iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis

• Published in: Nature communications Vol. 5; no. 1; p. 4028
• Main Authors: Schöndorf, David C., Aureli, Massimo, McAllister, Fiona E., Hindley, Christopher J., Mayer, Florian, Schmid, Benjamin, Sardi, S. Pablo, Valsecchi, Manuela, Hoffmann, Susanna, Schwarz, Lukas Kristoffer, Hedrich, Ulrike, Berg, Daniela, Shihabuddin, Lamya S., Hu, Jing, Pruszak, Jan, Gygi, Steven P., Sonnino, Sandro, Gasser, Thomas, Deleidi, Michela
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.06.2014; Nature Publishing Group
• Subjects: 13/1; 13/100; 13/109; 13/31; 13/51; 14/19; 14/34; 38/22; 38/23; 38/77; 631/80/39; 692/420/2489/144; 692/699/317; 692/699/375/365/1718; 82/58; Autophagy; Biology; Brain research; Calcium - metabolism; Cell Differentiation; Disease; Enzymes; Glucosylceramidase - genetics; Glycoside Hydrolases - metabolism; Health risk assessment; Homeostasis; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - enzymology; Induced Pluripotent Stem Cells - pathology; multidisciplinary; Mutation; Neurodegeneration; Neurons - enzymology; Neurons - pathology; Parkinson Disease - immunology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathogenesis; Proteins; Science; Science (multidisciplinary); Stem cells; United States > US; Germany
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms5028

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 protein levels, increase in glucosylceramide and α-synuclein levels as well as autophagic and lysosomal defects. Quantitative proteomic profiling reveals an increase of the neuronal calcium-binding protein 2 (NECAB2) in diseased neurons. Mutant neurons show a dysregulation of calcium homeostasis and increased vulnerability to stress responses involving elevation of cytosolic calcium. Importantly, correction of the mutations rescues such pathological phenotypes. These findings provide evidence for a link between GBA1 mutations and complex changes in the autophagic/lysosomal system and intracellular calcium homeostasis, which underlie vulnerability to neurodegeneration. Mutations in the gene, GBA1 , cause Gaucher’s disease, and are a strong risk factor for the development of Parkinson’s disease. Here the authors use cells derived from Parkinson’s patients with GBA1 mutations to model the disease, and reveal changes in cellular recycling systems that may promote neurodegeneration.