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Endoplasmic reticulum and lysosomal Ca(2+) stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts

Kilpatrick, BS; Magalhaes, J; Beavan, MS; McNeill, A; Gegg, ME; Cleeter, MW; Bloor-Young, D; ... Patel, S; + view all (2016) Endoplasmic reticulum and lysosomal Ca(2+) stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts. Cell Calcium , 59 (1) pp. 12-20. 10.1016/j.ceca.2015.11.002. Green open access

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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.

Type: Article
Title: Endoplasmic reticulum and lysosomal Ca(2+) stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ceca.2015.11.002
Publisher version: http://dx.doi.org/10.1016/j.ceca.2015.11.002
Language: English
Additional information: © 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Ca(2+), Endoplasmic reticulum, Gaucher disease, Lysosomes, Parkinson disease
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: http://discovery.ucl.ac.uk/id/eprint/1475821
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