Endoplasmic reticulum and lysosomal Ca2+ stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts. Issue 1 (January 2016)

• Record Type: Journal Article
• 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
• Is Part Of: Cell calcium. Volume 59:Issue 1(2016)
• Page Start: 12
• Page End: 20
• Publication Date: 2016-01
• Subjects: ER endoplasmic reticulum -- cADPR cyclic ADP-ribose -- SERCA sarco-endoplasmic reticulum Ca2+ ATPase -- PD Parkinson disease -- GD Gaucher disease -- ASX asymptomatic -- CBE conduritol B epoxide -- GPN glycyl-l-phenylalanine 2-naphthylamide -- LAMP lysosome associated membrane protein -- LC3 microtubule-associated protein 1A/1B-light chain 3; Ca2+ -- Endoplasmic reticulum -- Lysosomes -- Parkinson disease -- Gaucher disease; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2015.11.002
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: ER Ca 2+ signalling is potentiated in PD patient fibroblasts. Lysosomal Ca 2+ signalling is inhibited in PD patient fibroblasts. Remodelling of Ca 2+ stores is age-dependent. Abstract: 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.