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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788783/ https://www.ncbi.nlm.nih.gov/pubmed/26905200 http://dx.doi.org/10.1016/j.stemcr.2016.01.013 |
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author | Fernandes, Hugo J.R. Hartfield, Elizabeth M. Christian, Helen C. Emmanoulidou, Evangelia Zheng, Ying Booth, Heather Bogetofte, Helle Lang, Charmaine Ryan, Brent J. Sardi, S. Pablo Badger, Jennifer Vowles, Jane Evetts, Samuel Tofaris, George K. Vekrellis, Kostas Talbot, Kevin Hu, Michele T. James, William Cowley, Sally A. Wade-Martins, Richard |
author_facet | Fernandes, Hugo J.R. Hartfield, Elizabeth M. Christian, Helen C. Emmanoulidou, Evangelia Zheng, Ying Booth, Heather Bogetofte, Helle Lang, Charmaine Ryan, Brent J. Sardi, S. Pablo Badger, Jennifer Vowles, Jane Evetts, Samuel Tofaris, George K. Vekrellis, Kostas Talbot, Kevin Hu, Michele T. James, William Cowley, Sally A. Wade-Martins, Richard |
author_sort | Fernandes, Hugo J.R. |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-4788783 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-47887832016-03-24 ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons Fernandes, Hugo J.R. Hartfield, Elizabeth M. Christian, Helen C. Emmanoulidou, Evangelia Zheng, Ying Booth, Heather Bogetofte, Helle Lang, Charmaine Ryan, Brent J. Sardi, S. Pablo Badger, Jennifer Vowles, Jane Evetts, Samuel Tofaris, George K. Vekrellis, Kostas Talbot, Kevin Hu, Michele T. James, William Cowley, Sally A. Wade-Martins, Richard Stem Cell Reports Article 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. Elsevier 2016-02-18 /pmc/articles/PMC4788783/ /pubmed/26905200 http://dx.doi.org/10.1016/j.stemcr.2016.01.013 Text en © 2016 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Fernandes, Hugo J.R. Hartfield, Elizabeth M. Christian, Helen C. Emmanoulidou, Evangelia Zheng, Ying Booth, Heather Bogetofte, Helle Lang, Charmaine Ryan, Brent J. Sardi, S. Pablo Badger, Jennifer Vowles, Jane Evetts, Samuel Tofaris, George K. Vekrellis, Kostas Talbot, Kevin Hu, Michele T. James, William Cowley, Sally A. Wade-Martins, Richard ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons |
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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788783/ https://www.ncbi.nlm.nih.gov/pubmed/26905200 http://dx.doi.org/10.1016/j.stemcr.2016.01.013 |
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