Contrasting roles of autophagy in cellular prion infection.

Autophagy is a cellular degradation program that can exert both beneficial and adverse effects in various neurodegenerative diseases. We tested the role of macroautophagy/autophagy in prion infection and how this machinery affects the life cycle of prions. In mouse embryonic fibroblasts, we found a pronounced dependence of prion replication on autophagy competence, suggesting that autophagy provides functions needed for prion propagation. However, in neuronal cells, autophagy had mostly the opposite role. Cells ablated for autophagy competence by gene editing harbored elevated amounts of misfolded prion protein, indicating that neuronal cells use autophagy for prion degradation. These data show that autophagy can have two functions in the replication of prions, and depending on the cellular context, this can be protective against or supportive of prion infection. These findings demonstrate that prions use cellular machineries to benefit propagation in certain cell types, whereas other cell types employ the same machinery as a defense mechanism.