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C9orf72 hexanucleotide expansions are associated with altered ER calcium homeostasis and stress granule formation in iPSC-derived neurons from patients with amyotrophic lateral sclerosis and frontotemporal dementia

C9orf72 hexanucleotide expansions are associated with altered ER calcium homeostasis and stress granule formation in iPSC-derived neurons from patients with amyotrophic lateral sclerosis and frontotemporal dementia
C9orf72 hexanucleotide expansions are associated with altered ER calcium homeostasis and stress granule formation in iPSC-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 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 Ca2+ homeostasis, reduced levels of the anti-apoptotic 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 signalling and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia (FTD). This article is protected by copyright. All rights reserved.
amyotrophic lateral sclerosis, C9orf72, calcium dysregulation, frontotemporal dementia, induced pluripotent stem cells, motor neurons
0250-6793
1-44
Dafinca, Ruxandra
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Scaber, Jakub
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Ababneh, Nida'a
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Lalic, Tatjana
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Weir, Gregory
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Christian, Helen
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Vowles, Jane
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Douglas, Andrew G.L.
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Fletcher-Jones, Alexandra
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Browne, Cathy
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Nakanishi, Mahito
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Turner, Martin R.
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Wade-Martins, Richard
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Cowley, Sally A.
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Talbot, Kevin
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Dafinca, Ruxandra
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Scaber, Jakub
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Ababneh, Nida'a
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Lalic, Tatjana
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Weir, Gregory
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Christian, Helen
001082e8-11cf-4670-8f43-23a814ca32fd
Vowles, Jane
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Douglas, Andrew G.L.
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Fletcher-Jones, Alexandra
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Browne, Cathy
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Nakanishi, Mahito
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Turner, Martin R.
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Wade-Martins, Richard
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Cowley, Sally A.
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Talbot, Kevin
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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. and Talbot, Kevin (2016) C9orf72 hexanucleotide expansions are associated with altered ER calcium homeostasis and stress granule formation in iPSC-derived neurons from patients with amyotrophic lateral sclerosis and frontotemporal dementia. Stem Cells, 1-44. (doi:10.1002/stem.2388). (PMID:27097283)

Record type: Article

Abstract

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 Ca2+ homeostasis, reduced levels of the anti-apoptotic 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 signalling and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia (FTD). This article is protected by copyright. All rights reserved.

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Accepted/In Press date: 19 March 2016
e-pub ahead of print date: 20 April 2016
Keywords: amyotrophic lateral sclerosis, C9orf72, calcium dysregulation, frontotemporal dementia, induced pluripotent stem cells, motor neurons
Organisations: Human Development & Health

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Local EPrints ID: 393755
URI: http://eprints.soton.ac.uk/id/eprint/393755
ISSN: 0250-6793
PURE UUID: ae6b9ce3-e980-437f-ae9b-45e445fc8c87
ORCID for Andrew G.L. Douglas: ORCID iD orcid.org/0000-0001-5154-6714

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Date deposited: 04 May 2016 09:37
Last modified: 17 Dec 2019 06:50

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Contributors

Author: Ruxandra Dafinca
Author: Jakub Scaber
Author: Nida'a Ababneh
Author: Tatjana Lalic
Author: Gregory Weir
Author: Helen Christian
Author: Jane Vowles
Author: Alexandra Fletcher-Jones
Author: Cathy Browne
Author: Mahito Nakanishi
Author: Martin R. Turner
Author: Richard Wade-Martins
Author: Sally A. Cowley
Author: Kevin Talbot

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