Muskelin Coordinates PrP Lysosome versus Exosome Targeting and Impacts Prion Disease Progression.

Cellular prion protein (PrP) modulates cell adhesion and signaling in the brain. Conversion to its infectious isoform causes neurodegeneration, including Creutzfeldt-Jakob disease in humans. PrP undergoes rapid plasma membrane turnover and extracellular release via exosomes. However, the intracellular transport of PrP and its potential impact on prion disease progression is barely understood. Here we identify critical components of PrP trafficking that also link intracellular and extracellular PrP turnover. PrP associates with muskelin, dynein, and KIF5C at transport vesicles. Notably, muskelin coordinates bidirectional PrP transport and facilitates lysosomal degradation over exosomal PrP release. Muskelin gene knockout consequently causes PrP 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 PrP turnover. They propose a novel connection between neuronal intracellular lysosome targeting and extracellular exosome trafficking, relevant to the pathogenesis of neurodegenerative conditions.