Lentivirally Delivered Glial Cell Line-Derived Neurotrophic Factor Increases the Number of Striatal Dopaminergic Neurons in Primate Models of Nigrostriatal Degeneration

• Type of Material: Article
• Authors: Stephane Palfi, Rush University Medical Center; Liza Leventhal, Rush University Medical Center; Yaping Chu, Rush University Medical Center; Shuang Y. Ma, Rush University Medical Center; Marina Emborg, Rush University Medical Center; Roy Bakay, Emory University; Nicole Déglon, Université de Lausanne; Philippe Hantraye, Service Hospitalier Frédéric Joliot; Patrick Aebischer, Université de Lausanne; Jeffrey H. Kordower, Rush University Medical Center
• Language: English
• Date: 2002-06-15
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2002 Society for Neuroscience
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.22-12-04942.2002
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0888-0395
• Volume: 22
• Issue: 12
• Start Page: 4942
• End Page: 4954
• Grant/Funding Information: This work was supported by a grant from the Department of Defense; a grant from the Parkinson's Foundation of the National Capital Area; and the Charles and M. V. Shapiro Foundation
• Keywords: Animals; Aging; Neurons; Lentivirus; Tyrosine 3-Monooxygenase; Fluorescent Antibody Technique; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Corpus Striatum; Nerve Growth Factors; Genetic Therapy; Antiparkinson Agents; Microscopy, Fluorescence; Dopamine; Nerve Tissue Proteins; Genetic Vectors; Cell Count; Glial Cell Line-Derived Neurotrophic Factor; Substantia Nigra; Parkinson Disease; Haplorhini; Dopamine Agents
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Neuroscience

Abstract

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-β-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.