Lysosomal Lipid Dynamics in Health and Disease

Lysosomes are membrane-bound organelles in the cell that play key roles in nutrient acquisition and recycling of damaged cellular components. They contain hydrolases that enable the degradation of cargo delivered to lysosomes by the endocytic and autophagic pathways. The resulting metabolites (amino acids, lipids, sugars…) are exported out of lysosomes to fuel biosynthetic and signalling pathways. Lysosomal storage diseases (LSDs) are a group of inherited diseases characterized by the toxic accumulations of materials within lysosomes. This abnormal storage typically results from mutations impairing the digestion of the material or its transport out of lysosomes. For instance, Niemann-Pick disease type C (NPC) results from lysosomal cholesterol accumulation due to mutations in NPC1 or NPC2 that impair cholesterol export from lysosomes. The symptoms of LSDs range from neurodegeneration to liver disease, often leading to early death. Yet, no curative treatments exist for most LSDs, highlighting the urgent need to identify new therapeutic targets.

Our goal is to define new strategies to clear lysosomes of toxic lipid accumulations. We use a combination of cell models (iPSC-derived neurons, cell lines, patients’ fibroblasts…), super-resolution live imaging, and proteomic techniques to uncover molecular mechanisms governing lysosomal lipid clearance and identify novel therapeutic targets.

We are particularly interested in:

• Understanding how inter-organelle contacts can be harnessed to clear lysosomes of lipid accumulations
• Understanding why neuronal cells are especially vulnerable to lysosomal lipid accumulations
• Developing new recombinant and genetically encoded lipid biosensors to track lysosomal lipid dynamics with a high spatial and temporal resolution

This work will advance our fundamental understanding of lysosomal biology and establish a framework for developing targeted therapies against LSDs.