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Stem Cell Reports. 2016 Mar 8;6(3):342-56. doi: 10.1016/j.stemcr.2016.01.013. Epub 2016 Feb 18.

ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons.

Author information

1
Oxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UK; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
2
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
3
Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens 11526, Greece.
4
Oxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UK; Nuffield Department of Clinical Medicine, Division of Clinical Neurology, University of Oxford, Oxford OX3 9DU, UK.
5
Oxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UK; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK; Institute of Molecular Medicine, University of Southern Denmark, Odense 5230, Denmark.
6
Genzyme, a Sanofi Company, Framingham, MA 01701, USA.
7
Oxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UK; The James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
8
Oxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UK; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK. Electronic address: richard.wade-martins@dpag.ox.ac.uk.

Abstract

Heterozygous mutations in the glucocerebrosidase gene (GBA) represent the strongest common genetic risk factor for Parkinson's disease (PD), the second most common neurodegenerative disorder. However, the molecular mechanisms underlying this association are still poorly understood. Here, we have analyzed ten independent induced pluripotent stem cell (iPSC) lines from three controls and three unrelated PD patients heterozygous for the GBA-N370S mutation, and identified relevant disease mechanisms. After differentiation into dopaminergic neurons, we observed misprocessing of mutant glucocerebrosidase protein in the ER, associated with activation of ER stress and abnormal cellular lipid profiles. Furthermore, we observed autophagic perturbations and an enlargement of the lysosomal compartment specifically in dopamine neurons. Finally, we found increased extracellular α-synuclein in patient-derived neuronal culture medium, which was not associated with exosomes. Overall, ER stress, autophagic/lysosomal perturbations, and elevated extracellular α-synuclein likely represent critical early cellular phenotypes of PD, which might offer multiple therapeutic targets.

PMID:
26905200
PMCID:
PMC4788783
DOI:
10.1016/j.stemcr.2016.01.013
[Indexed for MEDLINE]
Free PMC Article

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