Prions disturb post-Golgi trafficking of membrane proteins

Conformational conversion of normal cellular prion protein PrPC into pathogenic PrPSc is central to the pathogenesis of prion diseases. However, the pathogenic mechanism remains unknown. Here we show that post-Golgi vesicular trafficking is significantly delayed in prion-infected N2a cells. Accordingly, cell surface expression of membrane proteins examined, including PrPC, insulin receptor involved in neuroprotection, and attractin, whose mutation causes prion disease-like spongiform neurodegeneration, is reduced. Instead, they accumulate in the Golgi apparatus. PrPSc is detected throughout endosomal compartments, being particularly abundant in recycling endosome. We also show reduced surface expression of PrPC and insulin receptor in prion-infected mouse brains well before the onset of disease. These results suggest that prion infection might impair post-Golgi trafficking of membrane proteins to the cell surface in neurons via PrPSc accumulated in recycling endosome, and eventually induce neuronal dysfunctions associated with prion diseases.