With the emerging concept that small molecule compounds can be used to stabilise Retromer to enhance its neuroprotective function85,86, our comprehensive cellular and molecular phenotyping of VPS35 KO H4 cells establishes a roadmap for future translational work to better understand the pathogenic link between Retromer-dependent regulation of lysosomal homoeostasis and individual neurodegenerative diseases, and to inform diagnostic and therapeutic strategies. Here, VPS35 is linked to neurodegenerative disease.