A model of GDNF gene therapy in mice with 6-Hydroxydopamine lesions: time course of Neurorestorative effects and ERK1/2 activation.
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.
Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Sweden.
Niklas
N
Lindgren
Veronica
V
Francardo
Luis
L
Quintino
Cecilia
C
Lundberg
M Angela
MA
Cenci
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*; D013997:Time Factors; D016896:Treatment Outcome; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D051100:Glial Cell Line-Derived Neurotrophic Factor; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase