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C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell‐Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is a major cause of amyotrophic lateral sclerosis (ALS), accounting for up to 40% of familial cases and 7% of sporadic ALS in European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts of...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979662/ https://www.ncbi.nlm.nih.gov/pubmed/27097283 http://dx.doi.org/10.1002/stem.2388 |
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author | Dafinca, Ruxandra Scaber, Jakub Ababneh, Nida'a Lalic, Tatjana Weir, Gregory Christian, Helen Vowles, Jane Douglas, Andrew G.L. Fletcher‐Jones, Alexandra Browne, Cathy Nakanishi, Mahito Turner, Martin R. Wade‐Martins, Richard Cowley, Sally A. Talbot, Kevin |
author_facet | Dafinca, Ruxandra Scaber, Jakub Ababneh, Nida'a Lalic, Tatjana Weir, Gregory Christian, Helen Vowles, Jane Douglas, Andrew G.L. Fletcher‐Jones, Alexandra Browne, Cathy Nakanishi, Mahito Turner, Martin R. Wade‐Martins, Richard Cowley, Sally A. Talbot, Kevin |
author_sort | Dafinca, Ruxandra |
collection | PubMed |
description | An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is a major cause of amyotrophic lateral sclerosis (ALS), accounting for up to 40% of familial cases and 7% of sporadic ALS in European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts of patients carrying C9orf72 hexanucleotide expansions, differentiated these to functional motor and cortical neurons, and performed an extensive phenotypic characterization. In C9orf72 iPSC‐derived motor neurons, decreased cell survival is correlated with dysfunction in Ca(2+) homeostasis, reduced levels of the antiapoptotic protein Bcl‐2, increased endoplasmic reticulum (ER) stress, and reduced mitochondrial membrane potential. Furthermore, C9orf72 motor neurons, and also cortical neurons, show evidence of abnormal protein aggregation and stress granule formation. This study is an extensive characterization of iPSC‐derived motor neurons as cellular models of ALS carrying C9orf72 hexanucleotide repeats, which describes a novel pathogenic link between C9orf72 mutations, dysregulation of calcium signaling, and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia. Stem Cells 2016;34:2063–2078 |
format | Online Article Text |
id | pubmed-4979662 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-49796622016-08-23 C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell‐Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Dafinca, Ruxandra Scaber, Jakub Ababneh, Nida'a Lalic, Tatjana Weir, Gregory Christian, Helen Vowles, Jane Douglas, Andrew G.L. Fletcher‐Jones, Alexandra Browne, Cathy Nakanishi, Mahito Turner, Martin R. Wade‐Martins, Richard Cowley, Sally A. Talbot, Kevin Stem Cells Embryonic Stem Cells/Induced Pluripotent Stem Cells An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is a major cause of amyotrophic lateral sclerosis (ALS), accounting for up to 40% of familial cases and 7% of sporadic ALS in European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts of patients carrying C9orf72 hexanucleotide expansions, differentiated these to functional motor and cortical neurons, and performed an extensive phenotypic characterization. In C9orf72 iPSC‐derived motor neurons, decreased cell survival is correlated with dysfunction in Ca(2+) homeostasis, reduced levels of the antiapoptotic protein Bcl‐2, increased endoplasmic reticulum (ER) stress, and reduced mitochondrial membrane potential. Furthermore, C9orf72 motor neurons, and also cortical neurons, show evidence of abnormal protein aggregation and stress granule formation. This study is an extensive characterization of iPSC‐derived motor neurons as cellular models of ALS carrying C9orf72 hexanucleotide repeats, which describes a novel pathogenic link between C9orf72 mutations, dysregulation of calcium signaling, and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia. Stem Cells 2016;34:2063–2078 John Wiley and Sons Inc. 2016-05-04 2016-08 /pmc/articles/PMC4979662/ /pubmed/27097283 http://dx.doi.org/10.1002/stem.2388 Text en © 2016 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Embryonic Stem Cells/Induced Pluripotent Stem Cells Dafinca, Ruxandra Scaber, Jakub Ababneh, Nida'a Lalic, Tatjana Weir, Gregory Christian, Helen Vowles, Jane Douglas, Andrew G.L. Fletcher‐Jones, Alexandra Browne, Cathy Nakanishi, Mahito Turner, Martin R. Wade‐Martins, Richard Cowley, Sally A. Talbot, Kevin C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell‐Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia |
title |
C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell‐Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia |
title_full |
C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell‐Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia |
title_fullStr |
C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell‐Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia |
title_full_unstemmed |
C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell‐Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia |
title_short |
C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell‐Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia |
title_sort | c9orf72 hexanucleotide expansions are associated with altered endoplasmic reticulum calcium homeostasis and stress granule formation in induced pluripotent stem cell‐derived neurons from patients with amyotrophic lateral sclerosis and frontotemporal dementia |
topic | Embryonic Stem Cells/Induced Pluripotent Stem Cells |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979662/ https://www.ncbi.nlm.nih.gov/pubmed/27097283 http://dx.doi.org/10.1002/stem.2388 |
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