A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation
Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated (ATM) and Aprataxin (APTX), respectively. Our mechanistic understanding and therapeutic repertoire for treating these di...
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2021
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oai:doaj.org-article:58f72a12e1074e83ad3fff4ba229dc942021-11-18T15:15:48ZA novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation10.7554/eLife.646952050-084Xe64695https://doaj.org/article/58f72a12e1074e83ad3fff4ba229dc942021-11-01T00:00:00Zhttps://elifesciences.org/articles/64695https://doaj.org/toc/2050-084XAtaxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated (ATM) and Aprataxin (APTX), respectively. Our mechanistic understanding and therapeutic repertoire for treating these disorders are severely lacking, in large part due to the failure of prior animal models with similar null mutations to recapitulate the characteristic loss of motor coordination (i.e., ataxia) and associated cerebellar defects. By increasing genotoxic stress through the insertion of null mutations in both the Atm (nonsense) and Aptx (knockout) genes in the same animal, we have generated a novel mouse model that for the first time develops a progressively severe ataxic phenotype associated with atrophy of the cerebellar molecular layer. We find biophysical properties of cerebellar Purkinje neurons (PNs) are significantly perturbed (e.g., reduced membrane capacitance, lower action potential [AP] thresholds, etc.), while properties of synaptic inputs remain largely unchanged. These perturbations significantly alter PN neural activity, including a progressive reduction in spontaneous AP firing frequency that correlates with both cerebellar atrophy and ataxia over the animal’s first year of life. Double mutant mice also exhibit a high predisposition to developing cancer (thymomas) and immune abnormalities (impaired early thymocyte development and T-cell maturation), symptoms characteristic of A-T. Finally, by inserting a clinically relevant nonsense-type null mutation in Atm, we demonstrate that Small Molecule Read-Through (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic.Harvey PerezMay F AbdallahJose I ChaviraAngelina S NorrisMartin T EgelandKaren L VoCallan L BuechsenschuetzValentina SanghezJeannie L KimMolly PindKotoka NakamuraGeoffrey G HicksRichard A GattiJoaquin MadrenasMichelina IacovinoPeter J McKinnonPaul J MathewseLife Sciences Publications LtdarticleAtaxia Telangiectasiacerebellumpurkinje neuronsataxiathymuscancerMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Ataxia Telangiectasia cerebellum purkinje neurons ataxia thymus cancer Medicine R Science Q Biology (General) QH301-705.5 |
| spellingShingle |
Ataxia Telangiectasia cerebellum purkinje neurons ataxia thymus cancer Medicine R Science Q Biology (General) QH301-705.5 Harvey Perez May F Abdallah Jose I Chavira Angelina S Norris Martin T Egeland Karen L Vo Callan L Buechsenschuetz Valentina Sanghez Jeannie L Kim Molly Pind Kotoka Nakamura Geoffrey G Hicks Richard A Gatti Joaquin Madrenas Michelina Iacovino Peter J McKinnon Paul J Mathews A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation |
| description |
Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated (ATM) and Aprataxin (APTX), respectively. Our mechanistic understanding and therapeutic repertoire for treating these disorders are severely lacking, in large part due to the failure of prior animal models with similar null mutations to recapitulate the characteristic loss of motor coordination (i.e., ataxia) and associated cerebellar defects. By increasing genotoxic stress through the insertion of null mutations in both the Atm (nonsense) and Aptx (knockout) genes in the same animal, we have generated a novel mouse model that for the first time develops a progressively severe ataxic phenotype associated with atrophy of the cerebellar molecular layer. We find biophysical properties of cerebellar Purkinje neurons (PNs) are significantly perturbed (e.g., reduced membrane capacitance, lower action potential [AP] thresholds, etc.), while properties of synaptic inputs remain largely unchanged. These perturbations significantly alter PN neural activity, including a progressive reduction in spontaneous AP firing frequency that correlates with both cerebellar atrophy and ataxia over the animal’s first year of life. Double mutant mice also exhibit a high predisposition to developing cancer (thymomas) and immune abnormalities (impaired early thymocyte development and T-cell maturation), symptoms characteristic of A-T. Finally, by inserting a clinically relevant nonsense-type null mutation in Atm, we demonstrate that Small Molecule Read-Through (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic. |
| format |
article |
| author |
Harvey Perez May F Abdallah Jose I Chavira Angelina S Norris Martin T Egeland Karen L Vo Callan L Buechsenschuetz Valentina Sanghez Jeannie L Kim Molly Pind Kotoka Nakamura Geoffrey G Hicks Richard A Gatti Joaquin Madrenas Michelina Iacovino Peter J McKinnon Paul J Mathews |
| author_facet |
Harvey Perez May F Abdallah Jose I Chavira Angelina S Norris Martin T Egeland Karen L Vo Callan L Buechsenschuetz Valentina Sanghez Jeannie L Kim Molly Pind Kotoka Nakamura Geoffrey G Hicks Richard A Gatti Joaquin Madrenas Michelina Iacovino Peter J McKinnon Paul J Mathews |
| author_sort |
Harvey Perez |
| title |
A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation |
| title_short |
A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation |
| title_full |
A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation |
| title_fullStr |
A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation |
| title_full_unstemmed |
A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation |
| title_sort |
novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation |
| publisher |
eLife Sciences Publications Ltd |
| publishDate |
2021 |
| url |
https://doaj.org/article/58f72a12e1074e83ad3fff4ba229dc94 |
| work_keys_str_mv |
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