Here, by systematically analyzing the neuronal trafficking itineraries of misfolded mutant PrP that causes familial prion disease in humans, we identified endosomal pathways that impose markedly different fates on mutant PrP: One pathway drives mutant PrP for degradation in the soma, while a second Arl8b/kinesin-1/HOPS axis propels mutant PrP into the axon for sorting, fusion, and aggregation inside endolysosomal structures that we term endoggresomes. Here, KIF5C is linked to prion disease.