Abstract
Ischemic stroke is known to cause the accumulation of misfolded proteins and loss of calcium homeostasis leading to impairment of endoplasmic reticulum (ER) function and activating the unfolded protein response (UPR). PARP16 is the only an active ADP-ribosyl transferase known tail-anchored ER transmembrane protein with a cytosolic catalytic domain. Here, we find PARP16 is highly expressed in ischemic cerebral hemisphere and Oxygen-glucose deprivation (OGD)-treated immortalized hippocampal neuroblasts HT22 cells. Using adeno-associated virus-mediated knockdown PARP16 mice, we find knockdown PARP16 decreases infarct demarcations and has a better neurological outcome after ischemic stroke. Our data indicate PARP16 overexpression promotes ER stress-mediated cell damage in primary cortical neurons, in turn, knockdown PARP16 decreases ER stress and neuronal death caused by OGD. Furthermore, PARP16 functions mechanistically as ADP-ribosyltransferase to modulate the level of ribosylation of the corresponding PERK and IRE1α arm of the UPR, and that such modification is required for activation of PERK and IRE1α. Indeed, pharmacological stimulation of the UPR using Brefeldin A counteracts knockdown of PARP16-mediated neuronal protection in OGD. On other hand, when an ER inhibitor Tauroursodeoxycholic acid present, permit more obvious protection and inactivation of PERK and IRF1α caused by knockdown of PARP16. In conclusion, PARP16 plays a crucial role in post-ischemic UPR and the knockdown of PARP16 alleviates brain injury after ischemic stroke. The rationale of this study is to explore the potentials of the PARP16-PERK/IRE1α axis as a target for neuronal survival in ischemic stroke.
Altered Unfolded Protein Response Is Implicated in the Age-Related Exacerbation of Proteinuria-Induced Proximal Tubular Cell Damage