SNX13 and SNX14 interorganelle tethers suppress lysosome membrane damage and neurodegeneration

Lysosome membrane permeabilization (LMP) is an emerging signature of neurodegenerative diseases, yet the mechanisms that enable an effective repair are largely undefined, particularly in neurons. Here, we reveal sorting nexin (SNX) proteins SNX13 and SNX14 maintain lysosome membrane lipid composition to support efficient LMP repair and neuronal survival. We identify loss of function mutations in SNX13 in children manifesting a previously unrecognized cerebellar neurodegenerative disorder. Consistently, Snx13 ablation in mice causes cerebellar Purkinje cell death and signatures of ataxia-like motor deficits. We show loss of SNX13 or its ataxia-linked paralog SNX14 perturbs lysosome morphology, positioning, and acidity and causes increased susceptibility to lysosome damage. Using lysosome immunoprecipitation and proteomics, we comprehensively map lysosome proteome remodeling during membrane damage and repair, finding that SNX13 or SNX14 deficiency blunts recruitment of repair machinery, including ESCRTs and PITT pathway proteins, to damaged lysosomes. Mechanistically, we determine SNX13 and SNX14 support lysosome integrity through interorganelle lipid crosstalk. We define SNX13 and SNX14 as lipid binding proteins that localize to ER-lysosome junctions, where they support lysosomal phosphoinositide levels in response to membrane damage. In line with this, loss of SNX13 or SNX14 impairs lysosome PtdIns4P signaling. Altogether, our work reveals a conserved mechanism of interorganelle lipid crosstalk by SNX13/14 family proteins that safeguards lysosome membranes, maintaining them competent for repair, and is defective in cerebellar neurodegeneration.