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Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients

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Abstract

Amyotrophic lateral sclerosis type 4 (ALS4) is a rare, early-onset, autosomal dominant form of ALS, characterized by slow disease progression and sparing of respiratory musculature. Dominant, gain-of-function mutations in the senataxin gene (SETX) cause ALS4, but the mechanistic basis for motor neuron toxicity is unknown. SETX is a RNA-binding protein with a highly conserved helicase domain, but does not possess a low-complexity domain, making it unique among ALS-linked disease proteins. We derived ALS4 mouse models by expressing two different senataxin gene mutations (R2136H and L389S) via transgenesis and knock-in gene targeting. Both approaches yielded SETX mutant mice that develop neuromuscular phenotypes and motor neuron degeneration. Neuropathological characterization of SETX mice revealed nuclear clearing of TDP-43, accompanied by TDP-43 cytosolic mislocalization, consistent with the hallmark pathology observed in human ALS patients. Postmortem material from ALS4 patients exhibited TDP-43 mislocalization in spinal cord motor neurons, and motor neurons from SETX ALS4 mice displayed enhanced stress granule formation. Immunostaining analysis for nucleocytoplasmic transport proteins Ran and RanGAP1 uncovered nuclear membrane abnormalities in the motor neurons of SETX ALS4 mice, and nuclear import was delayed in SETX ALS4 cortical neurons, indicative of impaired nucleocytoplasmic trafficking. SETX ALS4 mice thus recapitulated ALS disease phenotypes in association with TDP-43 mislocalization and provided insight into the basis for TDP-43 histopathology, linking SETX dysfunction to common pathways of ALS motor neuron degeneration.

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Acknowledgements

We are grateful to R. Palmiter (University of Washington) for providing the ES cell targeting vector (4317G9), B. Crain and L. Ostrow (Johns Hopkins Medical College) for providing ALS4 patient tissue samples and A. Wörner (Max-Planck Institute of Biochemistry) for providing the NLS-NES-eGFP shuttling reporter construct. We wish to thank J.F. Ervin for technical assistance. This work was supported by funding from the US National Institutes of Health (R01 GM094384 [C.L.B.]), the Robert Packard Center for ALS Research at Johns Hopkins School of Medicine [A.R.L.S.] and the Motor Neurone Disease Association (MNDA) [B.M. & L.G.].

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Author notes

  1. Craig L. Bennett and Somasish G. Dastidar contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Duke University School of Medicine, Durham, USA

    Craig L. Bennett, Somasish G. Dastidar, Mandheer Wadhwa & Albert R. La Spada

  2. Department of Physiology, National University of Singapore, Singapore, Singapore

    Shuo-Chien Ling

  3. Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, London, UK

    Bilal Malik & Linda Greensmith

  4. Department of Pediatrics, University of California, San Diego, LA JOLLA, USA

    Travis Ashe, Derek B. Miller, Changwoo Lee, Matthew B. Mitchell & Albert R. La Spada

  5. Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands

    Michael A. van Es

  6. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, USA

    Christopher Grunseich

  7. Department of Pediatrics, University of Washington Medical Center, Seattle, USA

    Yingzhang Chen

  8. Department of Neurology, University of Washington Medical Center, Seattle, USA

    Bryce L. Sopher

  9. The MRC Centre for Neuromuscular Diseases, University College London Institute of Neurology, London, UK

    Linda Greensmith

  10. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, USA

    Don W. Cleveland

  11. Department of Neurosciences, University of California, San Diego, La Jolla, USA

    Don W. Cleveland

  12. The Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, USA

    Don W. Cleveland

  13. Department of Neurobiology, Duke University School of Medicine, Durham, USA

    Albert R. La Spada

  14. Department of Cell Biology, Duke University School of Medicine, Durham, USA

    Albert R. La Spada

  15. Duke Center for Neurodegeneration and Neurotherapeutics, Duke University School of Medicine, Bryan Building, Room 401-E, DUMC 2900, Durham, NC, 27710, USA

    Albert R. La Spada

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  1. Craig L. Bennett
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  9. Matthew B. Mitchell
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  16. Albert R. La Spada
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Correspondence to Albert R. La Spada.

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Bennett, C.L., Dastidar, S.G., Ling, SC. et al. Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients. Acta Neuropathol 136, 425–443 (2018). https://doi.org/10.1007/s00401-018-1852-9

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  • DOI: https://doi.org/10.1007/s00401-018-1852-9

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