iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis
David C. Schöndorf,Massimo Aureli,Fiona E. McAllister,Christopher J. Hindley,Florian Mayer,Benjamin Schmid,S. Pablo Sardi,Manuela Valsecchi,Susanna A. Hoffmann,Lukas Kristoffer Schwarz,Ulrike Hedrich,Daniela Berg,Lamya S. Shihabuddin,Jing Hu,Jan Pruszak,Steven P. Gygi,Sandro Sonnino,Thomas Gasser,Michela Deleidi +18 more
TL;DR: Induced pluripotent stem cells are generated from subjects with GD and PD harbouring GBA1 mutations and complex changes in the autophagic/lysosomal system and intracellular calcium homeostasis, which underlie vulnerability to neurodegeneration are provided.
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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. 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.
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TL;DR: Data collected demonstrate that there is a strong association between GBA mutations and Parkinson's disease, and those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were morelikely to have atypical clinical manifestations.
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Sonja Kriks,Jae-Won Shim,Jinghua Piao,Yosif Ganat,Dustin R. Wakeman,Zhi-Zhong Xie,Luis Carrillo-Reid,Gordon Auyeung,Chris Antonacci,Amanda Buch,Lichuan Yang,M. Flint Beal,D. James Surmeier,Jeffrey H. Kordower,Viviane Tabar,Lorenz Studer +15 more
TL;DR: A novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo is presented, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells.
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