Lysosome Function, Dysfunction and Disease
Arising from the pioneering work of Christian De Duve and colleagues in the 1950s, lysosomes have long been recognized as an intracellular organelle that is responsible for macromolecule degradation and the clearance from cells of damaged organelles and protein aggregates. While 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. While the such degradative functions of lysosomes are of great importance, the cell biology of lysosomes has seen a renaissance in recent years such that lysosomes are no longer considered simply the “garbage disposal system” of the cell, but are additionally recognized as an important hub that coordinates signals that match cell growth 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 furthermore seek to place these findings in a physiological context through analysis of mouse models of neurodegenerative disease.