UCSF

Apoptosis, a form of programmed cell death, has been shown to be critical to the pathogenesis of a number of diseases, including neurodegenerative diseases. I investigated the role of BAX/BAK-dependent apoptosis in neurons in the context of neurodegeneration and maturation. BAX/BAK deficiency in the central nervous system of mice provides the ideal model by which to study the role of apoptosis in neurodegeneration. In a mouse model of Amyotrophic Lateral Sclerosis--a neurodegenerative disease that specifically affects motor neurons--deficiency of BAX and BAK preserves viability and function of neurons for an extended period. Moreover, this correlated

with a delay in symptom onset and extension of lifespan. Therefore, BAX/BAK dependent apoptosis is activated early in the disease process and represents a viable therapeutic target for neurodegenerative diseases. Regenerative medicine is currently one of the therapeutic strategies being considered for treatment of neurodegenerative diseases. Using this method, the patient's own stem cells are differentiated in vitro into the affected neuronal

subtype and re-implanted back into the patient. Because of the promise of regenerative medicine, it is critical to understand the signaling pathways mediating the differentiation process in stem cells. Caspase activity has been reported to mediate the differentiation of embryonic stem cells (ESCs), and I discovered that this process requires BAX and BAK. BAX/BAK deficient ESCs

undergoing differentiation express lower levels of neural markers and higher levels of pluripotency markers. These results indicate that ESCs lacking BAX and BAK are far less effective at differentiating down the neural lineage. Furthermore, engagement of BAX/BAK dependent apoptosis induces differentiation of ESCs. Therefore, the BAX/BAK apoptotic pathway mediates differentiation of stem cells.

These results underline the importance of the BAX/BAK apoptotic pathway in the development and survival of neurons. Deficiency of BAX and BAK prolongs survival in the context of neurodegeneration and delays the maturation of stem cells down the neural lineage. The findings of my thesis provide insight into the basic biology of neurons, and how to better treat neurologic disorders.