| First Author | Zou S | Year | 2019 |
| Journal | J Neurochem | Volume | 149 |
| Issue | 1 | Pages | 98-110 |
| PubMed ID | 30674062 | Mgi Jnum | J:273367 |
| Mgi Id | MGI:6286683 | Doi | 10.1111/jnc.14668 |
| Citation | Zou S, et al. (2019) Effects of HIV-1 Tat on oligodendrocyte viability are mediated by CaMKIIbeta-GSK3beta interactions. J Neurochem 149(1):98-110 |
| abstractText | 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 [Ca(2+) ]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 [Ca(2+) ]i is reduced in mature OLs. Tat exposure also increased the activity of Ca(2+) /calmodulin-dependent kinase IIbeta (CaMKIIbeta), the major isoform of CaMKII expressed by OLs, in both immature and mature OLs. Since CaMKIIbeta is reported to interact with glycogen synthase kinase 3beta (GSK3beta), and GSK3beta 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 CaMKIIbeta-GSK3beta activities. Tat expression in vivo led to increased CaMKIIbeta and GSK3beta activity in multiple brain regions in transgenic mice. In vitro, immature murine OLs expressed higher levels of GSK3beta, but much lower levels of CaMKIIbeta, than did mature OLs. Exogenous Tat up-regulated GSK3beta activity in immature, but not mature, OLs. Tat-induced death of immature OLs was rescued by the GSK3beta inhibitors valproic acid or SB415286, supporting involvement of GSK3beta signaling. Pharmacologically inhibiting CaMKIIbeta increased GSK3beta activity in Tat-treated OLs, and genetically knocking down CaMKIIbeta promoted death in mature OL cultures treated with Tat. Together, these results suggest that the effects of Tat on OL viability are dependent on CaMKIIbeta-GSK3beta interactions, and that increasing CaMKIIbeta activity is a potential approach for limiting OL/myelin injury with HIV infection. |
