title: Lacidipine remodels protein folding and Ca 2+ homeostasis in Gaucher's disease fibroblasts: a mechanism to rescue mutant glucocerebrosidase.
abstract: The hallmark of Gaucher's disease cellular pathogenesis is the lysosomal accumulation of glucosylceramide, which is caused by misfolding of mutated glucocerebrosidase (GC) and loss of lysosomal GC activity, and leads to depletion of [Ca(2+)](ER). We demonstrate that modulation of Ca(2+) homeostasis and enhancement of the cellular folding capacity synergize to rescue the folding of mutated GC variants. Lacidipine, an L-type Ca(2+) channel blocker that also inhibits [Ca(2+)](ER) efflux, enhances folding, trafficking, and activity of degradation-prone GC variants. Lacidipine remodels mutated GC proteostasis by simultaneously activating a series of distinct molecular mechanisms, namely modulation of Ca(2+) homeostasis, upregulation of the ER chaperone BiP, and moderate induction of the unfolded protein response. However, unlike previously reported proteostasis regulators, lacidipine treatment is not cytotoxic but prevents apoptosis induction typically associated with sustained activation of the unfolded protein response.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Ann
authors.initials: A
authors.lastname: Chou
authors.forename: Laura
authors.initials: L
authors.lastname: Segatori
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D005776:Gaucher Disease / Q000378:metabolism*; D005962:Glucosylceramidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009154:Mutation; D017510:Protein Folding; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C060285:lacidipine; D005962:Glucosylceramidase; D002118:Calcium