Muskelin Coordinates PrPC Lysosome versus Exosome Targeting and Impacts Prion Disease Progression

Cellular prion protein (PrPC) modulates cell adhesion and signaling in the brain. Conversion to its infectious isoform causes neurodegeneration, including Creutzfeldt-Jakob disease in humans. PrPC undergoes rapid plasma membrane turnover and extracellular release via exosomes. However, the intracellular transport of PrPC and its potential impact on prion disease progression is barely understood. Here we identify critical components of PrPC trafficking that also link intracellular and extracellular PrPC turnover. PrPC associates with muskelin, dynein, and KIF5C at transport vesicles. Notably, muskelin coordinates bidirectional PrPC transport and facilitates lysosomal degradation over exosomal PrPC release. Muskelin gene knockout consequently causes PrPC accumulation at the neuronal surface and on secreted exosomes. Moreover, prion disease onset is accelerated following injection of pathogenic prions into muskelin knockout mice. Our data identify an essential checkpoint in PrPC turnover. They propose a novel connection between neuronal intracellular lysosome targeting and extracellular exosome trafficking, relevant to the pathogenesis of neurodegenerative conditions. [Display omitted] •PrPC forms a complex with muskelin, dynein, and KIF5C at transport vesicles•Muskelin controls bidirectional PrPC transport and facilitates lysosomal degradation•Muskelin regulates a checkpoint of intra- versus extracellular protein turnover•Muskelin critically regulates the progression of prion disease Heisler et al. demonstrate that prion protein intracellular transport is important for the progression of prion disease. They identify a regulatory mechanism of bidirectional prion protein vesicle trafficking and propose a novel transport pathway that connects intracellular lysosomal degradation with extracellular exosome trafficking under neurodegenerative conditions.