@article{5266c07973034f41a0d43b731105035e,
title = "A Model of GDNF Gene Therapy in Mice with 6-Hydroxydopamine Lesions: Time Course of Neurorestorative Effects and ERK1/2 Activation",
abstract = "Background: Glial cell line-derived neurotrophic factor (GDNF) is the most promising neurotrophin for restorative treatments in Parkinson's disease, but its biological effects are not completely understood. Objective: To define a model of GDNF gene therapy in the mouse, we studied the long-term effects of lentiviral GDNF delivery in mice with striatal 6-hydroxydopamine (6-OHDA) lesions. Methods: Lentiviral vectors coding for GDNF or green fluorescent protein (GFP) were injected unilaterally in the striatum two weeks prior to the 6-OHDA lesion. Mice were monitored on tests of spontaneous activity and amphetamine-induced rotation at 1, 4, 10 and 35 weeks post-lesion. Brains were processed immunohistochemically for tyrosine hydroxylase (TH) and markers of extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation at the same time points. Results: Lentiviral GDNF significantly inhibited both spontaneous and amphetamine-induced rotation. Compared to the control vector, lentiviral GDNF resulted in a partial protection of TH-positive cells in the substantia nigra, and in a nearly total restoration of striatal TH immunostaining by 35 weeks. A progressive sprouting of TH-positive neurites occurred in both the globus pallidus and the substantia nigra, reaching a 4-5 fold increase above controls by 35 weeks. This effect was paralleled by a long-term supranormal activation of ERK1/2 and its downstream target, phospho-Ser31 TH. Conclusions: Lentiviral GDNF delivery produced robust long-term signaling responses and neurorestoration. This experimental model of GDNF gene therapy will be particularly suitable to study the molecular mechanisms of dopaminergic fiber sprouting, a long-term response to GDNF delivery that also occurs in Parkinson's disease patients.",
keywords = "Neurotoxin, neuroprotection, rodent, mitogen-activated protein kinases, MAPK, trophic factor, GDNF",
author = "Niklas Lindgren and Veronica Francardo and Luis Quintino and Cecilia Lundberg and {Cenci Nilsson}, Angela",
year = "2012",
doi = "10.3233/JPD-012146",
language = "English",
volume = "2",
pages = "333--348",
journal = "Journal of Parkinson's Disease",
issn = "1877-718X",
publisher = "IOS Press",
number = "4",
}