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, R. et al. (2016) 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. Stem Cells, 34(8), pp. 2063-2078. (doi:10.1002/stem.2388) (PMID:27097283) (PMCID:PMC4979662)

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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 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Weir, Dr Gregory
Authors: Dafinca, R., Scaber, J., Ababneh, N.'a., Lalic, T., Weir, G., Christian, H., Vowles, J., Douglas, A. G.L., Fletcher-Jones, A., Browne, C., Nakanishi, M., Turner, M. R., Wade-Martins, R., Cowley, S. A., and Talbot, K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Stem Cells
Publisher:Wiley
ISSN:1066-5099
ISSN (Online):1549-4918
Published Online:20 April 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Stem Cells 34(8): 2063-2078
Publisher Policy:Reproduced under a Creative Commons License

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