Affiliations: Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden | CNS Genetherapy, Department of Experimental Medical Science, Lund University, Lund, Sweden
Note: [] Correspondence to: M. Angela Cenci, Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, BMC F-11, S- 221 84 Lund, Sweden. Tel.: +46 46 2224446; Fax: +46 46 2224546; E-mail: [email protected]
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.
