Regulation of neuronal cell death by BH3-only molecules

Abstract

Apoptosis in metazoan organisms plays critical roles in normal development, tissue homeostasis and immunity, and its disturbed regulation leads to many pathological states, including cancer, autoimmunity, infection and degenerative disorders. Apoptosis can be triggered by the engagement of `death receptors' of the tumor necrosis factor receptor family on the cell surface or by diverse intracellular signals that act upon the BCL2 (B-cell CLL/lymphoma 2) protein family, which controls the integrity of the mitochondrial outer membrane through the complex interactions of family members. Both the pathways lead to cellular demolition by dedicated proteases termed caspases.

Different BH3-only proteins (or combinations of them) are critical for PCD in specific tissues or apoptosis in response to diverse cytotoxic stimuli by disrupting the interaction between anti-apoptotic BCL2 members (BCL-X _L, BCL2, BCL-w and MCL1) and pro-apoptotic BCL2 members (BAX, BAK and BOK). In this dissertation, I examined the role of BH3-only proteins in mediating neuronal cell death in response to toxic stimuli such as ethanol and Endoplasmic Reticulum (ER) stress and also in response to developmental cues.

Administration of ethanol to neonatal mice causes massive apoptosis of immature neurons during synaptogenesis. Our studies identify PUMA as a critical regulator of this cell death program, independent of p53. Programmed cell death in the nervous system in response to developmental cues is regulated by the interaction between pro-apoptotic BAX and anti-apoptotic BCL-X _L. HRK expression is increased in neuronal cells in response to stresses such as limited trophic factor support withdrawal. However, my studies indicate that HRK is not a critical regulator of the BAX-BCL-X_L axis during neurodevelopment. My studies also identify PUMA as a key initiator of apoptosis in response to ER stress, independent of p53 and demonstrate that CHOP (C/EBP homologous protein) in conjunction with FOXO3a (forkhead box, class O, 3a) mediates PUMA expression in neurons in response to ER stress.

Since BH3-only proteins are essential initiators of cell death pathways, understanding their regulation may provide novel therapeutic targets to prevent pathological cell death. Inhibitors of BH3-only proteins may help alleviate degenerative disorders, whereas small molecule mimetics may be used in various neoplastic and autoimmune diseases.