| Cell death is important for both development and for the natural aging process. However, diseases or cellular injury that affect the normal homeostatic balance within a cell can also initiate death. The mechanisms that underlie this cell death are both variable and complex. Much of the complexity is derived from the fact that this diversity in cellular response to injury is dependent on both cell type and insult. Therefore narrowing the complexity by selecting a specific cell type and cellular injury allows for better characterization and manipulation. Here, I have studied the effect of UV-exposure on cortical neurons.; In studying cell death in neurons one expects commonality but looks for differences. While caspases are the accepted common protease associated with cell death, other proteases such as calpain have also been shown to mediate cell death. Here I show that UV treatment induces a dose-dependent increase in neuronal death frequency. Furthermore, in response to UV exposure, cortical neurons increase their caspase and calpain activity. In addition, by using inhibitors of both caspases and calpains I show that, although caspases are active, calpains are the primary effecter in this UV-induced cell death model.; Because growth factors, in particular nerve growth factor (NGF), have been shown to provide neuroprotection in other models and cell types, I hypothesized that NGF would have a similar protective effect on UV exposed cortical neurons. Here, I show that NGF pretreatment protects cortical neurons from UV exposure. Furthermore, I demonstrated that this NGF neuroprotection requires p75NTR. In addition, I found involvement of ceramide and NFκB in this p75NTR-mediated NGF neuroprotection. Lastly, I showed an interaction between the UV-induced calpain-mediated cell death pathway and the p75NTR mediated NGF neuroprotective mechanism.; Taken together these observations suggest that an alternative pathway of neuronal death, with characteristics of apoptosis and necrosis, exists within cortical neurons. Furthermore, understanding that pathway will help expand our knowledge of how neurons undergo cell death when subjected to stress. Moreover, demonstrating preventative measures, such as NGF neuroprotection, suggests potential ways to counteract or prevent the neuronal death that results from injury and disease. |
