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 Hoffmann, Lukas Kristoffer Schwarz, Ulrike Hedrich, Daniela Berg, Lamya S. Shihabuddin, Jing Hu, Jan Pruszak, Steven P. Gygi, Sandro Sonnino, Thomas Gasser () and Michela Deleidi ()
Additional contact information
David C. Schöndorf: German Center for Neurodegenerative Diseases (DZNE)
Massimo Aureli: University of Milan
Fiona E. McAllister: Harvard Medical School
Christopher J. Hindley: Emmy Noether-Group for Stem Cell Biology, Institute of Anatomy and Cell Biology, University of Freiburg
Florian Mayer: Werner Reichardt Center for Integrative Neuroscience (CIN), University of Tübingen
Benjamin Schmid: German Center for Neurodegenerative Diseases (DZNE)
S. Pablo Sardi: Genzyme, a Sanofi Company
Manuela Valsecchi: University of Milan
Susanna Hoffmann: German Center for Neurodegenerative Diseases (DZNE)
Lukas Kristoffer Schwarz: German Center for Neurodegenerative Diseases (DZNE)
Ulrike Hedrich: Hertie-Institute for Clinical Brain Research, University of Tübingen
Daniela Berg: German Center for Neurodegenerative Diseases (DZNE)
Lamya S. Shihabuddin: Genzyme, a Sanofi Company
Jing Hu: Werner Reichardt Center for Integrative Neuroscience (CIN), University of Tübingen
Jan Pruszak: Emmy Noether-Group for Stem Cell Biology, Institute of Anatomy and Cell Biology, University of Freiburg
Steven P. Gygi: Harvard Medical School
Sandro Sonnino: University of Milan
Thomas Gasser: German Center for Neurodegenerative Diseases (DZNE)
Michela Deleidi: German Center for Neurodegenerative Diseases (DZNE)

Nature Communications, 2014, vol. 5, issue 1, 1-17

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5028

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