ABSTRACT Inflammatory reactive astrocytes lose homeostatic functions and can be neurotoxic, potentially contributing to neurodegenerative diseases. However, the underlying cell biological mechanisms are not fully understood. Here, we demonstrate that lysosomes are remodeled and alkalinized in inflammatory reactive astrocytes, and that lysosome exocytosis drives astrocyte-mediated neurotoxicity. CRISPRi screens uncover mTOR as a regulator of neurotoxic lysosome exocytosis. These results pinpoint lysosome remodeling and exocytosis in inflammatory reactive astrocytes as a potential therapeutic target.

mTOR controls neurotoxic lysosome exocytosis in inflammatory reactive astrocytes