Liachko, Nicole F.Saxton, Aleen D.McMillan, Pamela J.Strovas, Timothy J.Currey, Heather N.Taylor, Laura M.Wheeler, Jeanna M.Oblak, Adrian L.Ghetti, BernardinoMontine, Thomas J.Keene, C. DirkRaskind, Murray A.Bird, Thomas D.Kraemer, Brian C.2018-03-142018-03-142016-10Liachko, N. F., Saxton, A. D., McMillan, P. J., Strovas, T. J., Currey, H. N., Taylor, L. M., … 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-y0001-6322https://hdl.handle.net/1805/15516Detergent 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.en-USPublisher PolicyAmyotrophic lateral sclerosisCalcineurinFK506Frontotemporal lobar degenerationTARDBPTDP-43TacrolimuspTDPArticle