A mouse model with widespread expression of the C9orf72-linked glycine–arginine dipeptide displays non-lethal ALS/FTD-like phenotypes
Abstract Translation of the hexanucleotide G4C2 expansion associated with C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about the contribution of a single...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-09593-z |
| _version_ | 1811272487150813184 |
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| author | Brandie Morris Verdone Maria Elena Cicardi Xinmei Wen Sindhu Sriramoji Katelyn Russell Shashirekha S. Markandaiah Brigid K. Jensen Karthik Krishnamurthy Aaron R. Haeusler Piera Pasinelli Davide Trotti |
| author_facet | Brandie Morris Verdone Maria Elena Cicardi Xinmei Wen Sindhu Sriramoji Katelyn Russell Shashirekha S. Markandaiah Brigid K. Jensen Karthik Krishnamurthy Aaron R. Haeusler Piera Pasinelli Davide Trotti |
| author_sort | Brandie Morris Verdone |
| collection | DOAJ |
| description | Abstract Translation of the hexanucleotide G4C2 expansion associated with C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about the contribution of a single DPR to disease pathogenesis. We show here that a short repeat length is sufficient for the DPR poly-GR to confer neurotoxicity in vitro, a phenomenon previously unobserved. This toxicity is also reported in vivo in our novel knock-in mouse model characterized by widespread central nervous system (CNS) expression of the short-length poly-GR. We observe sex-specific chronic ALS/FTD-like phenotypes in these mice, including mild motor neuron loss, but no TDP-43 mis-localization, as well as motor and cognitive impairments. We suggest that this model can serve as the foundation for phenotypic exacerbation through second-hit forms of stress. |
| first_indexed | 2024-04-12T22:41:10Z |
| format | Article |
| id | doaj.art-19ca21d95d3242fdb4694723b5e2de9e |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T22:41:10Z |
| publishDate | 2022-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-19ca21d95d3242fdb4694723b5e2de9e2022-12-22T03:13:42ZengNature PortfolioScientific Reports2045-23222022-04-0112111710.1038/s41598-022-09593-zA mouse model with widespread expression of the C9orf72-linked glycine–arginine dipeptide displays non-lethal ALS/FTD-like phenotypesBrandie Morris Verdone0Maria Elena Cicardi1Xinmei Wen2Sindhu Sriramoji3Katelyn Russell4Shashirekha S. Markandaiah5Brigid K. Jensen6Karthik Krishnamurthy7Aaron R. Haeusler8Piera Pasinelli9Davide Trotti10Jefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson UniversityJefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson UniversityJefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson UniversityJefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson UniversityJefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson UniversityJefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson UniversityJefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson UniversityJefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson UniversityJefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson UniversityJefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson UniversityJefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson UniversityAbstract Translation of the hexanucleotide G4C2 expansion associated with C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about the contribution of a single DPR to disease pathogenesis. We show here that a short repeat length is sufficient for the DPR poly-GR to confer neurotoxicity in vitro, a phenomenon previously unobserved. This toxicity is also reported in vivo in our novel knock-in mouse model characterized by widespread central nervous system (CNS) expression of the short-length poly-GR. We observe sex-specific chronic ALS/FTD-like phenotypes in these mice, including mild motor neuron loss, but no TDP-43 mis-localization, as well as motor and cognitive impairments. We suggest that this model can serve as the foundation for phenotypic exacerbation through second-hit forms of stress.https://doi.org/10.1038/s41598-022-09593-z |
| spellingShingle | Brandie Morris Verdone Maria Elena Cicardi Xinmei Wen Sindhu Sriramoji Katelyn Russell Shashirekha S. Markandaiah Brigid K. Jensen Karthik Krishnamurthy Aaron R. Haeusler Piera Pasinelli Davide Trotti A mouse model with widespread expression of the C9orf72-linked glycine–arginine dipeptide displays non-lethal ALS/FTD-like phenotypes Scientific Reports |
| title | A mouse model with widespread expression of the C9orf72-linked glycine–arginine dipeptide displays non-lethal ALS/FTD-like phenotypes |
| title_full | A mouse model with widespread expression of the C9orf72-linked glycine–arginine dipeptide displays non-lethal ALS/FTD-like phenotypes |
| title_fullStr | A mouse model with widespread expression of the C9orf72-linked glycine–arginine dipeptide displays non-lethal ALS/FTD-like phenotypes |
| title_full_unstemmed | A mouse model with widespread expression of the C9orf72-linked glycine–arginine dipeptide displays non-lethal ALS/FTD-like phenotypes |
| title_short | A mouse model with widespread expression of the C9orf72-linked glycine–arginine dipeptide displays non-lethal ALS/FTD-like phenotypes |
| title_sort | mouse model with widespread expression of the c9orf72 linked glycine arginine dipeptide displays non lethal als ftd like phenotypes |
| url | https://doi.org/10.1038/s41598-022-09593-z |
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