors.lastname: Chen
authors.forename: E
authors.initials: E
authors.lastname: Kallwitz
authors.forename: S E
authors.initials: SE
authors.lastname: Leff
authors.forename: E J
authors.initials: EJ
authors.lastname: Cochran
authors.forename: E J
authors.initials: EJ
authors.lastname: Mufson
authors.forename: J H
authors.initials: JH
authors.lastname: Kordower
authors.forename: R J
authors.initials: RJ
authors.lastname: Mandel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000818:Animals; D005260:Female; D006136:GTP Cyclohydrolase / Q000378:metabolism*; D006801:Humans; D008253:Macaca mulatta / Q000378:metabolism*; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000201:enzymology; D008875:Middle Aged; D009474:Neurons / Q000201:enzymology*; D013378:Substantia Nigra / Q000166:cytology / Q000201:enzymology*; D014018:Tissue Distribution
chemical_list: D006136:GTP Cyclohydrolase