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PublicationA Role for Cell Cycle Protein E2F1 in HIV-Induced Neurotoxicity(2015-01-01) Zyskind, JacobHIV-associated neurocognitive disorders (HAND) are a spectrum of HIV-related conditions affecting the central nervous system that range from mild memory impairments to severe dementia. HAND results from the release of inflammatory factors and excitotoxins by HIV-infected macrophages in the brain. These factors alter the extracellular environment and provoke a neuronal response, ultimately causing dendritic damage, synaptic loss, and neuronal death. Our previous data indicate that components of the cell cycle regulatory machinery are elevated in neurons from post-mortem brain tissue of HAND patients. One of these upregulated proteins, the transcription factor E2F1, is known to activate gene targets required for G1-to-S phase progression as well as for apoptosis. Despite its increased neuronal expression, E2F1 target genes are unchanged by HIV-induced neuronal damage in vitro. Furthermore, E2F1 displays a predominantly cytoplasmic localization, a site inconsistent with its role as a transcription factor. Utilizing an in vitro model of HIV-induced neurotoxicity, we assessed the role of E2F1 in HIV-mediated neuronal damage. To begin, we evaluated the contributions of two death pathways - calpain-mediated and caspase-mediated cell death - in cortical neurons treated with H2O2 and NMDA as they mature in culture. Although both calpain-activated and caspase-activated death were detected in cortical neurons at 1 week of age, only calpain-mediated neuronal death was observed at 3 weeks of age, suggesting that calpain is the dominant death pathway. We then tested the effect of E2F1 gene disruption on HIV-induced neuronal loss. Neuronal damage and death was significantly attenuated in neurons expressing mutant E2F1 protein compared to wildtype cultures. Furthermore, we identified E2F1 as a novel calpain substrate and showed that E2F1 cleavage by calpain produces an E2F1 fragment that stably accumulates in neurons during HIV-mediated neuronal damage, suggesting a neurotoxic role for this E2F1 isoform. Finally, preliminary studies to investigate a putative RNA-binding role for E2F1 in the neuronal cytosol are outlined. Together, these data implicate E2F1 in a calpain-mediated pathway of HIV-induced neurotoxicity. Future work to understand the role of E2F1 in neurons and the consequences of calpain cleavage of E2F1 could provide important insights into disease progression and therapeutic strategies.