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The Journal of Neuroscience, July 21, 2004, 24(29):6437-6445; doi:10.1523/JNEUROSCI.1122-04.2004

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Development/Plasticity/Repair
Overexpression of Glial Cell Line-Derived Neurotrophic Factor Using a Lentiviral Vector Induces Time- and Dose-Dependent Downregulation of Tyrosine Hydroxylase in the Intact Nigrostriatal Dopamine System

Biljana Georgievska, Deniz Kirik, and Anders Björklund

Department of Physiological Sciences, Division of Neurobiology, Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden

The effects of continuous glial cell line-derived neurotrophic factor (GDNF) overexpression in the intact nigrostriatal dopamine (DA) system was studied using recombinant lentiviral (rLV) vector delivery of GDNF to the striatum or substantia nigra (SN) in the rat. Intrastriatal delivery of rLV-GDNF resulted in significant overexpression of GDNF in the striatum (2-4 ng/mg tissue) and anterograde transport of GDNF protein to the SN. Striatal rLV-GDNF delivery initially induced an increase in DA turnover (1-6 weeks), accompanied by significant contralateral turning in response to amphetamine, suggesting an enhancement of the DA system on the injected side. Starting 6 weeks after continuous GDNF delivery, we observed a selective downregulation of tyrosine hydroxylase (TH) protein (70%) that was maintained until the end of the experiment (24 weeks). A similar effect was observed when rLV-GDNF was injected into the SN. The magnitude of TH downregulation was related to the level of GDNF expression and was most pronounced in animals in which the striatal GDNF level exceeded 0.7 ng/mg tissue. The decreased TH protein levels were associated with similar reductions in the in vitro TH enzyme activity (70%); however, in vivo L-3,4-dihydroxyphenylalanine production rate and DA tissue levels were maintained at normal levels. The results indicate that downregulation of TH protein reflects a compensatory effect in response to continuous GDNF stimulation of the DA neurons mediated by a combination of overactivity at the DA synapse and a direct GDNF-induced action on TH gene expression. This compensatory mechanism is proposed to maintain long-term DA neuron function within the normal range.

Key words: dopamine; Parkinson; downregulation; gene therapy; glial cell line-derived neurotrophic factor; intact; overexpression; Parkinson's disease; tyrosine hydroxylase

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Received Dec 2, 2003; revised May 27, 2004; accepted May 27, 2004.

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