Voltage-gated K+ Channels and HIV-1-induced Neural Injury: Implications for Pathogenesis of HIV-1-associated Neurocognitive Disorders

Author

Han Liu, University of Nebraska Medical CenterFollow

Graduation Date

Summer 8-19-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Huangui Xiong

Abstract

Human immunodeficiency virus-1 (HIV-1)-associated neurocognitive disorder (HAND) is a subcortical disease involving neuronal loss and myelin damage. Myelin is deposited by oligodendrocytes through a complex process including oligodendrocyte progenitor cell (OPC) proliferation and maturation. Oligodendrocytes/OPCs are susceptible to viral proteins such as Tat and that myelin damage is associated with oligodendrocyte number decrease. It has been shown that activation of voltage-gated K⁺ (K_V) channels mediates apoptosis in various cell types. K_V1.3 is the most predominant K_V channel expressed in OPCs/oligodendrocytes and potentially involved in OPC developmental regulation. We studied the involvement of K_V1.3 in Tat-induced OPC/oligodendrocyte injury and OPC maturation deficit. Tat increased K_V1.3 currents in cultured OPCs and oligodendrocytes may through direct interaction and interrupting channel phosphorylating regulation, leading to OPC maturation retardation and OPC/oligodendrocyte apoptosis. Tat-caused myelin injury was validated in corpus callosum and striatum of cultured rat brain slices. These effects were prevented by K_V1.3 antagonists or K_V1.3-siRNA knockdown.

Gelsolin (GSN), an actin-binding protein best-known for its modulation of cell motility and secretion. Neurons appear to be a major source of GSN in CNS and GSN-null neurons have enhanced cell death. The GSN level is decreased in CSF of HIV-1-infected individuals. Studies have demonstrated that enhancement of K_V currents results in neuronal apoptosis. To understand how the decreased level of GSN causes neuronal injury in HAND, we studied the effects of GSN on HIV-1 glycoprotein 120 (gp120)-activated outward K⁺ currents in primary rat cortical neuronal cultures. Gp120 enhanced outward K⁺ and resulted in neuronal apoptosis. GSN suppressed the gp120-induced outward K⁺ current increase and reduced vulnerability to gp120-induced neuronal apoptosis. The GSN-mediated suppression of gp120 enhancement of neuronal outward K⁺ current was blocked by K_V2.1 inhibitor. In parallel, gp120 up-regulated K_V2.1 channel expression, which was also blocked by GSN.

Taken together, my thesis research demonstrates that Tat induces myelin damage by K_V1.3-mediated OPC/oligodendrocyte injury and maturation defects, which may have implications for the pathogenesis of HAND. GSN protects neurons from gp120-associated changes by suppression of gp120-induced enhancement of K_V2.1 K⁺ currents, which may reflect a neuroprotective role of GSN in HIV-1-infected brain.

Recommended Citation

Liu, Han, "Voltage-gated K+ Channels and HIV-1-induced Neural Injury: Implications for Pathogenesis of HIV-1-associated Neurocognitive Disorders" (2016). Theses & Dissertations. 142.
https://digitalcommons.unmc.edu/etd/142