Lentivirally Delivered Glial Cell Line-Derived Neurotrophic Factor Increases the Number of Striatal Dopaminergic Neurons in Primate Models of Nigrostriatal Degeneration
- Stephane Palfi1,2,*,
- Liza Leventhal1,*,
- Yaping Chu1,
- Shuang Y. Ma1,
- Marina Emborg1,
- Roy Bakay5,
- Nicole Déglon3,4,
- Philippe Hantraye2,
- Patrick Aebischer3,4, and
- Jeffrey H. Kordower1
- 1Department of Neurological Sciences, Rush–Presbyterian–St. Luke's Medical Center, Chicago, Illinois 60612,
- 2Commissariat à l'Energie Atomique, Centre National de la Recherche Scientifique, and Unité de Recherche Associée, 2210 Service Hospitalier Frederic Joliot, and Commissariat à l'Energie Atomique, 94000 Orsay Cedex, France,
- 3Division of Surgical Research and Gene Therapy Center, Lausanne University Medical School, 1015 Lausanne, Switzerland,
- 4The Neurosciences Institute, Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland, and
- 5Department of Neurosurgery, Emory University, Atlanta, Georgia 30322
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. Unilateral1-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.
- Received December 4, 2001.
- Revision received March 21, 2002.
- Accepted March 28, 2002.
- Copyright © 2002 Society for Neuroscience
