| Apoptosis is an evolutionarily conserved genetic cell-suicide program required for development, tissue homeostasis, and protection against pathogens. Genetic and biochemical studies have implicated the Bcl-2 family as the central regulator in this genetic program commanding the life-or-death decision. Dysregulation of this process results in many diseases, including cancer, autoimmunity, and degenerative disorders. Therefore, a better understanding of how the Bcl-2 family controls this process should provide insights into new therapeutic interventions.; This thesis is designed to examine the molecular mechanism(s) of Bak, a member of the Bcl-2 family proteins. In chapter I, we analyze the function of Bak in multiple mouse models of neurodegenerative diseases. We find that Bak either inhibits or promotes neuronal death, and that the function of Bak is modulated by factors including the types and maturity of the neurons and the death stimuli applied. In the second chapter, we show that Bak is cleaved by calpain. Furthermore, we demonstrate that this cleavage event is critical in activating the pro-apoptosic activity of Bak and initiating the cell death process. In the third chapter, we explore the issue concerning the functional redundancy of Bax and Bak. We find that, contrary to the existing findings, Bax and Bak function independently to inhibit neuronal apoptosis induced by Sindbis virus infection. This result is further supported by the observations reported in chapter I and by others that under certain death paradigms, the presence of Bax and Bak exert differential effects on cell fate. Lastly, we went on to study the relationship of mitochondrial fragmentation and cell death using yeast as a model system. Here we found that: (1) yeast cells might contain the primordial mitochondrial cell death machinery; (2) Fist, a component of normal mitochondrial fission machinery, protects yeast cells from multiple death stimuli via inhibiting mitochondrial fragmentation. |
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