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

• 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
• Journal Title: Journal of Neuroscience Nursing
• Volume: Volume 22, Number 12
• Publisher: Lippincott, Williams & Wilkins | 2002-06-15, Pages 4942-4954
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1523/JNEUROSCI.22-12-04942.2002
• Subjects: Biology, Neuroscience; Health Sciences, Medicine and Surgery
• Keywords: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Aging; Animals; Antiparkinson Agents; Cell Count; Corpus Striatum; Dopamine; Dopamine Agents; Fluorescent Antibody Technique; Genetic Therapy; Genetic Vectors; Glial Cell Line-Derived Neurotrophic Factor; Haplorhini; Lentivirus; Microscopy, Fluorescence; Nerve Growth Factors; Nerve Tissue Proteins; Neurons; Parkinson Disease; Substantia Nigra; Tyrosine 3-Monooxygenase

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.