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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
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.
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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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