Determining the Role of Trib3 in Neuronal Apoptosis

Naturally occurring apoptosis in the developing nervous system is an important event for the proper shaping of the system, for eliminating precursor cells with mutations and for curbing the population of post-mitotic neurons so that appropriate target innervation can take place. In the latter case, neurons are usually subjected to a competition for a limited supply of target-derived growth factor. A classic example includes neurons of the superior cervical ganglia that compete for nerve growth factor (NGF). Cell death arising from lack of NGF stimulation is a topic of intense research and remains enigmatic. Pro-apoptotic molecules that have been characterized so far are partially responsible for inducing death and furthermore, it is not fully understood how the homeostatic balance of the neuron is disrupted by NGF deprivation. In this thesis, a novel neuronal pro-apoptotic protein Trib3 is defined. It is shown to be required for developmental neuron death and to employ a cellular mechanism involving Akt and its substrates, the FoxO transcription factors. It is also shown that Trib3 is transcriptionally regulated by the FoxO, JNK and apoptotic cell-cycle pathways. The data further demonstrate that Trib3 functions in a feed-forward loop with the FoxOs and deactivates Akt in a self-propelled pathway that amplifies the apoptotic cascade resulting from NGF deprivation. Moreover, Trib3 is found to be induced and necessary for neuron death in cellular models of Alzheimer's and Parkinson's diseases. The latter preliminary findings have encouraged other researchers to begin exploring Trib3's mechanism and regulation in neurodegenerative disease models; this will advance our knowledge and understanding of the cellular processes of neuron death and may lead to development of novel therapeutic targets.