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The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

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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.

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References

  1. Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R, Graff-Radford NR, Hutton ML, Dickson DW (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445. doi:10.1002/ana.21154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611. doi:10.1016/j.bbrc.2006.10.093

    Article  CAS  PubMed  Google Scholar 

  3. Ayala YM, Zago P, D’Ambrogio A, Xu YF, Petrucelli L, Buratti E, Baralle FE (2008) Structural determinants of the cellular localization and shuttling of TDP-43. J Cell Sci 121:3778–3785. doi:10.1242/jcs.038950

    Article  CAS  PubMed  Google Scholar 

  4. Bandyopadhyay J, Lee J, Lee JI, Yu JR, Jee C, Cho JH, Jung S, Lee MH, Zannoni S, Singson A, Kim DH, Koo HS, Ahnn J (2002) Calcineurin, a calcium/calmodulin-dependent protein phosphatase, is involved in movement, fertility, egg laying, and growth in Caenorhabditis elegans. Mol Biol Cell 13:3281–3293. doi:10.1091/mbc.E02-01-0005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Baumgärtel K, Mansuy IM (2012) Neural functions of calcineurin in synaptic plasticity and memory. Learn Mem 19:375–384. doi:10.1101/lm.027201.112

    Article  PubMed  Google Scholar 

  6. Bolsover SR (2005) Calcium signalling in growth cone migration. Cell Calcium 37:395–402. doi:10.1016/j.ceca.2005.01.007

    Article  CAS  PubMed  Google Scholar 

  7. Brady OA, Meng P, Zheng Y, Mao Y, Hu F (2011) Regulation of TDP-43 aggregation by phosphorylation and p62/SQSTM1. J Neurochem 116:248–259. doi:10.1111/j.1471-4159.2010.07098.x

    Article  CAS  PubMed  Google Scholar 

  8. Che MX, Jiang LL, Li HY, Jiang YJ, Hu HY (2015) TDP-35 sequesters TDP-43 into cytoplasmic inclusions through binding with RNA. FEBS Lett 589:1920–1928. doi:10.1016/j.febslet.2015.06.009

    Article  CAS  PubMed  Google Scholar 

  9. Che MX, Jiang YJ, Xie YY, Jiang LL, Hu HY (2011) Aggregation of the 35-kDa fragment of TDP-43 causes formation of cytoplasmic inclusions and alteration of RNA processing. FASEB J 25:2344–2353. doi:10.1096/fj.10-174482

    Article  CAS  PubMed  Google Scholar 

  10. Cohen TJ, Hwang AW, Restrepo CR, Yuan CX, Trojanowski JQ, Lee VM (2015) An acetylation switch controls TDP-43 function and aggregation propensity. Nat Commun 6:5845. doi:10.1038/ncomms6845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. De Conti L, Akinyi MV, Mendoza-Maldonado R, Romano M, Baralle M, Buratti E (2015) TDP-43 affects splicing profiles and isoform production of genes involved in the apoptotic and mitotic cellular pathways. Nucleic Acids Res 43:8990–9005. doi:10.1093/nar/gkv814

    Article  PubMed  PubMed Central  Google Scholar 

  12. DiMartini A, Fontes P, Dew MA, Lotrich FE, de Vera M (2008) Age, model for end-stage liver disease score, and organ functioning predict posttransplant tacrolimus neurotoxicity. Liver Transpl 14:815–822. doi:10.1002/lt.21427

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ferri A, Nencini M, Battistini S, Giannini F, Siciliano G, Casali C, Damiano MG, Ceroni M, Chiò A, Rotilio G, Carrì MT (2004) Activity of protein phosphatase calcineurin is decreased in sporadic and familial amyotrophic lateral sclerosispatients. J Neurochem 90:1237–1242. doi:10.1111/j.1471-4159.2004.02588.x

    Article  CAS  PubMed  Google Scholar 

  14. Fiesel FC, Weber SS, Supper J, Zell A, Kahle PJ (2012) TDP-43 regulates global translational yield by splicing of exon junction complex component SKAR. Nucleic Acids Res 40:2668–2682. doi:10.1093/nar/gkr1082

    Article  CAS  PubMed  Google Scholar 

  15. Fujishiro H, Uchikado H, Arai T, Hasegawa M, Akiyama H, Yokota O, Tsuchiya K, Togo T, Iseki E, Hirayasu Y (2009) Accumulation of phosphorylated TDP-43 in brains of patients with argyrophilic grain disease. Acta Neuropathol 117:151–158. doi:10.1007/s00401-008-0463-2

    Article  CAS  PubMed  Google Scholar 

  16. Glass JD (2013) Immunosuppression in amyotrophic lateral sclerosis (ALS) (NIPALS2013). In: ClinicalTrials.gov, p NCT01884571

  17. Guthrie CR, Schellenberg GD, Kraemer BC (2009) SUT-2 potentiates tau-induced neurotoxicity in Caenorhabditis elegans. Hum Mol Genet 18:1825–1838. doi:10.1093/hmg/ddp099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hasegawa M, Arai T, Nonaka T, Kametani F, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle F, Morita M, Nakano I, Oda T, Tsuchiya K, Akiyama H (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 64:60–70. doi:10.1002/ana.21425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Higashi S, Iseki E, Yamamoto R, Minegishi M, Hino H, Fujisawa K, Togo T, Katsuse O, Uchikado H, Furukawa Y, Kosaka K, Arai H (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184:284–294. doi:10.1016/j.brainres.2007.09.048

    Article  CAS  PubMed  Google Scholar 

  20. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8:1–13. doi:10.1016/j.jalz.2011.10.007

    Article  PubMed  PubMed Central  Google Scholar 

  21. Iguchi Y, Katsuno M, Takagi S, Ishigaki S, Niwa J, Hasegawa M, Tanaka F, Sobue G (2012) Oxidative stress induced by glutathione depletion reproduces pathological modifications of TDP-43 linked to TDP-43 proteinopathies. Neurobiol Dis 45:862–870. doi:10.1016/j.nbd.2011.12.002

    Article  CAS  PubMed  Google Scholar 

  22. Inukai Y, Nonaka T, Arai T, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle FE, Akiyama H, Hisanaga S, Hasegawa M (2008) Abnormal phosphorylation of Ser409/410 of TDP-43 in FTLD-U and ALS. FEBS Lett 582:2899–2904. doi:10.1016/j.febslet.2008.07.027

    Article  CAS  PubMed  Google Scholar 

  23. Josephs KA, Whitwell JL, Knopman DS, Hu WT, Stroh DA, Baker M, Rademakers R, Boeve BF, Parisi JE, Smith GE, Ivnik RJ, Petersen RC, Jack CR Jr, Dickson DW (2008) Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology. doi:10.1212/01.wnl.0000304041.09418.b1

    Google Scholar 

  24. Josephs KA, Whitwell JL, Weigand SD, Murray ME, Tosakulwong N, Liesinger AM, Petrucelli L, Senjem ML, Knopman DS, Boeve BF, Ivnik RJ, Smith GE, Jack CR, Parisi JE, Petersen RC, Dickson DW (2014) TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol 127:811–824. doi:10.1007/s00401-014-1269-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, Pradat PF, Camu W, Meininger V, Dupre N, Rouleau GA (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574. doi:10.1038/ng.132

    Article  CAS  PubMed  Google Scholar 

  26. Kabuta C, Kono K, Wada K, Kabuta T (2015) 4-Hydroxynonenal induces persistent insolubilization of TDP-43 and alters its intracellular localization. Biochem Biophys Res Commun 463:82–87. doi:10.1016/j.bbrc.2015.05.027

    Article  CAS  PubMed  Google Scholar 

  27. Kim SH, Shanware NP, Bowler MJ, Tibbetts RS (2010) Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA. J Biol Chem 285:34097–34105. doi:10.1074/jbc.M110.154831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. King MM, Huang CY (1983) Activation of calcineurin by nickel ions. Biochem Biophys Res Commun 114:955–961

    Article  CAS  PubMed  Google Scholar 

  29. Klee CB, Crouch TH, Krinks MH (1979) Calcineurin: a calcium- and calmodulin-binding protein of the nervous system. Proc Natl Acad Sci USA 76:6270–6273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kuhara A, Inada H, Katsura I, Mori I (2002) Negative regulation and gain control of sensory neurons by the C. elegans calcineurin TAX-6. Neuron 33:751–763

    Article  CAS  PubMed  Google Scholar 

  31. Kuhnlein P, Sperfeld AD, Vanmassenhove B, Van Deerlin V, Lee VM, Trojanowski JQ, Kretzschmar HA, Ludolph AC, Neumann M (2008) Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations. Arch Neurol 65:1185–1189. doi:10.1001/archneur.65.9.1185

    Article  PubMed  PubMed Central  Google Scholar 

  32. Liachko NF, Guthrie CR, Kraemer BC (2010) Phosphorylation promotes neurotoxicity in a Caenorhabditis elegans model of TDP-43 proteinopathy. J Neurosci 30:16208–16219. doi:10.1523/JNEUROSCI.2911-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liachko NF, McMillan PJ, Guthrie CR, Bird TD, Leverenz JB, Kraemer BC (2013) CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration. Ann Neurol 74:39–52. doi:10.1002/ana.23870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liachko NF, McMillan PJ, Strovas TJ, Loomis E, Greenup L, Murrell JR, Ghetti B, Raskind MA, Montine TJ, Bird TD, Leverenz JB, Kraemer BC (2014) The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43. PLoS Genet 10:e1004803. doi:10.1371/journal.pgen.1004803

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ling H, Holton JL, Lees AJ, Revesz T (2014) TDP-43 pathology is present in most post-encephalitic parkinsonism brains. Neuropathol Appl Neurobiol 40:654–657. doi:10.1111/nan.12067

    Article  PubMed  Google Scholar 

  36. Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66:807–815

    Article  CAS  PubMed  Google Scholar 

  37. Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113. doi:10.1007/s00401-011-0845-8

    Article  PubMed  PubMed Central  Google Scholar 

  38. Masuda S, Inui K (2006) An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients. Pharmacol Ther 112:184–198. doi:10.1016/j.pharmthera.2006.04.006

    Article  CAS  PubMed  Google Scholar 

  39. McIntire SL, Reimer RJ, Schuske K, Edwards RH, Jorgensen EM (1997) Identification and characterization of the vesicular GABA transporter. Nature 389:870–876. doi:10.1038/39908

    Article  CAS  PubMed  Google Scholar 

  40. McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, Perl DP, Hedley-Whyte ET, Price B, Sullivan C, Morin P, Lee HS, Kubilus CA, Daneshvar DH, Wulff M, Budson AE (2010) TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 69:918–929. doi:10.1097/NEN.0b013e3181ee7d85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV, Hyman BT, Aging NIo, Association As (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11. doi:10.1007/s00401-011-0910-3

    Article  CAS  PubMed  Google Scholar 

  42. Morioka M, Hamada J, Ushio Y, Miyamoto E (1999) Potential role of calcineurin for brain ischemia and traumatic injury. Prog Neurobiol 58:1–30

    Article  CAS  PubMed  Google Scholar 

  43. Muramatsu T, Kincaid RL (1992) Molecular cloning and chromosomal mapping of the human gene for the testis-specific catalytic subunit of calmodulin-dependent protein phosphatase (calcineurin A). Biochem Biophys Res Commun 188:265–271

    Article  CAS  PubMed  Google Scholar 

  44. Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE, Arnold SE, Siderowf A, Grossman M, Leverenz JB, Woltjer R, Lopez OL, Hamilton R, Tsuang DW, Galasko D, Masliah E, Kaye J, Clark CM, Montine TJ, Lee VM, Trojanowski JQ (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229. doi:10.1007/s00401-007-0261-2

    Article  CAS  PubMed  Google Scholar 

  45. Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y, Forman MS, Troost D, Kretzschmar HA, Trojanowski JQ, Lee VM (2009) Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117:137–149. doi:10.1007/s00401-008-0477-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. doi:10.1126/science.1134108

    Article  CAS  PubMed  Google Scholar 

  47. Ng AS, Rademakers R, Miller BL (2015) Frontotemporal dementia: a bridge between dementia and neuromuscular disease. Ann N Y Acad Sci 1338:71–93. doi:10.1111/nyas.12638

    Article  CAS  PubMed  Google Scholar 

  48. Pallen CJ, Wang JH (1984) Regulation of calcineurin by metal ions. Mechanism of activation by Ni2+ and an enhanced response to Ca2+/calmodulin. J Biol Chem 259:6134–6141

    CAS  PubMed  Google Scholar 

  49. Polli JW, Billingsley ML, Kincaid RL (1991) Expression of the calmodulin-dependent protein phosphatase, calcineurin, in rat brain: developmental patterns and the role of nigrostriatal innervation. Brain Res Dev Brain Res 63:105–119

    Article  CAS  PubMed  Google Scholar 

  50. Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ, Sreedharan J, Vance C, Sorenson E, Lippa C, Bigio EH, Geschwind DH, Knopman DS, Mitsumoto H, Petersen RC, Cashman NR, Hutton M, Shaw CE, Boylan KB, Boeve B, Graff-Radford NR, Wszolek ZK, Caselli RJ, Dickson DW, Mackenzie IR, Petrucelli L, Rademakers R (2008) Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet 4:e1000193. doi:10.1371/journal.pgen.1000193

    Article  PubMed  PubMed Central  Google Scholar 

  51. Savoia CP, Liu QH, Zheng YM, Yadav V, Zhang Z, Wu LG, Wang YX (2014) Calcineurin upregulates local Ca(2 +) signaling through ryanodine receptor-1 in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 307:L781–L790. doi:10.1152/ajplung.00149.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Schwab C, Arai T, Hasegawa M, Yu S, McGeer PL (2008) Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease. J Neuropathol Exp Neurol 67:1159–1165. doi:10.1097/NEN.0b013e31818e8951

    Article  PubMed  Google Scholar 

  53. Seyfried NT, Gozal YM, Dammer EB, Xia Q, Duong DM, Cheng D, Lah JJ, Levey AI, Peng J (2010) Multiplex SILAC analysis of a cellular TDP-43 proteinopathy model reveals protein inclusions associated with SUMOylation and diverse polyubiquitin chains. Mol Cell Proteomics 9:705–718. doi:10.1074/mcp.M800390-MCP200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shibasaki F, Hallin U, Uchino H (2002) Calcineurin as a multifunctional regulator. J Biochem 131:1–15

    Article  CAS  PubMed  Google Scholar 

  55. Shiga A, Ishihara T, Miyashita A, Kuwabara M, Kato T, Watanabe N, Yamahira A, Kondo C, Yokoseki A, Takahashi M, Kuwano R, Kakita A, Nishizawa M, Takahashi H, Onodera O (2012) Alteration of POLDIP3 splicing associated with loss of function of TDP-43 in tissues affected with ALS. PLoS One 7:e43120. doi:10.1371/journal.pone.0043120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672. doi:10.1126/science.1154584

    Article  CAS  PubMed  Google Scholar 

  57. Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, Miller BL, Kretzschmar HA, Lee VM, Trojanowski JQ, Neumann M (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67:555–564. doi:10.1097/NEN.0b013e31817713b5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, Clay D, Wood EM, Chen-Plotkin AS, Martinez-Lage M, Steinbart E, McCluskey L, Grossman M, Neumann M, Wu IL, Yang WS, Kalb R, Galasko DR, Montine TJ, Trojanowski JQ, Lee VM, Schellenberg GD, Yu CE (2008) TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 7:409–416. doi:10.1016/S1474-4422(08)70071-1

    Article  PubMed  PubMed Central  Google Scholar 

  59. Wilson RS, Yu L, Trojanowski JQ, Chen EY, Boyle PA, Bennett DA, Schneider JA (2013) TDP-43 pathology, cognitive decline, and dementia in old age. JAMA Neurol 70:1418–1424. doi:10.1001/jamaneurol.2013.3961

    Article  PubMed  Google Scholar 

  60. Wu Q, Marescaux C, Wolff V, Jeung MY, Kessler R, Lauer V, Chen Y (2010) Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation. Eur Neurol 64:169–177. doi:10.1159/000319032

    Article  CAS  PubMed  Google Scholar 

  61. Yokota O, Davidson Y, Bigio EH, Ishizu H, Terada S, Arai T, Hasegawa M, Akiyama H, Sikkink S, Pickering-Brown S, Mann DM (2010) Phosphorylated TDP-43 pathology and hippocampal sclerosis in progressive supranuclear palsy. Acta Neuropathol 120:55–66. doi:10.1007/s00401-010-0702-1

    Article  PubMed  PubMed Central  Google Scholar 

  62. Zhang YJ, Gendron TF, Xu YF, Ko LW, Yen SH, Petrucelli L (2010) Phosphorylation regulates proteasomal-mediated degradation and solubility of TAR DNA binding protein-43 C-terminal fragments. Mol Neurodegener 5:33. doi:10.1186/1750-1326-5-33

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank the reviewers for helpful comments and suggestions. We thank Michael Gitcho for constructive discussion about calcineurin and TDP-43. We thank Elaine Loomis, John Kushleika, Kaili Chickering, Susan Danner, and Samantha Rice for outstanding technical assistance and Allison Beller for outstanding administrative support. We thank Virginia Lee and Manuela Neumann for antibodies and the Developmental Studies Hybridoma Bank (NICHD) for the β-tubulin antibody E7. We thank WormBase (WS251) for C. elegans genetic information. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440), and other strains were provided by the National Bioresource Project (Japan). 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 and P50AG05136 for T. J. M. and C. D. K. for the UW ADRC for A. L. O and B. G.].

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Authors and Affiliations

  1. Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA

    Nicole F. Liachko, Aleen D. Saxton, Pamela J. McMillan, Timothy J. Strovas, Heather N. Currey, Jeanna M. Wheeler, Thomas D. Bird & Brian C. Kraemer

  2. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104, USA

    Nicole F. Liachko, Laura M. Taylor & Brian C. Kraemer

  3. Mental Illness Research Education and Clinical Centers, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA

    Pamela J. McMillan & Murray A. Raskind

  4. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA

    Pamela J. McMillan, Murray A. Raskind & Brian C. Kraemer

  5. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Adrian L. Oblak & Bernardino Ghetti

  6. Department of Pathology, University of Washington, Seattle, WA, 98195, USA

    Thomas J. Montine, C. Dirk Keene & Brian C. Kraemer

  7. Department of Neurology, University of Washington, Seattle, WA, 98195, USA

    Thomas D. Bird

  8. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, 98104, USA

    Thomas D. Bird

  9. Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, 94305, USA

    Thomas J. Montine

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  1. Nicole F. Liachko
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Liachko, N.F., Saxton, A.D., McMillan, P.J. et al. The phosphatase calcineurin regulates pathological TDP-43 phosphorylation. Acta Neuropathol 132, 545–561 (2016). https://doi.org/10.1007/s00401-016-1600-y

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  • DOI: https://doi.org/10.1007/s00401-016-1600-y

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