A novel, ataxic mouse model of Ataxia Telangiectasia caused by a clinically relevant nonsense mutation

  1. Harvey Perez
  2. May F Abdallah
  3. Jose I Chavira
  4. Angelina S Norris
  5. Martin T Egeland
  6. Karen L Vo
  7. Callan L Buechsenschuetz
  8. Valentina Sanghez
  9. Jeannie L Kim
  10. Molly Pind
  11. Kotoka Nakamura
  12. Geoffrey G Hicks
  13. Richard A Gatti
  14. Joaquin Madrenas
  15. Michelina Iacovino
  16. Peter McKinnon
  17. Paul J Mathews  Is a corresponding author
  1. The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, United States
  2. University of Manitoba, Canada
  3. University of California, Los Angeles, United States
  4. 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

  1. Harvey Perez

    Neurology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. May F Abdallah

    Neurology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jose I Chavira

    Neurology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Angelina S Norris

    Neurology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Martin T Egeland

    Neurology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Karen L Vo

    Neurology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Callan L Buechsenschuetz

    Undergraduate Studies, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Valentina Sanghez

    Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jeannie L Kim

    Neurology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Molly Pind

    Biochemistry and Medical Genetics, University of Manitoba, Manitoba, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. Kotoka Nakamura

    Laboratory Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Geoffrey G Hicks

    Department of Biochemistry and Medical Genetics, University of Manitoba, Manitoba, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Richard A Gatti

    Department of Laboratory Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Joaquin Madrenas

    Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6191-3733
  15. Michelina Iacovino

    Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Peter McKinnon

    St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Paul J Mathews

    Neurology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, United States
    For correspondence
    pmathews@ucla.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1991-0798

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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  1. Harvey Perez
  2. May F Abdallah
  3. Jose I Chavira
  4. Angelina S Norris
  5. Martin T Egeland
  6. Karen L Vo
  7. Callan L Buechsenschuetz
  8. Valentina Sanghez
  9. Jeannie L Kim
  10. Molly Pind
  11. Kotoka Nakamura
  12. Geoffrey G Hicks
  13. Richard A Gatti
  14. Joaquin Madrenas
  15. Michelina Iacovino
  16. Peter McKinnon
  17. Paul J Mathews
(2021)
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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https://doi.org/10.7554/eLife.64695

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