HIV-1 Tat-mediated inhibition of the tyrosine hydroxylase gene expression in dopaminergic neuronal cells.
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.
Zauli
G
G
Department of Morphology and Embryology, Anatomy Section, University of Ferrara, Via Fossato di Mortara 66, 44100 Ferrara, Italy. zlg@dns.unife.it
Secchiero
P
P
Rodella
L
L
Gibellini
D
D
Mirandola
P
P
Mazzoni
M
M
Milani
D
D
Dowd
D R
DR
Capitani
S
S
Vitale
M
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D051786:Cyclic AMP Response Element Modulator; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015696:Gene Products, tat / Q000235:genetics / Q000494:pharmacology*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000473:pathology; D008854:Microscopy, Electron; D016627:Oxidopamine / Q000494:pharmacology; D016716:PC12 Cells; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000235:genetics*; D054322:tat Gene Products, Human Immunodeficiency Virus
D004268:DNA-Binding Proteins; D015696:Gene Products, tat; D012333:RNA, Messenger; D012097:Repressor Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D051786:Cyclic AMP Response Element Modulator; D005576:Colforsin; D016627:Oxidopamine; D000242:Cyclic AMP; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine