Synaptic Dysfunction in Prion Diseases: A Trafficking Problem?

Figure 1

UPR signaling pathways in mammalian cells. The UPR is mediated by three ER-resident transmembrane proteins that sense ER stress through Grp78/BiP binding/release to their luminal domains and/or through direct interaction with unfolded proteins. The kinase PERK (double-stranded RNA-activated protein kinase-like ER kinase) is activated by dimerization and phosphorylation. Once activated, it phosphorylates eIF2𝛼 (eukaryotic translation initiation factor 2). This inhibits protein translation, reducing the overload of misfolded proteins. This pathway also selectively enhances translation of ATF4 (activating transcription factor 4) that induces the expression of CHOP. In ER-stressed cells, IRE1𝛼 (inositol-requiring transmembrane kinase and endonuclease) multimerizes and autophosphorylates, setting in motion its RNAse activity. Activated IRE1𝛼 initiates the unconventional splicing of the mRNA encoding the transcriptional factor XBP1 (X-box-binding protein 1) to produce sXBP1, a more stable form of XBP1 with a potent transactivator domain that enhances transcription of genes involved in protein folding, secretion, and ER-associated degradation. Another ER stress sensor is ATF6 (activating transcription factor 6). This is a type II ER transmembrane protein whose cytosolic domain contains a bZIP transcriptional factor. ATF6 is transported to the Golgi where it is processed within the transmembrane domain to release the cytosolic domain, which translocates to the nucleus and induces expression of the ER chaperone Grp78/BiP and XBP1. GADD34, a protein phosphatase upregulated by the PERK pathway, dephosphorylates eIF2𝛼 to restore global protein synthesis. ERSEs: ER stress responsive elements.