Imbalanced expression of glutamate-glutamine cycle enzymes induced by human T-cell lymphotropic virus type 1 Tax protein in cultivated astrocytes.
Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent involved in the disease HTLV-1-associated myelopathy, or tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is poorly understood, but it is probable that viral infection has an indirect, deleterious effect on neural function. In this regard, dysfunction in astrocytes may be severely detrimental, as they supply neurons with metabolic precursors, control the extracellular levels of ion and excitatory neurotransmitters, and are electrically coupled with oligodendrocytes. In a model in vitro, we demonstrate that HTLV-1 induces an imbalance in the expression of two astrocyte enzymes, at both the transcriptional and translational levels. In both human astrocyte precursors and rat glial cells, the levels of expression of glutamine synthetase (GS) and glutamate dehydrogenase (GDH) were increased and decreased, respectively, after coculture with HTLV-1 T cells. The enhancement of GS expression may result from the action of the protein Tax, which is demonstrated to transactivate the GS gene promoter, while the decreased expression of GDH seems to reflect some compensatory mechanism in response to GS induction. GS and GDH are involved in the conversion of glutamate into glutamine or alpha-ketoglutarate, which then acts as a precursor for glutamatergic and gamma-aminobutyric acid (GABA)-ergic neurons. Metabolism in astrocytes altered by Tax protein may lead to deleterious effects if it modifies the extracellular levels of glutamine, glutamate, and GABA and thus modulates neuronal excitability and osmotic equilibrium in the central nervous system of HTLV-1-infected patients.
Akaoka
H
H
Institut National de la Santé et de la Recherche Médicale Unité 433,Neurobiologie Expérimentale et Physiopathologie, Lyon, France.
Hardin-Pouzet
H
H
Bernard
A
A
Verrier
B
B
Belin
M F
MF
Giraudon
P
P
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology*; D002460:Cell Line; D016356:Gene Products, tax / Q000378:metabolism*; D005969:Glutamate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D005974:Glutamate-Ammonia Ligase / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D009457:Neuroglia / Q000166:cytology / Q000201:enzymology*; D011401:Promoter Regions, Genetic; D051381:Rats; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D016356:Gene Products, tax; D005969:Glutamate Dehydrogenase; D005974:Glutamate-Ammonia Ligase