Proteostasis Regulation in the Endoplasmic Reticulum: An Emerging Theme in the Molecular Pathology and Therapeutic Management of Familial Hypercholesterolemia

Abstract

Familial hypercholesterolemia (FH) is an autosomal genetic disease characterized by high serum low-density lipoprotein (LDL) content leading to premature coronary artery disease. The main genetic and molecular causes of FH are mutations in low-density lipoprotein receptor gene ( LDLR ) resulting in the non-clearance of LDL from the blood by hepatocytes and consequently the formation of plaques. LDLR is synthesized and glycosylated in the endoplasmic reticulum (ER) and then transported to the plasma membrane via Golgi. It is estimated that more than 50% of reported FH-causing mutations in LDLR result in misfolded proteins that are transport-defective and hence retained in ER. ER accumulation of misfolded proteins causes ER-stress and activates unfolded protein response (UPR). UPR aids protein folding, blocks further protein synthesis, and eliminates misfolded proteins via ER-associated degradation (ERAD) to alleviate ER stress. Various studies demonstrated that ER-retained LDLR mutants are subjected to ERAD. Interestingly, chemical chaperones and genetic or pharmacological inhibition of ERAD have been reported to rescue the transport defective mutant LDLR alleles from ERAD and restore their ER-Golgi transport resulting in the expression of functional plasma membrane LDLR. This suggests the possibility of pharmacological modulation of proteostasis in the ER as a therapeutic strategy for FH. In this review, we picture a detailed analysis of UPR and the ERAD processes activated by ER-retained LDLR mutants associated with FH. In addition, we discuss and critically evaluate the potential role of chemical chaperones and ERAD modulators in the therapeutic management of FH.

Relationship between Brain Metabolic Disorders and Cognitive Impairment: LDL Receptor Defect

“…LDLr deficiency can lead to cognitive impairment due to interactions between ER stress and mitochondria. In particular, the brain is vulnerable to oxidative damage and apoptosis induction by abnormal calcium and ATP levels due to its high energy metabolism rate, high oxygen consumption, and high ratio of polyunsaturated fatty acids [ 105 , 106 , 107 , 108 , 109 , 110 ]. Oxidative stress is attracting attention as a cause of several neurodegenerative diseases [ 111 , 112 , 113 ].…”

Joint genotypic and phenotypic outcome modeling improves base editing variant effect quantification

“…Boxplot shows the metrics of 6 2-replicate combinations of the 4 replicates. e) LDLR domain structure adopted from Oommen et al 71 . f) BEAN z-scores for variants in the 7 LDLR class A repeat domains aligned with the Pfam profile HMM logo.…”

Small extracellular vesicles containing LDLRQ722* protein reconstructed the lipid metabolism via heparan sulphate proteoglycans and clathrin‐mediated endocytosis

“…Yingchao Zhou 1,2 Qiang Xie 3 Silin Pan 2 Jianfei Wu 1 Xiangyi Wang 1 Zhubing Cao 1 Mengru Wang 1 Lingfeng Zha 4 Mengchen Zhou 4 Qianqian Li 1 Qing Wang 1 Xiang Cheng 4 Gang Wu 5 Xin Tu…”

“…LDLR is a transmembrane glycoprotein composed of 860 amino acids, which is used for receptor‐mediated endocytosis of LDL. 5 The mutant LDLR translated into a truncated protein (1‐722 amino acids, Figure S1A,B ). We referred to this truncated LDLR as “LDLR Q722* ” to distinguish from the wild‐type LDLR.…”

“…LDLR is a transmembrane glycoprotein composed of 860 amino acids, which is used for receptormediated endocytosis of LDL. 5 The mutant LDLR translated into a truncated protein (1-722 amino acids, Figure S1A,B). We referred to this truncated LDLR as "LDLR Q722* " to distinguish from the wild-type LDLR.Given the absence of the O-linked sugar, transmembrane and intracellular domain of LDLR Q722* , LDLR Q722* could not anchor to cell membrane (Figure 1C), secreted to extracellular and not glycosylated (Figure 1D, S1C-E).…”