Lentivirally delivered glial cell line-derived neurotrophic factor increases the number of striatal dopaminergic neurons in primate models of nigrostriatal degeneration.
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-beta-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.
Palfi
Stephane
S
Department of Neurological Sciences, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.
Leventhal
Liza
L
Chu
Yaping
Y
Ma
Shuang Y
SY
Emborg
Marina
M
Bakay
Roy
R
Déglon
Nicole
N
Hantraye
Philippe
P
Aebischer
Patrick
P
Kordower
Jeffrey H
JH
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000375:Aging; D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism*; D002452:Cell Count; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D000882:Haplorhini; D016086:Lentivirus / Q000235:genetics; D008856:Microscopy, Fluorescence; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010300:Parkinson Disease / Q000201:enzymology / Q000473:pathology* / Q000628:therapy; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000276:immunology
D000978:Antiparkinson Agents; D015259:Dopamine Agents; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine