Proteomics

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IPSC-derived neurons from GBA1-associated Parkinson's disease patients show autophagic/lysosomal dysfunction and impaired calcium homeostasis


ABSTRACT: Mutations in the acid β-glucocerebrosidase (GBA1) gene, responsible for the lysosomal storage disorder Gaucher’s disease (GD), are the strongest genetic risk factor for Parkinson’s disease (PD) known to date. To elucidate the mechanisms underlying neurodegeneration in these patients, we generated induced pluripotent stem cells from subjects with GD and PD harboring GBA1 mutations and differentiated them to midbrain dopaminergic neurons. Highly enriched neurons showed a reduction of glucocerebrosidase activity and protein levels, increased glucosylceramide and α-synuclein levels and autophagic/lysosomal defects. Quantitative proteomics profiling revealed an increase of the neuronal calcium-binding protein 2 (NECAB2) in diseased neurons. We found dysregulation of calcium homeostasis and increased vulnerability to stress responses involving elevation of cytosolic calcium in mutant neurons. Importantly, correction of the mutations rescued such pathological phenotypes. Our findings provide evidence for a link between GBA1 mutations and complex changes in autophagic/lysosomal system and intracellular calcium homeostasis, which underlie vulnerability to neurodegeneration.

REANALYSED by: PAe005155

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pluripotent Stem Cell, Cell Culture

DISEASE(S): Parkinson's Disease

SUBMITTER: Fiona McAllister  

LAB HEAD: Michela Deleidi

PROVIDER: PXD000866 | Pride | 2014-06-03

REPOSITORIES: pride

Dataset's files

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Action DRS
20130724_Purified_neurons_final.xlsx Xlsx
C10_v15918.raw Raw
C11_v15919.raw Raw
C12_v15920.raw Raw
C1_v15902.raw Raw
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Mutations in the acid β-glucocerebrosidase (GBA1) gene, responsible for the lysosomal storage disorder Gaucher's disease (GD), are the strongest genetic risk factor for Parkinson's disease (PD) known to date. Here we generate induced pluripotent stem cells from subjects with GD and PD harbouring GBA1 mutations, and differentiate them into midbrain dopaminergic neurons followed by enrichment using fluorescence-activated cell sorting. Neurons show a reduction in glucocerebrosidase activity and pro  ...[more]

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