Article: article from journal or magazin.
Lentivirally delivered glial cell line-derived neurotrophic factor increases the number of striatal dopaminergic neurons in primate models of nigrostriatal degeneration.
Journal of Neuroscience
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.Publication Status: ppublish
The primate striatum contains tyrosine hydroxylase (TH)-immunoreactive (ir) neurons, the numbers of which are augmented after dopamine depletion. Glial cell line-derived neurotrophic factor (GDNF) strongly modulates the viability and phenotypic expression of dopamine ventral mesencephalic neurons. The effect of GDNF on TH-ir neurons intrinsic to the striatum has yet to be investigated. In the present study, stereological counts of TH-ir striatal neurons in aged and parkinsonian nonhuman primates revealed that GDNF delivered via a lentiviral vector (lenti-) further increased the number of these cells. Aged monkeys treated with lenti-GDNF displayed an eightfold increase in TH-ir neurons relative to lenti-beta-galactosidase-treated monkeys. Unilateral 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine treatment alone in young monkeys resulted in a bilateral eightfold increase in TH-ir striatal cells. This effect was further magnified sevenfold on the side of lenti-GDNF treatment. These cells colocalized with the neuronal marker neuronal-specific nuclear protein. Some of these cells colocalized with GDNF-ir, indicating that an alteration in phenotype may occur by the direct actions of this trophic factor. Thus, GDNF may mediate plasticity in the dopamine-depleted primate brain, which may serve to compensate for cell loss by converting striatal neurons to a dopaminergic phenotype.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology, Aging, Animals, Antiparkinson Agents/metabolism, Cell Count, Corpus Striatum/cytology, Corpus Striatum/drug effects, Dopamine/metabolism, Dopamine Agents/pharmacology, Fluorescent Antibody Technique, Gene Therapy, Genetic Vectors, Glial Cell Line-Derived Neurotrophic Factor, Haplorhini, Lentivirus/genetics, Microscopy, Fluorescence, Nerve Growth Factors, Nerve Tissue Proteins/genetics, Neurons/cytology, Neurons/drug effects, Parkinson Disease/enzymology, Parkinson Disease/pathology, Substantia Nigra/cytology, Substantia Nigra/drug effects, Tyrosine 3-Monooxygenase/analysis, Tyrosine 3-Monooxygenase/immunology
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