Figure 5.

Deregulation of the PrP^C-ROCK connection contributes to the endoplasmic reticulum stress and reduces protein translation in prion-infected neurons. (A) In 1C11^5−HT cells, PrP^Sc induces PERK and eIF2α phosphorylation. ROCK inhibition with Y-27632 (100 μM) reduces PrP^Sc-induced phosphorylation of PERK and eIF2α, indicating that ROCKs contribute to the UPR activation pathway within a prion infectious context. (B) Model showing the implication of ROCKs in the Unfolded Protein Response in prion-infected neurons. In the endoplasmic reticulum (ER), PrP^Sc proteostress activates the chaperone BIP. Binding of BIP to the intraluminal tail of PERK then induces PERK dimerization and phosphorylation at the surface of ER. In parallel, overactivated ROCKs on prion infection attach to the ER membrane where ROCKs fuel and/or amplify PERK phosphorylation. Activated PERK then phosphorylates eIF2α leading to a reduction of protein translation.