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Nat Commun. 2014 Jun 6;5:4028. doi: 10.1038/ncomms5028.

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

Author information

1
1] Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen 72076, Germany [2] Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany.
2
1] Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan 20090, Italy [2].
3
1] Department of Cell Biology, Harvard Medical School, Boston, Massacchusetts 02115, USA [2].
4
1] Emmy Noether-Group for Stem Cell Biology, Department of Molecular Embryology, Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg 79104, Germany [2].
5
Werner Reichardt Center for Integrative Neuroscience (CIN), University of Tübingen, Tübingen 72076, Germany.
6
Genzyme, a Sanofi Company, Framingham, Massachusetts 01701, USA.
7
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan 20090, Italy.
8
1] Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany [2] Department of Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen and German Center for Neurodegenerative Diseases, Tübingen 72076, Germany.
9
1] Emmy Noether-Group for Stem Cell Biology, Department of Molecular Embryology, Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg 79104, Germany [2] Center for Biological Signaling Studies (BIOSS), University of Freiburg, Freiburg 79104 Germany.
10
Department of Cell Biology, Harvard Medical School, Boston, Massacchusetts 02115, USA.

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.

PMID:
24905578
DOI:
10.1038/ncomms5028
[Indexed for MEDLINE]

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