The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

• Published in: Acta neuropathologica Vol. 132; no. 4; pp. 545 - 561
• Main Authors: 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, Bernardino, Montine, Thomas J., Keene, C. Dirk, Raskind, Murray A., Bird, Thomas D., Kraemer, Brian C.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2016; Springer; Springer Nature B.V
• Subjects: Alzheimer's disease; Amino acids; Amyotrophic lateral sclerosis; Animals; Brain - metabolism; Brain - pathology; Caenorhabditis elegans; Calcineurin - metabolism; Cells (Biology); Dementia; Disease; DNA-Binding Proteins - metabolism; Inclusion Bodies - pathology; Kinases; Medicine; Medicine & Public Health; Nervous system diseases; Neurodegeneration; Neurons - metabolism; Neurons - pathology; Neuropathology; Neurosciences; Original Paper; Pathology; Phosphatase; Phosphatases; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; Phosphotransferases; Plasmids; Proteins; TDP-43 Proteinopathies - metabolism; TDP-43 Proteinopathies - pathology; United States > US; Puget Sound; Tacrolimus; pTDP; Calcineurin; TDP-43; Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; FK506; TARDBP
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-016-1600-y

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.