Fig. 1.

PrP^Sc formation, trafficking and degradation.

Schematic illustrating PrP^Sc metabolism. PrP^Sc forms at the plasma membrane or shortly after endocytosis in endosomes, the ERC or lysosomes. Recycling of PrP^Sc to the plasma membrane allows prion propagation. Newly formed PrP^Sc undergoes retrograde transport to the trans Golgi network (TGN) and Golgi where it is subject to Golgi quality control and trafficked to lysosomes for degradation. More mature forms of PrP^Sc are trafficked to lysosomes via the endolysosomal and autophagic pathways. PrP^Sc may reach the cytosol through lysosomal rupture or ERAD, and accumulates in aggresomes under conditions of proteasome impairment. Unfolding and ubiquitination precede proteasomal degradation (UPS pathways shown in red). Aggresomal PrP^Sc and smaller insoluble forms are engulfed by phagophores and degraded by autophagic pathways (shown in orange).