Date of Award
Doctor of Philosophy (PhD)
Kelly L. Jordan-Sciutto
HIV-associated neurocognitive disorders (HAND) are comprised of a host of cognitive, motor, and behavioral impairments affecting approximately 30-50% of HIV-infected individuals. Despite the development of combination antiretrovirals as a therapy to suppress viral replication, there is currently no effective treatment for HAND-associated neurological symptoms. Advanced understanding of HAND neuropathogenesis is necessary to identify novel therapeutic targets that mediate the neuronal damage and neuronal death associated with this disease. One of the molecular pathways implicated in HAND progression is the aberrant activation of the cell cycle machinery. Activation of the cell cycle machinery leads to the coordinated disinhibiton of the transcription factor E2F1, which initiates the irreversible entry from G1 to S phase in cycling cells, leading to neuronal dysfunction and death. Although E2F1 is well-studied in the context of neuronal death, little is known regarding its physiologic role in the healthy central nervous system (CNS). In the present dissertation work, we aimed to elucidate the role of E2F1 in the healthy CNS, providing implications for E2F1 contribution to HAND neuropathogenesis. We first provided data to suggest that E2F1 does not mediate neuronal damage through its classical functions as a transcriptional regulator of apoptotic and cell cycle-related genes in vitro model of HIV-associated toxicity. Next, we characterized the age-dependent behavioral deficits and synaptic disruptions and the impairment in adult neurogenesis in mice with E2F1 gene mutation. Furthermore, we verified that E2F1 can regulate the expression of postsynaptic density protein-95 and neuronal morphology independently from of its effects on neurogenesis. We also found that E2F1 in the brain, unlike in other peripheral tissues, is regulated through alternative splicing. Lastly, we presented evidence that mice classically described as E2F1 null animals do indeed express residual mutant E2F1 mRNA transcript and protein. Taken together, our results suggest that E2F1 plays additional roles in the CNS and that E2F1 is regulated by unique mechanisms in the CNS. Understanding these new functions of E2F1 and how they are regulated will provide new insights into CNS development, disease and therapeutic intervention.
Ting, Jenhao Harry, "Novel Roles of Cell Cycle Regulator E2f1 in the Cns: Implications for Synaptic Damage in HIV-Associated Neurocognitive Disorders" (2014). Publicly Accessible Penn Dissertations. 1471.