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

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)545-561
Number of pages17
JournalActa Neuropathologica
Volume132
Issue number4
DOIs
StatePublished - Oct 1 2016

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Liachko, N. F., Saxton, A. D., McMillan, P. J., Strovas, T. J., Currey, H. N., Taylor, L. M., Wheeler, J. M., Oblak, A. L., Ghetti, B., Montine, T. J., Keene, C. D., Raskind, M. A., Bird, T. D., & Kraemer, B. C. (2016). The phosphatase calcineurin regulates pathological TDP-43 phosphorylation. Acta Neuropathologica, 132(4), 545-561. https://doi.org/10.1007/s00401-016-1600-y