Effects of HIV-1 Tat on oligodendrocyte viability are mediated by CaMKIIß-GSK3ß interactions.
J Neurochem
; 149(1): 98-110, 2019 04.
Article
em En
| MEDLINE
| ID: mdl-30674062
ABSTRACT
Myelin disruptions are frequently reported in human immunodeficiency virus (HIV)-infected individuals and can occur in the CNS very early in the disease process. Immature oligodendrocytes (OLs) are quite sensitive to toxic increases in [Ca2+ ]i caused by exposure to HIV-1 Tat (transactivator of transcription, a protein essential for HIV replication and gene expression), but sensitivity to Tat-induced [Ca2+ ]i is reduced in mature OLs. Tat exposure also increased the activity of Ca2+ /calmodulin-dependent kinase IIß (CaMKIIß), the major isoform of CaMKII expressed by OLs, in both immature and mature OLs. Since CaMKIIß is reported to interact with glycogen synthase kinase 3ß (GSK3ß), and GSK3ß activity is implicated in OL apoptosis as well as HIV neuropathology, we hypothesized that disparate effects of Tat on OL viability with maturity might be because of an altered balance of CaMKIIß-GSK3ß activities. Tat expression in vivo led to increased CaMKIIß and GSK3ß activity in multiple brain regions in transgenic mice. In vitro, immature murine OLs expressed higher levels of GSK3ß, but much lower levels of CaMKIIß, than did mature OLs. Exogenous Tat up-regulated GSK3ß activity in immature, but not mature, OLs. Tat-induced death of immature OLs was rescued by the GSK3ß inhibitors valproic acid or SB415286, supporting involvement of GSK3ß signaling. Pharmacologically inhibiting CaMKIIß increased GSK3ß activity in Tat-treated OLs, and genetically knocking down CaMKIIß promoted death in mature OL cultures treated with Tat. Together, these results suggest that the effects of Tat on OL viability are dependent on CaMKIIß-GSK3ß interactions, and that increasing CaMKIIß activity is a potential approach for limiting OL/myelin injury with HIV infection.
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Base de dados:
MEDLINE
Assunto principal:
Infecções por HIV
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Oligodendroglia
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina
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Produtos do Gene tat do Vírus da Imunodeficiência Humana
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Glicogênio Sintase Quinase 3 beta
Limite:
Animals
Idioma:
En
Revista:
J Neurochem
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos