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J Biol Chem, Vol. 275, Issue 6, 4159-4165, February 11, 2000

HIV-1 Tat-mediated Inhibition of the Tyrosine Hydroxylase Gene Expression in Dopaminergic Neuronal Cells^*

Giorgio Zauli^§¶, Paola Secchiero, Luigi Rodella, Davide Gibellini^**, Prisco Mirandola, Meri Mazzoni, Daniela Milani^§, Diane R. Dowd, Silvano Capitani, and Marco Vitale^§§

From the  Department of Morphology and Embryology, Anatomy Section, University of Ferrara, Via Fossato di Mortara 66, 44100 Ferrara, Italy, the ^§ Institute of Human Morphology, "Gabriele D'Annunzio" University of Chieti, via dei Vestini 6, 66100 Chieti, Italy, the  Department of Biomedical Sciences and Biotechnology, Human Anatomy Section, University of Brescia, Via Valsabbina 19, 25123 Brescia, Italy, the ^** Department of Clinical and Experimental Medicine, Microbiology Section, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy, the  Doisy Department of Biochemistry and Molecular Biology, Saint Louis University Health Sciences Center, St. Louis, Missouri 63104, and the ^§§ Institute of Normal and Pathological Cytomorphology of Consiglio Nazionale delle Richerche c/o Institute of Research "Codivilla Putti", Via di Barbiano 1/10, 40136 Bologna, Italy

Treatment of dopaminergic rat PC12 cells with human immunodeficiency virus, type 1 (HIV-1) Tat protein or tat cDNA inhibited the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme for the dopamine biosynthetic pathway, as well as the production and release of dopamine into the culture medium. Moreover, the Tat addition to PC12 cells up-regulated the expression of the inducible cAMP early repressor (ICER), a specific member of the cAMP-responsive element modulator transcription factor family, in a cAMP-dependent manner. In turn, ICER overexpression abrogated the transcription activity of the TH promoter in PC12 cells, strongly suggesting ICER involvement in Tat-mediated inhibition of TH gene expression. In vivo injection of synthetic HIV-1 Tat protein into the striatum of healthy rats induced a subclinical Parkinson's-like disease that became manifested only when the animals were treated with amphetamine. As early as one week postinjection, the histochemical examination of the rat substantia nigra showed a reduced staining of neurons expressing TH followed by a loss of TH⁺ neurons at later time points. As Tat protein can be locally released into the central nervous system by HIV-1-infected microglial cells, our findings may contribute to the explanation of the pathogenesis of the motorial abnormalities often reported in HIV-1 seropositive individuals.

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