Lysosomes have long been recognized as organelles that are responsible for macromolecule degradation and the clearance from cells of pathogens, damaged organelles and protein aggregates. Although such functions of lysosomes are important in all eukaryotic cells, long-lived cells such as neurons are especially dependent on optimal levels of lysosome function to prevent the accumulation of damaged macromolecules. Indeed, failure to clear misfolded proteins and damaged organelles is observed across multiple neurodegenerative diseases. In addition to neurons, another class of cells that are particularly dependent on robust lysosome function are professional scavengers such as macrophages and microglia that ingest huge amounts of material that must be broken down within their lysosomes. Although these critical degradative functions of lysosomes are well established, it has more recently become clear that lysosomes are also an important hub that coordinates signals that match cell growth and physiology with nutrient availability. With this growing appreciation of the roles played by lysosomes in health and disease, we ultimately seek to address the following fundamental questions:
- How do cells sense and regulate the status of their lysosomes?
- How is lysosome function altered in disease states?
- Can lysosomal function be modulated for therapeutic purposes?
To address these questions, we combine live cell imaging to monitor the dynamic recruitment of proteins to lysosomes with proteomic approaches to define the molecular basis for this recruitment and high-throughput siRNA screening to identify new mechanisms controlling lysosomal homeostasis. We seek to place these findings in a physiological context through analysis of mouse models of neurodegenerative disease. With the advent of robust protocols for the differentiation of human induced pluripotent stem cells (iPSCs) to neurons combined with CRISPR-based tools for genome editing, we are increasingly using human neurons as a model system to investigate both the physiological functions of lysosome as well as their contributions to neurodegenerative disease.