The goal of research in the Ferguson lab is to understand how the status of lysosomes is sensed and how lysosomal function is regulated to meet cellular demands. The basic building blocks (amino acids, sugars, lipids and nucleotides) released by degradation of lysosomal substrates represent important sources of energy during starvation and of material for new macromolecule synthesis to support cell growth and/or remodeling. Conversely, lysosomes are critical for the turnover and clearance from cells of damaged organelles and protein aggregates. The importance of maintaining optimal lysosomal function is demonstrated by contributions of lysosome dysfunction to human neurodevelopmental and neurodegenerative diseases. Furthermore, the role played by lysosomes in sensing cellular energy and nutrient levels and transducing this information into signals controlling growth represents a potential therapeutic target in cancer. With this growing appreciation of the roles played by lysosomes in health and disease, we ultimately seek to address the following fundamental questions:
(A) How do cells sense and regulate the status of their lysosomes?
(B) How does impaired lysosome function contribute to disease states?
(C) How can lysosome function be modulated for therapeutic purposes?
Specific projects under development include:
1. Understanding signaling mechanisms that coordinate lysosomal function (macromolecule degradation) with lysosomal biogenesis. How does a cell match lysosomal capacity with demand? How are signals transduced from the interior of the lysosome to the cytoplasm?
2. Investigation of mechanisms that adapt lysosome function to the unique demands of neurons. In particular, we are highly interested in the mechanisms that support movement of lysosomes over the long distances that are required to provide optimal lysosome function in axons.
3. Investigation of the contributions of lysosome dysfunction to neurodegenerative diseases. We are actively working on projects related to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia as well as a neurodevelopmental disorder arising from mutations in the MAPK8IP3 gene.
4. Determining how macrophages and microglia adapt the function of their lysosomes to support efficient degradation and recycling of materials delivered to them by phagocytosis.
Alzheimer Disease; Axonal Transport; Lysosomes; Parkinson Disease; Tauopathies; TDP-43 Proteinopathies; Frontotemporal Dementia