title: The phosphatase calcineurin regulates pathological TDP-43 phosphorylation.
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.
authors.affiliation: Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.|Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104, USA.
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Liachko
authors.affiliation: Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.
authors.forename: Aleen D
authors.initials: AD
authors.lastname: Saxton
authors.affiliation: Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.|Mental Illness Research Education and Clinical Centers, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.|Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McMillan
authors.affiliation: Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Strovas
authors.affiliation: Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.
authors.forename: Heather N
authors.initials: HN
authors.lastname: Currey
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Taylor
authors.affiliation: Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.
authors.forename: Jeanna M
authors.initials: JM
authors.lastname: Wheeler
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Oblak
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, 98195, USA.|Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, 94305, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, 98195, USA.
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.affiliation: Mental Illness Research Education and Clinical Centers, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.|Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Murray A
authors.initials: MA
authors.lastname: Raskind
authors.affiliation: Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.|Department of Neurology, University of Washington, Seattle, WA, 98195, USA.|Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, 98104, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.affiliation: Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA. kraemerb@u.washington.edu.|Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104, USA. kraemerb@u.washington.edu.|Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA. kraemerb@u.washington.edu.|Department of Pathology, University of Washington, Seattle, WA, 98195, USA. kraemerb@u.washington.edu.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Kraemer
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D017173:Caenorhabditis elegans; D019703:Calcineurin / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D002479:Inclusion Bodies / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D057177:TDP-43 Proteinopathies / Q000378:metabolism* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C120817:calcineurin phosphatase; D019703:Calcineurin; D010744:Phosphoric Monoester Hydrolases
keywords: Amyotrophic lateral sclerosis; Calcineurin; FK506; Frontotemporal lobar degeneration; TARDBP; TDP-43; Tacrolimus; pTDP