Astrocyte-specific expression of tyrosine hydroxylase after intracerebral gene transfer induces behavioral recovery in experimental Parkinsonism

Parkinson's neurodegenerative disorder characterized by the depletion of do pamine in the caudate putamen. Dopamine replacement with levodopa, a precur sor of the neurotransmitter, is presently the most common treatment for thi s disease. However. in an effort to obtain better therapeutic results, tiss ue or cells that synthesize catecholamines have been grafted into experimen tal animals and human patients. In this paper, we present a novel technique to express tyrosine hydroxylase (TH) in the host's own astrocytes. This pr ocedure uses a transgene in which the expression of a TH cDNA is under the control of a glial fibrillary acidic protein (GFAP) promoter, which confers astrocyte-specific expression and also increases its-specific expression a nd also increases its activity in response to brain injury. The method was tested in a rat model of Parkinson ase produced by lesioning the striatum w ith 6-hydroxydopamine. Following microinjection of the transgene into the d enervated striatum as a DNA-liposome complex, expression of the transgene w as detected by RT-PCR and TH protein was observed specifically in astrocyte s by using double-labeling immunofluorescence for GFAP and TH coupled with laser confocal microscopy. Efficacy was demonstrated by significant behavio ral recovery, as assessed by a decrease in the pharmacologically induced tu rning behavior generated by the unilateral denervation of the rat striatum. These results suggest this is a valuable technique to express molecules of therapeutic interest in the brain.