Lysosome homeostasis in aging-related diseases

Abstract Lysosomes are important for maintaining cellular health and their dysfunction is linked to numerous aging-related diseases. Lysosome function is regulated by homeostatic mechanisms that allow cells to sense lysosomal stress and either eliminate or repair damaged lysosomes, or generate new lysosomes through transcriptional activation. Our research has shown that lysosomal stress is sensed through a mechanism that involves the direct modification of lysosomal membranes by autophagy proteins called ATG8s, through a process called Conjugation of ATG8s onto Single Membranes (CASM). This mechanism coordinates the turnover of damaged lysosomal membranes through microautophagy with the biogenesis of new lysosomes, but how these different activities are balanced to maintain lysosomal health is not well understood. We have shown that membrane turnover and biogenesis are regulated through separable mechanisms, and that the induction of biogenesis, which occurs through activation of the transcription factor TFEB, occurs only at particular stress thresholds that engage turnover across a lysosome network. The long-term goal of this research program is to elucidate how lysosomal stress is mitigated by lysosome turnover and biogenesis and to uncover how these activities are balanced to maintain lysosomal health. In my predoctoral research (Aim 1), I propose to test the hypothesis that lysosome biogenesis is coordinated with turnover by a threshold mechanism that engages biogenesis only at significant levels of stress, and I will seek to uncover this regulation in neurons and other cell types. Specific Aim 1.1 will determine how biogenesis is activated by stress thresholding in response to signaling through CASM, and Specific Aim 1.2 will explore this mode of regulation in normal and diseased human cortical and dopamine neurons. My postdoctoral research (Aim 2) will study organelle stress signaling and mechanisms of biogenesis in aging-related neurodegenerative or other diseases using physiologic models like iPSC neurons and also animal models like mouse or even fish. Overall, these two projects will uncover significant new insights into the cellular dysfunctions that underlie the development of aging-related diseases, and will reveal new knowledge about how lysosome function can be maintained or even restored in aging or diseased cells. The research and training plan outlined in this proposal will be completed with the mentorship of Dr. Michael Overholtzer at the Memorial Sloan Kettering Cancer Center (MSK) along with a collaborative team that has the expertise to support the proposed studies. MSK's world class research environment and abundant resources in conjunction with the support of the Weill Cornell Graduate School will guarantee the successful completion of the proposed research and career development plans.