Viral delivery of C9orf72 hexanucleotide repeat expansions in mice leads to repeat-length-dependent neuropathology and behavioural deficits
Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2017-07-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/10/7/859 |
| _version_ | 1828473589073969152 |
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| author | Saul Herranz-Martin Jayanth Chandran Katherine Lewis Padraig Mulcahy Adrian Higginbottom Callum Walker Isabel Martinez-Pena y Valenzuela Ross A. Jones Ian Coldicott Tommaso Iannitti Mohammed Akaaboune Sherif F. El-Khamisy Thomas H. Gillingwater Pamela J. Shaw Mimoun Azzouz |
| author_facet | Saul Herranz-Martin Jayanth Chandran Katherine Lewis Padraig Mulcahy Adrian Higginbottom Callum Walker Isabel Martinez-Pena y Valenzuela Ross A. Jones Ian Coldicott Tommaso Iannitti Mohammed Akaaboune Sherif F. El-Khamisy Thomas H. Gillingwater Pamela J. Shaw Mimoun Azzouz |
| author_sort | Saul Herranz-Martin |
| collection | DOAJ |
| description | Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, although it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here, we describe two novel lines of mice that overexpress either 10 pure or 102 interrupted GGGGCC repeats mediated by adeno-associated virus (AAV) and recapitulate the relevant human pathology and disease-related behavioural phenotypes. Similar levels of intracellular RNA foci developed in both lines of mice, but only mice expressing 102 repeats generated C9orf72 RAN pathology, neuromuscular junction (NMJ) abnormalities, dispersal of the hippocampal CA1, enhanced apoptosis, and deficits in gait and cognition. Neither line of mice, however, showed extensive TAR DNA-binding protein 43 (TDP-43) pathology or neurodegeneration. Our data suggest that RNA foci pathology is not a good predictor of C9orf72 RAN dipeptide formation, and that RAN dipeptides and NMJ dysfunction are drivers of C9orf72 disease pathogenesis. These AAV-mediated models of C9orf72-associated ALS/FTD will be useful tools for studying disease pathophysiology and developing new therapeutic approaches. |
| first_indexed | 2024-12-11T05:46:36Z |
| format | Article |
| id | doaj.art-3b09a5da67e5486faef92f4f057cb7f5 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-11T05:46:36Z |
| publishDate | 2017-07-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-3b09a5da67e5486faef92f4f057cb7f52022-12-22T01:18:56ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112017-07-0110785986810.1242/dmm.029892029892Viral delivery of C9orf72 hexanucleotide repeat expansions in mice leads to repeat-length-dependent neuropathology and behavioural deficitsSaul Herranz-Martin0Jayanth Chandran1Katherine Lewis2Padraig Mulcahy3Adrian Higginbottom4Callum Walker5Isabel Martinez-Pena y Valenzuela6Ross A. Jones7Ian Coldicott8Tommaso Iannitti9Mohammed Akaaboune10Sherif F. El-Khamisy11Thomas H. Gillingwater12Pamela J. Shaw13Mimoun Azzouz14 Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK Molecular, Cellular and Developmental Biology, University of Michigan, 830 North University, Ann Arbor, MI 48109-1048, USA Centre for Integrative Physiology & Euan MacDonald Centre for Motor Neurone Disease Research, Hugh Robson Building, The University of Edinburgh, 15 George Square, Edinburgh EH8 9XD, UK Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK Molecular, Cellular and Developmental Biology, University of Michigan, 830 North University, Ann Arbor, MI 48109-1048, USA Department of Molecular Biology and Biotechnology, Krebs and Sheffield Institute for Nucleic Acids, Firth Court, University of Sheffield, Sheffield S10 2TN, UK Centre for Integrative Physiology & Euan MacDonald Centre for Motor Neurone Disease Research, Hugh Robson Building, The University of Edinburgh, 15 George Square, Edinburgh EH8 9XD, UK Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, although it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here, we describe two novel lines of mice that overexpress either 10 pure or 102 interrupted GGGGCC repeats mediated by adeno-associated virus (AAV) and recapitulate the relevant human pathology and disease-related behavioural phenotypes. Similar levels of intracellular RNA foci developed in both lines of mice, but only mice expressing 102 repeats generated C9orf72 RAN pathology, neuromuscular junction (NMJ) abnormalities, dispersal of the hippocampal CA1, enhanced apoptosis, and deficits in gait and cognition. Neither line of mice, however, showed extensive TAR DNA-binding protein 43 (TDP-43) pathology or neurodegeneration. Our data suggest that RNA foci pathology is not a good predictor of C9orf72 RAN dipeptide formation, and that RAN dipeptides and NMJ dysfunction are drivers of C9orf72 disease pathogenesis. These AAV-mediated models of C9orf72-associated ALS/FTD will be useful tools for studying disease pathophysiology and developing new therapeutic approaches.http://dmm.biologists.org/content/10/7/859C9orf72NeurodegenerationALS/FTDMouse modelC9RAN aggregates |
| spellingShingle | Saul Herranz-Martin Jayanth Chandran Katherine Lewis Padraig Mulcahy Adrian Higginbottom Callum Walker Isabel Martinez-Pena y Valenzuela Ross A. Jones Ian Coldicott Tommaso Iannitti Mohammed Akaaboune Sherif F. El-Khamisy Thomas H. Gillingwater Pamela J. Shaw Mimoun Azzouz Viral delivery of C9orf72 hexanucleotide repeat expansions in mice leads to repeat-length-dependent neuropathology and behavioural deficits Disease Models & Mechanisms C9orf72 Neurodegeneration ALS/FTD Mouse model C9RAN aggregates |
| title | Viral delivery of C9orf72 hexanucleotide repeat expansions in mice leads to repeat-length-dependent neuropathology and behavioural deficits |
| title_full | Viral delivery of C9orf72 hexanucleotide repeat expansions in mice leads to repeat-length-dependent neuropathology and behavioural deficits |
| title_fullStr | Viral delivery of C9orf72 hexanucleotide repeat expansions in mice leads to repeat-length-dependent neuropathology and behavioural deficits |
| title_full_unstemmed | Viral delivery of C9orf72 hexanucleotide repeat expansions in mice leads to repeat-length-dependent neuropathology and behavioural deficits |
| title_short | Viral delivery of C9orf72 hexanucleotide repeat expansions in mice leads to repeat-length-dependent neuropathology and behavioural deficits |
| title_sort | viral delivery of c9orf72 hexanucleotide repeat expansions in mice leads to repeat length dependent neuropathology and behavioural deficits |
| topic | C9orf72 Neurodegeneration ALS/FTD Mouse model C9RAN aggregates |
| url | http://dmm.biologists.org/content/10/7/859 |
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