Intra-axonal misfolded protein aggregates are a pathological feature of neurodegenerative diseases. How aggregates are formed and cleared is key to maintaining proteostasis. By systematically analyzing the trafficking itinerary of a misfolded GPI-anchored prion protein (PrP) mutant, we unveil endocytic pathways that drive its immediate degradation in the soma, versus its aggregation in axons inside endosomal structures we termed endoggresomes. Axonal sorting occurs post-Golgi, by association of mutant PrP vesicles with Arl8b/kinesin-1/HOPS, a complex that earmarks them for axonal entry, fusion, and aggregation via a mechanism of axonal rapid endosomal sorting and transport-dependent aggregation (ARESTA). Endoggresomes persist in axons due to transport and lysosomal deficits, impairing calcium dynamics and accelerating neuronal death. Reducing ARESTA inhibits endoggresome formation and circumvents these defects. These data identify the endo-lysosomal system as critical for the sorting of misfolded PrP, and ARESTA as an actionable anti-aggregation target that can ameliorate axonal dysfunction in the prionopathies.
bioRxiv Subject Collection: Neuroscience