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Mutations in β-glucocerebrosidase (encoded by GBA1) cause Gaucher disease (GD), a lysosomal storage disorder, and increase the risk of developing Parkinson disease (PD). The pathogenetic relationship between the two disorders is unclear. Here, we characterised Ca(2+) release in fibroblasts from type I GD and PD patients together with age-matched, asymptomatic carriers, all with the common N370S mutation in β-glucocerebrosidase. We show that endoplasmic reticulum (ER) Ca(2+) release was potentiated in GD and PD patient fibroblasts but not in cells from asymptomatic carriers. ER Ca(2+) signalling was also potentiated in fibroblasts from aged healthy subjects relative to younger individuals but not further increased in aged PD patient cells. Chemical or molecular inhibition of β-glucocerebrosidase in fibroblasts and a neuronal cell line did not affect ER Ca(2+) signalling suggesting defects are independent of enzymatic activity loss. Conversely, lysosomal Ca(2+) store content was reduced in PD fibroblasts and associated with age-dependent alterations in lysosomal morphology. Accelerated remodelling of Ca(2+) stores by pathogenic GBA1 mutations may therefore feature in PD.

Original publication

DOI

10.1016/j.ceca.2015.11.002

Type

Journal article

Journal

Cell Calcium

Publication Date

01/2016

Volume

59

Pages

12 - 20

Keywords

Ca(2+), Endoplasmic reticulum, Gaucher disease, Lysosomes, Parkinson disease, Calcium, Cell Line, Tumor, Cells, Cultured, Endoplasmic Reticulum, Fibroblasts, Glucosylceramidase, Humans, Lysosomes, Parkinson Disease