Abstract
Astrocyte reactivity, a phenomenon observed in a variety of neurodegenerative disorders, can have both beneficial and detrimental manifestations which significantly affect neuronal physiology. In neuroAIDS, reactive astrocytes have been observed to severely affect the neuronal population present in their vicinity. Calcium signaling plays a central role in mediating astrocyte reactivity. Coronin 1A, an actin-binding protein, majorly reported in hematopoietic cells, regulates cell activity in a calcium-dependent manner, but its role in astrocyte physiology and reactivity is largely unknown. Using a well-characterized primary culture of human astroglia and neurons, we explored the roles of coronin 1A in astrocyte physiology and its involvement in facilitating astrocyte reactivity. In this study, we report coronin 1A expression in human primary astrocytes and autopsy brain sections, and that it plays activity-dependent roles by facilitating calcium mobilization from the intracellular stores. HIV-1 Tat, a potent neurotoxicant that turns astrocytes reactive, augments coronin 1A expression, apart from affecting GFAP and pro-inflammatory molecules. Also, the autopsy brain tissue of HIV-1 infected individuals has a higher expression of coronin 1A. Downregulation of coronin 1A attenuated the HIV-1 Tat-induced deleterious effects of reactive astrocytes, measured as the upregulated expression of GFAP, pro-inflammatory molecules, and enhanced release of IL-6, and hence reduced astrocyte-mediated neurodegeneration. Our findings also suggest that out of a pool of dysregulated miRNAs studied by us, hsa-miR-92b-5p regulates coronin 1A expression under the effect of HIV-1 Tat. These findings highlight the novel roles of coronin 1A in regulating astrocyte activity in stimulated conditions and astrocyte reactivity observed in HIV-1 neuropathogenesis.
Keywords:
astrocytes; calcium mobilization; coronin 1A; glia‐mediated neurodegeneration; reactive astrocytes.