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The Journal of Neuroscience, June 15, 2002, 22(12):4942-4954
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
1 Department of Neurological Sciences,
Rush-Presbyterian-St. Luke's Medical Center, Chicago,
Illinois 60612, 2 Commissariat 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, 3 Division of Surgical Research and Gene
Therapy Center, Lausanne University Medical School, 1015 Lausanne,
Switzerland, 4 The Neurosciences Institute, Swiss
Federal Institute of Technology, 1015 Lausanne, Switzerland, and
5 Department of Neurosurgery, Emory University, Atlanta,
Georgia 30322
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- -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.
Key words:
striatum; dopaminergic neurons; Parkinson's disease; primates; GDNF gene therapy; lentivirus
*
S.P. and L.L. contributed equally to this work.
Copyright © 2002 Society for Neuroscience 0270-6474/02/22124942-13$05.00/0
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