Acta Neuropathologica

, Volume 132, Issue 4, pp 545–561 | Cite as

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

  • Nicole F. Liachko
  • Aleen D. Saxton
  • Pamela J. McMillan
  • Timothy J. Strovas
  • Heather N. Currey
  • Laura M. Taylor
  • Jeanna M. Wheeler
  • Adrian L. Oblak
  • Bernardino Ghetti
  • Thomas J. Montine
  • C. Dirk Keene
  • Murray A. Raskind
  • Thomas D. Bird
  • Brian C. Kraemer
Original Paper

Abstract

Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90 % of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To date, several different kinases have been implicated in the genesis of pTDP, but no phosphatases have been shown to reverse pathological TDP-43 phosphorylation. We have identified the phosphatase calcineurin as an enzyme binding to and catalyzing the removal of pathological C-terminal phosphorylation of TDP-43 in vitro. In C. elegans models of TDP-43 proteinopathy, genetic elimination of calcineurin results in accumulation of excess pTDP, exacerbated motor dysfunction, and accelerated neurodegenerative changes. In cultured human cells, treatment with FK506 (tacrolimus), a calcineurin inhibitor, results in accumulation of pTDP species. Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ALS. Taken together, these findings suggest calcineurin acts on pTDP as a phosphatase in neurons. Furthermore, patient treatment with calcineurin inhibitors may have unappreciated adverse neuropathological consequences.

Keywords

Calcineurin TDP-43 TARDBP Amyotrophic lateral sclerosis Frontotemporal lobar degeneration FK506 Tacrolimus pTDP 

Supplementary material

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Supplementary material 1 (PDF 15061 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2016

Authors and Affiliations

  • Nicole F. Liachko
    • 1
    • 2
  • Aleen D. Saxton
    • 1
  • Pamela J. McMillan
    • 1
    • 3
    • 4
  • Timothy J. Strovas
    • 1
  • Heather N. Currey
    • 1
  • Laura M. Taylor
    • 2
  • Jeanna M. Wheeler
    • 1
  • Adrian L. Oblak
    • 5
  • Bernardino Ghetti
    • 5
  • Thomas J. Montine
    • 6
    • 9
  • C. Dirk Keene
    • 6
  • Murray A. Raskind
    • 3
    • 4
  • Thomas D. Bird
    • 1
    • 7
    • 8
  • Brian C. Kraemer
    • 1
    • 2
    • 4
    • 6
  1. 1.Geriatrics Research Education and Clinical CenterVeterans Affairs Puget Sound Health Care SystemSeattleUSA
  2. 2.Division of Gerontology and Geriatric Medicine, Department of MedicineUniversity of WashingtonSeattleUSA
  3. 3.Mental Illness Research Education and Clinical CentersVeterans Affairs Puget Sound Health Care SystemSeattleUSA
  4. 4.Department of Psychiatry and Behavioral SciencesUniversity of WashingtonSeattleUSA
  5. 5.Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisUSA
  6. 6.Department of PathologyUniversity of WashingtonSeattleUSA
  7. 7.Department of NeurologyUniversity of WashingtonSeattleUSA
  8. 8.Division of Medical Genetics, Department of MedicineUniversity of WashingtonSeattleUSA
  9. 9.Department of PathologyStanford University School of MedicinePalo Alto, CAUSA

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