Cardiomyopathy and aging integrally contribute to the unfolded protein response collective pathways

their defect would have deleterious consequences. A finely tuned conserved biological machinery known as the protein quality control (PQC) is in place to correct the defect. The PQC includes the unfolded protein response (UPR), devoted to recognizing, unfolding and refolding abnormally arranged proteins, and the clearance apparatuses composed of the Ubiquitin Proteasome System (UPS) and the Endoplasmic Reticulum Associated Protein Degradation (ERAD). Abnormally folded proteins accumulate in idiopathic dilated cardiomyopathy (iDCM). In this study we investigated the transcriptional and translational landscapes of the UPR and UPS systems using polymerase chain reaction (PCR) and western blotting (WB) of myocardial tissues from iDCM patients and age, ethnicity and biological sex matched control cases. Our results show an increase of the three main UPR axis at the transcription and translational levels, suggesting an activation/inactivation of all axes, with altered PTM/cleavage/splicing eliciting abnormal downstream function. Notably, aging independently affects this machinery in diseased and control individuals. In addition, mutation in presenilin gene associated with Alzheimer's disease led to post-translational changes of the UPR components suggesting that genetic risk may exacerbate the natural age and disease-driven protein dyshomeostasis. In conclusion, our findings highlight that abnormalities of UPR are a still largely unexplored feature in heart failure to be view in its entirely. The combined alteration of several target proteins of these pathways configures defective proteostasis as a condition of misfolded peptides accumulation ultimately exhausting the cell survival capabilities.