Hyperexcitability in young iPSC-derived <i>C9ORF72</i> mutant motor neurons is associated with increased intracellular calcium release

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Abstract

A large hexanucleotide repeat expansion in the C9ORF72 gene is the most prevalent cause of amyotrophic lateral sclerosis (ALS). To better understand neuronal dysfunction during ALS progression, we studied motor neuron (MN) cultures derived from iPSC lines generated from C9ORF72 (C9) expansion carriers and unaffected controls. C9 and control MN cultures showed comparable mRNA levels for MN markers SMI-32, HB9 and ISL1 and similar MN yields (> 50% TUJ1/SMI-32 double-positive MNs). Using whole-cell patch clamp we showed that C9-MNs have normal membrane capacitance, resistance and resting potential. However, immature (day 40) C9-MNs exhibited a hyperexcitable phenotype concurrent with increased release of calcium (Ca ²⁺) from internal stores, but with no changes to Na _V and K _V currents. Interestingly, this was a transient phenotype. By day 47, maturing C9-MNs demonstrated normal electrophysiological activity, displaying only subtle alterations on mitochondrial Ca ²⁺ release. Together, these findings suggest the potential importance of a developmental component to C9ORF72-related ALS.

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Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.

Mariely DeJesus-Hernandez, Ian R. Mackenzie, Bradley F. Boeve … (2011)

Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS. Copyright © 2011 Elsevier Inc. All rights reserved.

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A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.

Alan E. Renton, Elisa Majounie, Adrian Waite … (2011)

The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date. Copyright © 2011 Elsevier Inc. All rights reserved.

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Prognostic factors in ALS: A critical review.

Adriano Chiò, Giancarlo Logroscino, Orla Hardiman … (2009)

We have performed a systematic review to summarize current knowledge concerning factors related to survival in ALS and to evaluate the implications of these data for clinical trials design. The median survival time from onset to death ranges from 20 to 48 months, but 10-20% of ALS patients have a survival longer than 10 years. Older age and bulbar onset are consistently reported to have a worse outcome. There are conflicting data on gender, diagnostic delay and El Escorial criteria. The rate of symptom progression was revealed to be an independent prognostic factor. Psychosocial factors, FTD, nutritional status, and respiratory function are also related to ALS outcome. The effect of enteral nutrition on survival is still unclear, while NIPPV has been found to improve survival. There are no well established biological markers of progression, although some are likely to emerge in the near future. These findings have relevant implications for the design of future trials. Randomization, besides the type of onset, should take into account age, respiratory status at entry, and a measure of disease progression pre-entry. Alternative trial designs can include the use of natural history controls, the so-called minimization method for treatment allocation, and the futility approach.

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Author and article information

Contributors

Richard Wade-Martins: richard.wade-martins@dpag.ox.ac.uk

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 5 May 2022

Publication date PMC-release: 5 May 2022

Publication date Collection: 2022

Volume: 12

Electronic Location Identifier: 7378

Affiliations

[1 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Department of Physiology, Anatomy and Genetics, , University of Oxford, ; South Parks Road, Oxford, UK

[2 ]GRID grid.8348.7, ISNI 0000 0001 2306 7492, Nuffield Department of Clinical Neurosciences, , University of Oxford, John Radcliffe Hospital, ; Oxford, UK

[3 ]GRID grid.11914.3c, ISNI 0000 0001 0721 1626, Present Address: School of Biology, , University of St Andrews, North Haugh, ; St Andrews, UK

[4 ]GRID grid.5600.3, ISNI 0000 0001 0807 5670, Present Address: UK Dementia Research Institute, , University of Cardiff, ; Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ UK

[5 ]GRID grid.5337.2, ISNI 0000 0004 1936 7603, Present Address: Bristol Medical School, Translational Health Sciences, , University of Bristol, ; Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY UK

Article

Publisher ID: 9751

DOI: 10.1038/s41598-022-09751-3

PMC ID: 9072315

PubMed ID: 35513421

SO-VID: 63e25f22-b951-4499-a3da-2a69272cb2d4

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 21 July 2021

Date accepted : 21 February 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000406, Motor Neurone Disease Association;

Funded by: FundRef http://dx.doi.org/10.13039/501100000304, Parkinson's UK;

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ScienceOpen disciplines: Uncategorized

Keywords: amyotrophic lateral sclerosis,induced pluripotent stem cells,patch clamp

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ScienceOpen disciplines: Uncategorized

Keywords: amyotrophic lateral sclerosis, induced pluripotent stem cells, patch clamp

Hyperexcitability in young iPSC-derived C9ORF72 mutant motor neurons is associated with increased intracellular calcium release

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Most cited references 35

Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.

A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.

Prognostic factors in ALS: A critical review.

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