Inhibition of Endoplasmic Reticulum Associated Degradation Reduces Endoplasmic Reticulum Stress and Alters Lysosomal Morphology and Distribution

Disturbances in proteostasis are observed in many neu-rodegenerative diseases. This leads to activation of pro-tein quality control to restore proteostasis, with a key role for the removal of aberrant proteins by proteolysis. The unfolded protein response (UPR) is a protein quality con-trol mechanism of the endoplasmic reticulum (ER) that is activated in several neurodegenerative diseases. Recently we showed that the major proteolytic pathway during UPR activation is via the autophagy/lysosomal system. Here we investigate UPR induction if the other major proteolytic pathway of the ER-ER associated degradation (ERAD)- is inhibited. Surprisingly, impairment of ERAD results in de-creased UPR activation and protects against ER stress toxicity. Autophagy induction is not affected under these conditions, however, a striking relocalization of the lyso-somes is observed. Our data suggest that a protective UPR-modulating mechanism is activated if ERAD is inhib-ited, which involves lysosomes. Our data provide insight in the cross-talk between proteolytic pathways involved in ER proteostasis. This has implications for neurodegenera-tive diseases like Alzheimer’s disease where disturbed ER proteostasis and proteolytic impairment are early phe-nomena in the pathology