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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).
amyotrophic lateral sclerosis, C9orf72, calcium dysregulation, frontotemporal dementia, induced pluripotent stem cells, motor neurons
1066-5099
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
1633ff82-2d24-4fb2-82b2-9039f1c72f75
Douglas, Andrew G.L.
2c789ec4-a222-43bc-a040-522ca64fea42
Fletcher-Jones, Alexandra
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Browne, Cathy
432a4aec-1710-47c4-a18b-9d1a1d6c78d9
Nakanishi, Mahito
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Turner, Martin R.
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Wade-Martins, Richard
e04b9f70-fc8c-49b0-b994-4dd9f0cc950b
Cowley, Sally A.
abb767a0-b182-48d9-912c-0c81485beacc
Talbot, Kevin
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Dafinca, Ruxandra
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Scaber, Jakub
e451a1fd-2c26-40df-905b-eac272f59b89
Ababneh, Nida'a
224bb118-98c6-4eb7-9de5-e3177c69a909
Lalic, Tatjana
5a2ae67a-7647-4f38-b5e9-f6a7956ced73
Weir, Gregory
6751f372-d997-4b5f-82e3-b08864e016d0
Christian, Helen
001082e8-11cf-4670-8f43-23a814ca32fd
Vowles, Jane
1633ff82-2d24-4fb2-82b2-9039f1c72f75
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.
abb767a0-b182-48d9-912c-0c81485beacc
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).

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More information

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

Identifiers

Local EPrints ID: 393755
URI: http://eprints.soton.ac.uk/id/eprint/393755
ISSN: 1066-5099
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: 15 Mar 2024 05:33

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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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