Acta Neuropathologica

, Volume 136, Issue 3, pp 425–443 | Cite as

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

  • Craig L. Bennett
  • Somasish G. Dastidar
  • Shuo-Chien Ling
  • Bilal Malik
  • Travis Ashe
  • Mandheer Wadhwa
  • Derek B. Miller
  • Changwoo Lee
  • Matthew B. Mitchell
  • Michael A. van Es
  • Christopher Grunseich
  • Yingzhang Chen
  • Bryce L. Sopher
  • Linda Greensmith
  • Don W. Cleveland
  • Albert R. La SpadaEmail author
Original Paper


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.


Amyotrophic lateral sclerosis Senataxin Transgenesis Gene targeting TDP-43 Nucleocytoplasmic transport Ran RanGAP1 Motor neuron Neurodegeneration 



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.].

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Craig L. Bennett
    • 1
  • Somasish G. Dastidar
    • 1
  • Shuo-Chien Ling
    • 2
  • Bilal Malik
    • 3
  • Travis Ashe
    • 4
  • Mandheer Wadhwa
    • 1
  • Derek B. Miller
    • 4
  • Changwoo Lee
    • 4
  • Matthew B. Mitchell
    • 4
  • Michael A. van Es
    • 5
  • Christopher Grunseich
    • 6
  • Yingzhang Chen
    • 7
  • Bryce L. Sopher
    • 8
  • Linda Greensmith
    • 3
    • 9
  • Don W. Cleveland
    • 10
    • 11
    • 12
  • Albert R. La Spada
    • 1
    • 4
    • 13
    • 14
    • 15
    Email author
  1. 1.Department of NeurologyDuke University School of MedicineDurhamUSA
  2. 2.Department of PhysiologyNational University of SingaporeSingaporeSingapore
  3. 3.Sobell Department of Motor Neuroscience and Movement DisordersUniversity College London Institute of NeurologyLondonUK
  4. 4.Department of PediatricsUniversity of CaliforniaSan DiegoUSA
  5. 5.Department of Neurology, Brain Center Rudolf MagnusUniversity Medical Center UtrechtUtrechtThe Netherlands
  6. 6.Neurogenetics BranchNational Institute of Neurological Disorders and Stroke, NIHBethesdaUSA
  7. 7.Department of PediatricsUniversity of Washington Medical CenterSeattleUSA
  8. 8.Department of NeurologyUniversity of Washington Medical CenterSeattleUSA
  9. 9.The MRC Centre for Neuromuscular DiseasesUniversity College London Institute of NeurologyLondonUK
  10. 10.Department of Cellular and Molecular MedicineUniversity of California, San DiegoLa JollaUSA
  11. 11.Department of NeurosciencesUniversity of California, San DiegoLa JollaUSA
  12. 12.The Ludwig Institute for Cancer ResearchUniversity of California, San DiegoLa JollaUSA
  13. 13.Department of NeurobiologyDuke University School of MedicineDurhamUSA
  14. 14.Department of Cell BiologyDuke University School of MedicineDurhamUSA
  15. 15.Duke Center for Neurodegeneration and NeurotherapeuticsDuke University School of MedicineDurhamUSA

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