A novel, ataxic mouse model of Ataxia Telangiectasia caused by a clinically relevant nonsense mutation
- The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, United States
- University of Manitoba, Canada
- University of California, Los Angeles, United States
- St Jude Children's Research Hospital, United States
Abstract
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 is 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 are significantly perturbed (e.g., reduced membrane capacitance, lower action potential thresholds, etc.), while properties of synaptic inputs remain largely unchanged. These perturbations significantly alter Purkinje neuron neural activity, including a progressive reduction in spontaneous action potential 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. Lastly, 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.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting source data files.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (R21NS108117)
- Paul J Mathews
Sparks (13CAL01)
- Richard A Gatti
National Institute of Neurological Disorders and Stroke (R33NS096044)
- Michelina Iacovino
National Institute of Neurological Disorders and Stroke (R21NS108117-01S1)
- Paul J Mathews
National Institute of Neurological Disorders and Stroke (R03NS103066)
- Paul J Mathews
American Lebanese and Syrian Associated Charities of St. Jude Children's Hospital (N/A)
- Peter McKinnon
National Institute of Neurological Disorders and Stroke (R01NS037956)
- Peter McKinnon
National Cancer Institute (P01CA096832)
- Peter McKinnon
National Center for Advancing Translational Sciences (UL1TR001881)
- Paul J Mathews
Manitoba Research Innovation (312864)
- Geoffrey G Hicks
Cancer Care Manitoba Foundation (761023032)
- Geoffrey G Hicks
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All the animals were handled according to approved institutional animal care and use committee (IACUC) protocols at The Lundquist Institute (31374-03, 31773-02) and UCLA (ARC-2007-082, ARC-2013-068). The protocol was approved by the Committee on the Ethics of Animal Experiments of the Lundquist Institute (Assurance Number: D16-00213). Every effort was made to minimize pain and suffering by providing support when necessary and choosing ethical endpoints.
Copyright
© 2021, Perez et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A novel, ataxic mouse model of Ataxia Telangiectasia caused by a clinically relevant nonsense mutation
eLife 10:e64695.
https://doi.org/10.7554/eLife.64695
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