Crosstalk between Endoplasmic Reticulum Stress and Protein Misfolding in Neurodegenerative Diseases
Figure 1
Adaptive signaling of the UPR and ER stress-mediated apoptotic pathways. (a) In unstressed cells, the three UPR transducers, ATF6, IRE1α, and PERK, are associated with the ER chaperone GRP78. Upon accumulation of misfolded proteins in the ER lumen, these sensors are released and activated: ATF6 translocates to the Golgi where it is cleaved, the cytosolic fragment of ATF6 migrates to the nucleus, and IRE1α and PERK are oligomerized and autophosphorylated. Phosphorylated IRE1α catalyzes the splicing of XBP1 mRNA, and activated PERK phosphorylates eIF2α, which attenuates the general translation rate while inducing the translation of selective mRNAs such as ATF4. These downstream effectors of the UPR branches induce the expression of the genes encoding proteins that function to augment the ER protein-folding capacity. Simultaneously, ERAD is accelerated to remove terminally misfolded proteins through degradation in the proteasome, and aggregated proteins are degraded through the autophagic lysosomal pathway. ER-to-mitochondria Ca2+ transfer maintains mitochondrial metabolism and ATP production and preserves cell survival. (b) Under conditions of prolonged or severe ER stress, the sensors ATF6, IRE1α, and PERK also initiate apoptotic signaling cascades. ER Ca2+ efflux through the RyRs and IP3Rs induces mitochondrial Ca2+ overload, ROS accumulation, and ATP depletion and thus activates the mitochondria-dependent apoptosis. CHOP, one of the PERK downstream effectors, inhibits the expression of Bcl-2 and triggers ROS generation, thus promoting apoptosis. Activated IRE1α recruits TRAF2, which leads to the activation of JNK and also activates the ER-resident caspase-12 leading to activation of the caspase cascade.
