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

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

The relationship between glucocerebrosidase mutations and Parkinson disease

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease, whereas Gaucher disease (GD) is the most frequent lysosomal storage disorder caused by homozygous mutations in the glucocerebrosidase (GBA1) gene. Increased risk of developing PD has been observed in both GD patients and carriers. It has been estimated that GBA1 mutations confer a 20- to 30-fold...

Direct mobilisation of lysosomal Ca2+ triggers complex Ca2+ signals.

Accumulating evidence implicates acidic organelles of the endolysosomal system as mobilisable stores of Ca(2+) but their relationship to the better-characterised endoplasmic reticulum (ER) Ca(2+) store remains unclear. Here we show that rapid osmotic permeabilisation of lysosomes evokes prolonged, spatiotemporally complex Ca(2+) signals in primary cultured human fibroblasts. These Ca(2+) signal...

Ca2+ homeostasis modulation enhances the amenability of L444P glucosylcerebrosidase to proteostasis regulation in patient-derived fibroblasts.

Gaucher's disease is caused by deficiency of lysosomal glucocerebrosidase (GC) activity and accumulation of GC substrate, glucosylceramide. A number of point mutations in GC encoding gene have been reported to destabilize the enzyme native structure, resulting in protein misfolding and degradation. Particularly, the L444P GC variant, often associated with neuropathic manifestations of the disea...

The endoplasmic reticulum, not the pH gradient, drives calcium refilling of lysosomes

Impaired homeostasis of lysosomal Ca(2+) causes lysosome dysfunction and lysosomal storage diseases (LSDs), but the mechanisms by which lysosomes acquire and refill Ca(2+) are not known. We developed a physiological assay to monitor lysosomal Ca(2+) store refilling using specific activators of lysosomal Ca(2+) channels to repeatedly induce lysosomal Ca(2+) release. In contrast to the prevailing...