PROJECT SUMMARY/ABSTRACT Amyotrophic lateral sclerosis (ALS) is a progressive, uniformly fatal neurodegenerative disorder caused by the loss of upper and lower motor neurons. Despite multiple advanced clinical trials, there are currently no therapies that can stabilize or reverse the motor deficits of ALS. My goal in pursuing a K08 Mentored Clinical Scientist Research Career Development Award is to acquire the knowledge and practical training to make major advances in our understanding of the mechanisms underlying neuronal loss in ALS. With my career, I seek to develop novel therapies that will prevent motor neuron death and preserve function. In 2006 Neumann and colleagues discovered that TAR DNA-binding protein 43 (TDP43) accumulated abnormally within diseased neurons and represented a unifying, end-stage neuropathologic hallmark of ALS. With this observation, the field then converged on the cellular process of autophagy — the method by which cells use lysosomes to purge proteins aggregates and maintain homeostasis — as a critical pathway involved in ALS’ pathogenesis. Lysosomes, however, are tremendously intricate and not well understood compartments within neurons. Lysosomes house many complex, hydrolytic enzymes; they assist in adaptive stress responses; and they promote cell survival broadly. While it has been shown that TDP43 can be directed to the lysosome for clearance, past efforts have stopped their investigations at the lysosomal membrane, presuming that presuming that TDP43 degradation happens efficiently by an array of unspecified enzymes thereafter. My preliminary data demonstrates that only a subset of lysosomal enzymes (cathepsins B, D, E, G, L, K, S, and V) can degrade TDP43 in a pH-dependent manner and that ALS-causing TDP43 mutations have the potential to disrupt the functions of these enzymes. Therefore, I hypothesize that cathepsins B, D, E, G, L, K, S, and V are responsible for TDP43 degradation, pathogenic TDP43 mutations are capable of conferring resistance to these cathepsins, and that impaired cathepsin activity (whether due to TDP43 mutations or age- related changes in pH) contributes to TDP43 buildup, TDP43 aggregation, and neurodegeneration over time. This proposal builds upon my solid foundation in neurobiology and neurology that I have cultivated working as a basic research scientist during my undergraduate, medical school, residency, fellowship, and early faculty years. My current research mentor has an established record of impactful discoveries in the field of neurodegeneration. I have also assembled a team of highly accomplished advisors at UCSF to guide me through this next phase of training on my path to becoming an independent investigator. My training plan is specifically designed to provide me with the mentorship, training in advanced experimental skills, and experience required to run a research group. Completing the research and obtaining the skill sets and mentorship outlined in this proposal will prepa...