title: Endoplasmic reticulum and lysosomal Ca²⁺ stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts.
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.
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: bethan.kilpatrick.10@ucl.ac.uk.
authors.forename: Bethan S
authors.initials: BS
authors.lastname: Kilpatrick
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, UK.
authors.forename: Joana
authors.initials: J
authors.lastname: Magalhaes
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, UK.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Beavan
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, UK.
authors.forename: Alisdair
authors.initials: A
authors.lastname: McNeill
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Gegg
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, UK.
authors.forename: Michael W J
authors.initials: MW
authors.lastname: Cleeter
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Bloor-Young
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
authors.forename: Grant C
authors.initials: GC
authors.lastname: Churchill
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, UK.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Schapira
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: patel.s@ucl.ac.uk.
authors.forename: Sandip
authors.initials: S
authors.lastname: Patel
mesh_terms: D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005962:Glucosylceramidase / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology
chemical_list: D005962:Glucosylceramidase; D002118:Calcium
keywords: Ca(2+); Endoplasmic reticulum; Gaucher disease; Lysosomes; Parkinson disease