166 Chapter 7 of 14-3-3 to β-adrenergic-stimulated cardiomyocytes led to prolonged SERCA activation.147 Since the phosphorylation of Ser16 is disrupted in the PLN-R14del, phosphorylation of Thr17 by CaMKII might become highly important for 14-3-3 recruitment to the PLN-R14del protein. Understanding the inhibitory mechanism of PLN-R14del and its reversal upon phosphorylation or Ca2+ increase is essential for developing novel interventional strategies. Protein Toxicity and Unfolded Protein Response Due to the limited regenerative capacity of cardiomyocytes, the survival of the existing cardiomyocytes by protein quality control is critical for optimal cardiomyocyte function.148,149 Pathological circumstances such as oxidative stress150, disturbance of calcium homeostasis151, and protein misfolding152 cause ER stress.153,154 Consequent disturbed protein homeostasis results in increased misfolded proteins, followed by the formation of protein aggregates and aggresomes.155 PLN-R14del cardiomyopathy has been associated with large cytoplasmic perinuclear PLN-containing aggregates in both human156–158 and mouse heart tissues.159,160 Te Rijdt et al. have demonstrated that PLN aggregates have a typical appearance of aggresomes, where PLN aggregates colocalize with p62 and microtubule-associated protein light chain 3 (LC3)161, indicating evidence for protein aggregates degradation.162 A recent study identified a homogeneous distribution of p62-positive aggregates in the myocardium of PLNR14del patients, independent of fibrosis distribution.158 These data suggest that the autophagy system is not able to remove all the mutant PLN protein, resulting in the accumulation of p62-positive proteotoxic perinuclear aggregates in the cardiomyocytes163, which can interfere with cellular function, and ultimately induce cell death.164 Interestingly, immunohistochemical analysis in specimens harvested during left ventricular assist device (LVAD) implantation is a highly sensitive and specific method for demonstrating PLN protein aggregates and for diagnosing PLN-R14del cardiomyopathy.165 Moreover, a recent study by Eijgenraam et al,166 showed that alterations in proteostasis and PLN protein aggregation were already present before functional impairments were observed in homozygous PLN-R14 mice. Misfolded/ aggregated proteins can accumulate within the endoplasmic reticulum (ER), causing activation of the unfolded protein response (UPR). Cuello et al,167 have recently shown impairment of the ER compartment and activation of UPR in a patient-specific PLN-R14del iPSC line compared to the isogenic control. Similarly, Feyen et al,168 observed an increased ER stress and UPR in PLN-R14del hiPSC-CMs. More importantly, they found that activation of the UPR preserves cell function and, therefore, plays a protective role in alleviating ER stress and potentially blunts disease pathogenesis. Pharmacological and molecular modulation of the UPR suggests a compensatory role in PLN R14del cardiomyopathy. These findings have high value as they could be harnessed therapeutically to delay the onset or slow down the progression of the disease.
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