Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K+ current conducted by KV1.3

Abstract

Brain white matter damage is frequently detected in patients infected with human immunodeficiency virus type 1 (HIV-1). White matter is composed of neuronal axons sheathed by oligodendrocytes (Ols), the myelin-forming cells in central nervous system. Ols are susceptible to HIV-1 viral trans-activator of transcription (Tat) and injury of Ols results in myelin sheath damage. It has been demonstrated that activation of voltage-gated K+ (KV) channels induces cell apoptosis and Ols predominantly express K+ channel KV1.3. It is our hypothesis that Tat injures Ols via activation of KV1.3. To test this hypothesis, we studied the involvement of KV1.3 in Tat-induced Ol/myelin injury both in vitro and ex vivo. Application of Tat to primary rat Ol cultures enhanced whole-cell KV1.3 current recorded under voltage clamp configuration and confirmed by specific KV1.3 antagonists Margatoxin (MgTx) and 5-(4-phenoxybutoxy) psoralen (PAP). The Tat enhancement of KV1.3 current was associated with Tat-induced Ol apoptosis, which was blocked by MgTx and PAP or by siRNA knockdown of KV1.3 gene. The Tat-induced Ol injury was validated in cultured rat brain slices, particularly in corpus callosum and striatum, that incubation of the slices with Tat resulted in myelin damage and reduction of myelin basic protein which were also blocked by aforementioned KV1.3 antagonists. Further studies revealed that Tat interacts with KV1.3 as determined by protein pull-down of recombinant GST-Tat with KV1.3 expressed in rat brains and HEK293 cells. Such protein-protein interaction may alter channel protein phosphorylation, resultant channel activity and consequent Ol/myelin injury. Taken together, these results demonstrate an involvement of KV1.3 in Tat- induced Ol/myelin injury, a potential mechanism for the pathogenesis of HIV-1-associated white matter damage.

Mutant BCL11B in a Patient With a Neurodevelopmental Disorder and T-Cell Abnormalities

“…Thus, our case suggests that the damage of brain white matter might be associated with the absence of functional BCL11B. Oligodendrocytes, the myelin-forming cells, are thought to differentiate from neural stem cells via oligodendrocyte precursor cells (18,19). Many cytokines were reported to participate in the differentiation of oligodendrocytes (20), including cyclin-dependent kinase inhibitor p27/Kip1, which increased the differentiation of oligodendrocytes from induced pluripotent stem cells (21).…”

Replicable association between human cytomegalovirus infection and reduced white matter fractional anisotropy in major depressive disorder

“…The oligodendroglia responsible for white matter myelination are thought to be particularly vulnerable to the damaging effects of viral infections and inflammatory processes [3,57,58], potentially explaining why one of the most prominent findings in MDD at postmortem is a reduction in the number or density of oligodendrocytes [3,59]. The fractional anisotropy (FA) value derived from diffusion tensor imaging (DTI) has been reported to be highly sensitive to axon myelination [60,61] (although it likely also serves as a general index of neuronal integrity reflecting a combination of myelination, neural fiber compactness, axon diameter, and orientation [62]).…”

Evaluation of apamin effects on myelination process in C57BL/6 mice model of multiple sclerosis

“…It should be noted that oligodendrocytes are supportive cells in the central nervous system and are responsible for the production of myelin. It has been proven that the activation of these channels is essential for the planned cell death, and an increase in the removal of potassium ions from the neuronal cell causes neuronal apoptosis (30). Most likely inhibition of the above mentioned channels with apamin could enhance myelin content that could be the result of microglia cells inhibition or oligodendrocytes stimulation and needs further evaluation.…”