ENDOSOME ESCAPE

This lecture will explore a recently uncovered cellular mechanism, transient

perforations in the limiting membrane of endo-lysosomes, that reshapes our

understanding of cytosol-organelle communication. We will discuss how these nanoscale

disruptions, visualized with unprecedented resolution through high-speed 3D

live-cell fluorescence imaging, volume electron microscopy, and unsupervised vision

transformer–based segmentation, create bidirectional conduits for macromolecular

exchange. In neurons, such perforations mediate the access of internalized, preformed

aggregates of tau and α-synuclein to cytosolic monomers, initiating templated

misfolding and the propagation of toxic assemblies central to neurodegenerative

disease. These findings redefine endosomal escape not as an exception but as a

regulated, dynamic process with essential physiological and pathological roles. This

lecture will lay the mechanistic groundwork and imaging advances and cellular

consequences in neurons, offering a conceptual framework for understanding cargo

trafficking and prion-like spread in disease. This is a story at the interface of membrane

biology and neurodegeneration, one that challenges dogma and opens new potential

therapeutic avenues.