Lacidipine Remodels Protein Folding and Ca2+ Homeostasis in Gaucher's Disease Fibroblasts: A Mechanism to Rescue Mutant Glucocerebrosidase

SummaryThe 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 [Ca2+]ER. We demonstrate that modulation of Ca2+ homeostasis and enhancement of the cellular folding capacity synergize to rescue the folding of mutated GC variants. Lacidipine, an L-type Ca2+ channel blocker that also inhibits [Ca2+]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 Ca2+ 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.

► The LTCC blocker lacidipine rescues folding and activity of mutated GC variants
► Increase in mutant GC activity correlates with decrease in intracellular [Ca2+]
► UPR activation and BiP upregulation mediate lacidipine-induced GC rescue
► Lacidipine treatment prevents UPR-induced toxicity and apoptosis