HIV-1 Tat-mediated inhibition of the tyrosine hydroxylase gene expression in dopaminergic neuronal cells

lTreatment of dopaminergic rat PC12 cells with human immunodeficiency virus , type 1 (HIV-1) Tat protein or tat cDNA inhibited the expression of tyrosi ne hydroxylase (TR), the rate limiting enzyme for the dopamine biosynthetic pathway, as well as the production and release of dopamine into the cultur e medium. Moreover, the: Tat addition to PC12 cells up-regulated the expres sion of the inducible cAMP early repressor (ICER), a specific member of the cAMP-responsive element modulator transcription factor family, in a cAMP-d ependent manner. In turn, ICER overexpression abrogated the transcription a ctivity of the TH promoter in PC12 cells, strongly suggesting ICER involvem ent in Tat-mediated inhibition of TH gene expression. lit vivo injection of synthetic HIV-1 Tat protein into the striatum of healthy rats induced a su bclinical Parkinson's-like disease that became manifested only when the ani mals were treated with amphetamine. As early as one week postinjection, the histochemical examination of the rat substantia nigra showed a reduced sta ining of neurons expressing TH followed by a loss of TH+ neurons at later t ime 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 rep orted in HIV-1 seropositive individuals.