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.
Preview |
Text
Kilpatrick_1-s2.0-S0143416015001712-main.pdf Download (2MB) | Preview |
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.
Archive Staff Only
 |
View Item |
