Journal
STEM CELL REPORTS
Volume 6, Issue 3, Pages 342-356Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2016.01.013
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Funding
- Monument Trust Discovery Award from Parkinson's UK
- Oxford Martin School
- Innovative Medicines Initiative Joint Undertaking [115439]
- European Union's Seventh Framework Program
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust
- University of Oxford
- Dementias and Neurodegenerative Diseases Research Network [DeNDRoN]
- Fundacao para a Ciencia e Tecnologia (FCT) grant [SFRH/BD/65787/2009]
- Wellcome Trust Career Re-Entry Fellowship [WT082260/Z/07/Z]
- Wellcome Trust grant [090532/Z/09/Z]
- MRC Hub grant [G090074791070]
- MRC [MR/L023784/2, MR/L023784/1, MR/M024962/1, MC_EX_MR/N50192X/1] Funding Source: UKRI
- Medical Research Council [MR/L023784/1, MR/L023784/2, MR/M024962/1, MC_EX_MR/N50192X/1] Funding Source: researchfish
- Parkinson's UK [H-1102, J-0901, J-1403] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [SFRH/BD/65787/2009] Funding Source: FCT
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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 alpha-synuclein in patient-derived neuronal culture medium, which was not associated with exosomes. Overall, ER stress, autophagic/lysosomal perturbations, and elevated extracellular alpha-synuclein likely represent critical early cellular phenotypes of PD, which might offer multiple therapeutic targets.
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