Endoplasmic reticulum and lysosomal Ca2+ stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts

• Published in: Cell calcium (Edinburgh) Vol. 59; no. 1; pp. 12 - 20
• Main Authors: Kilpatrick, Bethan S., Magalhaes, Joana, Beavan, Michelle S., McNeill, Alisdair, Gegg, Matthew E., Cleeter, Michael W.J., Bloor-Young, Duncan, Churchill, Grant C., Duchen, Michael R., Schapira, Anthony H., Patel, Sandip
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.01.2016; Elsevier
• Subjects: Advanced Basic Science; Ca2; Calcium - metabolism; Cell Line, Tumor; Cells, Cultured; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Fibroblasts - metabolism; Fibroblasts - pathology; Gaucher disease; Glucosylceramidase - metabolism; Humans; Lysosomes; Lysosomes - metabolism; Lysosomes - pathology; Parkinson disease; Parkinson Disease - metabolism; Parkinson Disease - pathology; GPN; ASX; CBE; Lysosomes; Parkinson disease; SERCA; ER; Gaucher disease; PD; Ca2; cADPR; LAMP; GD; LC3; Endoplasmic reticulum; cyclic ADP-ribose; microtubule-associated protein 1A/1B-light chain 3; asymptomatic; conduritol B epoxide; Ca 2; lysosome associated membrane protein; glycyl- l-phenylalanine 2-naphthylamide; sarco-endoplasmic reticulum Ca 2+ ATPase; endoplasmic reticulum; Ca(2+)
• ISSN: 0143-4160; 1532-1991; 1532-1991
• DOI: 10.1016/j.ceca.2015.11.002

•ER Ca2+ signalling is potentiated in PD patient fibroblasts.•Lysosomal Ca2+ signalling is inhibited in PD patient fibroblasts.•Remodelling of Ca2+ stores is age-dependent. 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 Ca2+ 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) Ca2+ release was potentiated in GD and PD patient fibroblasts but not in cells from asymptomatic carriers. ER Ca2+ 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 Ca2+ signalling suggesting defects are independent of enzymatic activity loss. Conversely, lysosomal Ca2+ store content was reduced in PD fibroblasts and associated with age-dependent alterations in lysosomal morphology. Accelerated remodelling of Ca2+ stores by pathogenic GBA1 mutations may therefore feature in PD.