title: Remodeling the proteostasis network to rescue glucocerebrosidase variants by inhibiting ER-associated degradation and enhancing ER folding.
abstract: Gaucher's disease (GD) is characterized by loss of lysosomal glucocerebrosidase (GC) activity. Mutations in the gene encoding GC destabilize the protein's native folding leading to ER-associated degradation (ERAD) of the misfolded enzyme. Enhancing the cellular folding capacity by remodeling the proteostasis network promotes native folding and lysosomal activity of mutated GC variants. However, proteostasis modulators reported so far, including ERAD inhibitors, trigger cellular stress and lead to induction of apoptosis. We show herein that lacidipine, an L-type Ca(2+) channel blocker that also inhibits ryanodine receptors on the ER membrane, enhances folding, trafficking and lysosomal activity of the most severely destabilized GC variant achieved via ERAD inhibition in fibroblasts derived from patients with GD. Interestingly, reprogramming the proteostasis network by combining modulation of Ca(2+) homeostasis and ERAD inhibition remodels the unfolded protein response and dramatically lowers apoptosis induction typically associated with ERAD inhibition.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Laura
authors.initials: L
authors.lastname: Segatori
mesh_terms: D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D060746:Endoplasmic Reticulum-Associated Degradation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005776:Gaucher Disease / Q000201:enzymology / Q000473:pathology; D020868:Gene Silencing / Q000187:drug effects; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D017510:Protein Folding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004095:Dihydropyridines; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D050505:Mutant Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C060285:lacidipine; D005962:Glucosylceramidase; D002118:Calcium