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

Stephane Palfi, Liza Leventhal, Yaping Chu, Shuang Y. Ma, Marina Emborg, Roy Bakay, Nicole Déglon, Philippe Hantraye, Patrick Aebischer, Jeffrey H. Kordower

Research output: Contribution to journalArticlepeer-review

182 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4942-4954
Number of pages13
JournalJournal of Neuroscience
Volume22
Issue number12
DOIs
StatePublished - Jun 15 2002
Externally publishedYes

Keywords

  • Dopaminergic neurons
  • GDNF gene therapy
  • Lentivirus
  • Parkinson's disease
  • Primates
  • Striatum

ASJC Scopus subject areas

  • Neuroscience(all)

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