Calcineurin protects against pathological phosphorylated TDP-43
Nicole F. Liachko1,2*, Heather Currey1, Brian Kraemer1,2
1Geriatrics Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108; 2Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98104
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 shown to mediate TDP-43 protein stability and turnover, cellular localization, protein aggregation, and neurotoxicity in neurodegenerative disease models. 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 disease relevant brain regions in subjects with FTLD-TDP and in spinal cord motor neurons from subjects with ALS. Taken together these findings suggest calcineurin acts on pTDP-43 as a phosphatase in neurons . Calcineurin activation may be a novel neuroprotective therapeutic strategy. We are testing this hypothesis using C. elegans, mammalian cultured cells, and mouse primary neuron models of TDP-43 proteinopathy. Our preliminary data support this approach for preventing accumulation of pTDP and subsequent neurotoxicity.
1. Liachko, N. F., A. D. Saxton, P. J. McMillan, T. J. Strovas, H. N. Currey, L. M. Taylor, J. M. Wheeler, A. L. Oblak, B. Ghetti, T. J. Montine, C. D. Keene, M. A. Raskind, T. D. Bird and B. C. Kraemer (2016). "The phosphatase calcineurin regulates pathological TDP-43 phosphorylation." Acta Neuropathologica 132(4): 545-561.
This work was supported by grants from the Department of Veterans Affairs [Merit Review Grant #I01BX002619 to B.K., Career Development Award 2 #I01BX007080 to N.L.] and National Institutes of Health [R01NS064131 to B.K.].