ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons
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 hav...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-03-01
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| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671116000308 |
| _version_ | 1818447775822512128 |
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| author | Hugo J.R. Fernandes Elizabeth M. Hartfield Helen C. Christian Evangelia Emmanoulidou Ying Zheng Heather Booth Helle Bogetofte Charmaine Lang Brent J. Ryan S. Pablo Sardi Jennifer Badger Jane Vowles Samuel Evetts George K. Tofaris Kostas Vekrellis Kevin Talbot Michele T. Hu William James Sally A. Cowley Richard Wade-Martins |
| author_facet | Hugo J.R. Fernandes Elizabeth M. Hartfield Helen C. Christian Evangelia Emmanoulidou Ying Zheng Heather Booth Helle Bogetofte Charmaine Lang Brent J. Ryan S. Pablo Sardi Jennifer Badger Jane Vowles Samuel Evetts George K. Tofaris Kostas Vekrellis Kevin Talbot Michele T. Hu William James Sally A. Cowley Richard Wade-Martins |
| author_sort | Hugo J.R. Fernandes |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T20:08:59Z |
| format | Article |
| id | doaj.art-20acb6da0a224454831f8f80ba1147cd |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-12-14T20:08:59Z |
| publishDate | 2016-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-20acb6da0a224454831f8f80ba1147cd2022-12-21T22:48:57ZengElsevierStem Cell Reports2213-67112016-03-016334235610.1016/j.stemcr.2016.01.013ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine NeuronsHugo J.R. Fernandes0Elizabeth M. Hartfield1Helen C. Christian2Evangelia Emmanoulidou3Ying Zheng4Heather Booth5Helle Bogetofte6Charmaine Lang7Brent J. Ryan8S. Pablo Sardi9Jennifer Badger10Jane Vowles11Samuel Evetts12George K. Tofaris13Kostas Vekrellis14Kevin Talbot15Michele T. Hu16William James17Sally A. Cowley18Richard Wade-Martins19Oxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKDepartment of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UKDivision of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens 11526, GreeceOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKGenzyme, a Sanofi Company, Framingham, MA 01701, USAOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKDivision of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens 11526, GreeceOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKOxford Parkinson's Disease Centre, University of Oxford, South Parks Road, Oxford OX1 3QX, UKHeterozygous 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.http://www.sciencedirect.com/science/article/pii/S2213671116000308 |
| spellingShingle | Hugo J.R. Fernandes Elizabeth M. Hartfield Helen C. Christian Evangelia Emmanoulidou Ying Zheng Heather Booth Helle Bogetofte Charmaine Lang Brent J. Ryan S. Pablo Sardi Jennifer Badger Jane Vowles Samuel Evetts George K. Tofaris Kostas Vekrellis Kevin Talbot Michele T. Hu William James Sally A. Cowley Richard Wade-Martins ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons Stem Cell Reports |
| title | ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons |
| title_full | ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons |
| title_fullStr | ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons |
| title_full_unstemmed | ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons |
| title_short | ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons |
| title_sort | er stress and autophagic perturbations lead to elevated extracellular α synuclein in gba n370s parkinson s ipsc derived dopamine neurons |
| url | http://www.sciencedirect.com/science/article/pii/S2213671116000308 |
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