P060 - TARGETING THE ABERRANT ACTIVATION OF PERK TO RESCUE PROTEIN AND REDOX HOMEOSTASIS IN DOWN SYNDROME NEUROPATHOLOGY (ID 256)
Abstract
Aims
Long-term activation of the unfolded protein response (UPR) leads to eIF2α-associated sustained repression of protein synthesis, Nrf2-related reduction of antioxidant response and cell death, as observed the brain from in Alzheimer disease (AD) patients. Down syndrome (DS) neuropathology share many neuropathological feature with AD including aberrant proteostasis and increased oxidative stress (OS). In this study, we aimed to identify the molecular mechanisms associating DS with the early chronic induction of the UPR induction, and with the development of proteotoxicity and redox dys-homeostasis in DS brain.
Methods
We analyzed the induction of the UPR in human brain from DS, DS-AD and AD subjects. Further by proteomics, we analyzed blood-derived cell from DS young to confirm the burden of DS genotype in promoting altered proteostasis. At final, we pharmacologically rescued PERK to discern its role in DS neuropathology.
Results
We found the early and sustained activation of PERK along with eIF2a-mediated inhibition of translation in young DS and AD subjects supporting their involvement in neurodegeneration. Surprisingly, we also found in DS the uncoupling between PERK and Nrf2 response, whose antioxidant effect is repressed early by a mechanism implicating the overexpression of Bach1. The pharmacological inhibition of PERK reduced eIF2α-driven repression of translation rescuing proteostasis, and promoted the rebalance of Nrf2/Bach1 ratio favoring redox homeostasis.
Conclusions
Our results suggest that the failure to regulate the PERK pathway may be an essential step to promoting cellular dysfunction in AD-like pathologies. These data also support the exploration of PERK inhibition as a therapeutic option for AD in DS.
