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Emerging roles of 14-3-3γ in the brain disorder

  • Cho, Eunsil (School of Biosystem and Biomedical Science, College of Health Science, Korea University) ;
  • Park, Jae-Yong (School of Biosystem and Biomedical Science, College of Health Science, Korea University)
  • Received : 2020.07.16
  • Published : 2020.10.31
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Abstract

14-3-3 proteins are mostly expressed in the brain and are closely involved in numerous brain functions and various brain disorders. Among the isotypes of the 14-3-3 proteins, 14-3-3γ is mainly expressed in neurons and is highly produced during brain development, which could indicate that it has a significance in neural development. Furthermore, the distinctive levels of temporally and locally regulated 14-3-3γ expression in various brain disorders suggest that it could play a substantial role in brain plasticity of the diseased states. In this review, we introduce the various brain disorders reported to be involved with 14-3-3γ, and summarize the changes of 14-3-3γ expression in each brain disease. We also discuss the potential of 14-3-3γ for treatment and the importance of research on specific 14-3-3 isotypes for an effective therapeutic approach.

Keywords

References

  1. Moore BE and Perez VJ (1967) Specific acidic proteins of the nervous system. Physiological and Biochemical aspects of Nervous integration. A symposium, Prentice Hall, Englewood Cliffs, NJ. 343-359
  2. Ichimura T, Isobe T, Okuyama T et al (1987) Brain 14-3-3 protein is an activator protein that activates tryptophan 5-monooxygenase and tyrosine 3-monooxygenase in the presence of Ca2+,calmodulindependent protein kinase II. FEBS Letts 219, 79-82 https://doi.org/10.1016/0014-5793(87)81194-8
  3. Jones DH, Ley S and Aitken A (1995) Isoforms of 14-3-3 protein can form homo- and heterodimers in vivo and in vitro: implications for function as adapter proteins. FEBS Lett 368, 55-58 https://doi.org/10.1016/0014-5793(95)00598-4
  4. Jin J, Smith FD, Stark C et al (2004) Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. Curr Biol 14, 1436-1450 https://doi.org/10.1016/j.cub.2004.07.051
  5. Darling DL, Yingling J and Wynshaw-Boris A (2005) Role of 14-3-3 Proteins in Eukaryotic Signaling and Development. Curr Top Dev Biol 68, 281-315 https://doi.org/10.1016/S0070-2153(05)68010-6
  6. Wang W and Shakes DC (1996) Molecular evolution of the 14-3-3 protein family. J Mol Evol 43, 384-398 https://doi.org/10.1007/BF02339012
  7. Rosenquist M, Alsterfjord M, Larsson C and Sommarin M (2001) Data mining the arabidopsis genome reveals fifteen 14-3-3 genes. Expression is demonstrated for two out of five novel genes. Plant Physiol 127, 142-149 https://doi.org/10.1104/pp.127.1.142
  8. Su TT, Parry DH, Donahoe B, Chien CT, O'Farrell PH and Purdy A (2001) Cell cycle roles for two 14-3-3 proteins during drosophila development. J Cell Sci 114, 3445-3454 https://doi.org/10.1242/jcs.114.19.3445
  9. Aitken A, Howell S, Jones D, Madrazo J and Patel Y (1995) 14-3-3 alpha and delta are the phosphorylated forms of Raf-activating 14-3-3 beta and zeta. J Biol Chem 270, 5706-5709 https://doi.org/10.1074/jbc.270.11.5706
  10. Dougherty MK and Morrison DK (2004) Unlocking the code of 14-3-3. J Cell Sci 117, 1875-1884 https://doi.org/10.1242/jcs.01171
  11. van Heusden GP (2005) 14-3-3 proteins: regulators of numerous eukaryotic proteins. IUBMB Life 57, 623-629 https://doi.org/10.1080/15216540500252666
  12. Bridges D and Moorhead GB (2004) 14-3-3 proteins: a number of functions for a numbered protein. Sci STKE 296, re10
  13. Sluchanko NN and Gusev NB (2017) Moonlighting chaperone-like activity of the universal regulatory 14-3-3 proteins. FEBS J 284, 1279-1295 https://doi.org/10.1111/febs.13986
  14. Fan X, Cui L, Zeng Y et al (2019) 14-3-3 proteins are on the crossroads of cancer, aging, and age-related neurodegenerative disease. Int J Mol Sci 20, 3518 https://doi.org/10.3390/ijms20143518
  15. Muslin AJ and Xing H (2000) 14-3-3 proteins: regulation of subcellular localization by molecular interference. Cell Signal 12, 703-709 https://doi.org/10.1016/S0898-6568(00)00131-5
  16. Obsil T and Obsilova V (2011) Structural basis of 14-3-3 protein functions. Semin Cell Dev Biol 22, 663-672 https://doi.org/10.1016/j.semcdb.2011.09.001
  17. Fu H, Subramanian RR and Masters SC (2000) 14-3-3 proteins: structure, function, and regulation. Annu Rev Pharmacol Toxicol 40, 617-647 https://doi.org/10.1146/annurev.pharmtox.40.1.617
  18. Yaffe MB, Volinia S, Caron PR et al (1997) The Structural basis for 14-3-3: phosphopeptide Binding Specificity. Cell 91, 961-971 https://doi.org/10.1016/S0092-8674(00)80487-0
  19. Wilker EW, Grant RA, Artim SC and Yaffe MB (2005) 14-3-3 proteins: a family of versatile molecular regulators. J Biol Chem 280, 18891-18898 https://doi.org/10.1074/jbc.M500982200
  20. Chaudhri M, Scarabel M and Aitken A (2003) Mammalian and yeast 14-3-3 isoforms form distinct patterns of dimers in vivo. Biochem Biophys Res Commun 300, 679-685 https://doi.org/10.1016/S0006-291X(02)02902-9
  21. Gardino AK, Smerdon SJ and Yaffe MB (2006) Structural determinants of 14-3-3 binding specificities and regulation of subcellular localization of 14-3-3-ligand complexes: a comparison of the X-ray crystal structures of all human 14-3-3 isoforms. Semin Cancer Biol 16, 173-182 https://doi.org/10.1016/j.semcancer.2006.03.007
  22. Yang X, Lee WH, Sobott F et al (2006) Structural basis for protein-protein interactions in the 14-3-3 protein family. Proc Natl Acad Sci U S A 103, 17237-17242 https://doi.org/10.1073/pnas.0605779103
  23. Tzivion G, Luo Z and Avruch J (1998) A Dimeric 14-3-3 protein is an essential cofactor for Raf Kinase Activity. Nature 394, 88-92 https://doi.org/10.1038/27938
  24. Zhou Y, Reddy S, Murrey H, Fei H and Levitan IB (2003) Monomeric 14-3-3 protein is sufficient to modulate the activity of the drosophila slowpoke calcium-dependent potassium channel. J Biol Chem 278, 10073-10080 https://doi.org/10.1074/jbc.M211907200
  25. Xiao B, Smerdon SJ, Jones DH et al (1995) Structure of a 14-3-3 protein and implications for coordination of multiple signalling pathways. Nature 376, 188-191 https://doi.org/10.1038/376188a0
  26. Liu D, Bienkowska J, Petosa C, Collier RJ, Fu H and Liddington R (1995) Crystal structure of the zeta isoform of the 14-3-3 protein. Nature 376, 191-194 https://doi.org/10.1038/376191a0
  27. Rittinger K, Budman J, Xu J et al (1999) Structural analysis of 14-3-3 phosphopeptide complexes identifies a dual role for the nuclear export signal of 14-3-3 in ligand binding. Mol Cell 4, 153-166 https://doi.org/10.1016/S1097-2765(00)80363-9
  28. Coblitz B, Shikano S, Wu M et al (2005) C-terminal recognition by 14-3-3 proteins for surface expression of membrane receptors. J Biol Chem 280, 36263-36272 https://doi.org/10.1074/jbc.M507559200
  29. Coblitz B, Wu M, Shikano S and Li M (2006) C-terminal binding: an expanded repertoire and function of 14-3-3 proteins. FEBS Lett 580, 1531-1535 https://doi.org/10.1016/j.febslet.2006.02.014
  30. Petosa C, Masters SC, Bankston LA et al (1998) 14-3-3zeta binds a phosphorylated Raf peptide and an unphosphorylated peptide via its conserved amphipathic groove. J Biol Chem 273, 16305-16310 https://doi.org/10.1074/jbc.273.26.16305
  31. Masters SC, Pederson KJ, Zhang L, Barbieri JT and Fu H (1999) Interaction of 14-3-3 with a nonphosphorylated protein ligand, exoenzyme S of Pseudomonas aeruginosa. Biochemistry 38, 5216-5221 https://doi.org/10.1021/bi982492m
  32. Zhai J, Lin H, Shamim M, Schlaepfer WW and Canete-Soler R (2001) Identification of a novel interaction of 14-3-3 with p190RhoGEF. J Biol Chem 276, 41318-41324 https://doi.org/10.1074/jbc.M107709200
  33. Wang B, Yang H, Liu Y et al (1999) Isolation of high-affinity peptide antagonists of 14-3-3 proteins by phage display. Biochemistry 38, 12499-12504 https://doi.org/10.1021/bi991353h
  34. Aitken A, Baxter H, Dubois T et al (2002) Specificity of 14-3-3 isoform dimer interactions and phosphorylation. Biochem Soc Trans 30, 351-360 https://doi.org/10.1042/bst0300351
  35. Aitken A (2011) Post-translational modification of 14-3-3 isoforms and regulation of cellular function. Semin Cell Dev Biol 22, 673-680 https://doi.org/10.1016/j.semcdb.2011.08.003
  36. Truong AB, Masters SC, Yang H and Fu H (2002) Role of the 14-3-3 C-terminal loop in ligand interaction. Proteins 49, 321-325 https://doi.org/10.1002/prot.10210
  37. Silhan J, Obsilova V, Vecer J et al (2004) 14-3-3 protein C-terminal stretch occupies ligand binding groove and is displaced by phosphopeptide binding. J Biol Chem 279, 49113-49119 https://doi.org/10.1074/jbc.M408671200
  38. Pennington KL, Chan TY, Torres MP and Andersen JL (2018) The Dynamic and stress-adaptive signaling hub of 14-3-3: Emerging mechanisms of regulation and contextdependent protein-protein interactions. Oncogene 37, 5587-5604 https://doi.org/10.1038/s41388-018-0348-3
  39. Boston PF, Jackson P, Kynoch PA and Thompson RJ (1982) Human 14-3-3 protein: radioimmunoassay, tissue distribution, and cerebrospinal fluid levels in patients with neurological disorders. J Neurochem 38, 1466-1474 https://doi.org/10.1111/j.1471-4159.1982.tb07927.x
  40. Aghazadeh V and Papadopoulos Y (2016) The role of the 14-3-3 protein family in health, disease, and drug development. Drug Discov Today 21, 278-287 https://doi.org/10.1016/j.drudis.2015.09.012
  41. Leffers H, Madsen P, Rasmussen HH et al (1993) Molecular cloning and expression of the transformation sensitive epithelial marker stratifin. A member of a protein family that has been involved in the protein kinase C signalling pathway. J Mol Biol 231, 982-998 https://doi.org/10.1006/jmbi.1993.1346
  42. Watanabe M, Isobe T, Ichimura T, Kuwano R, Takahashi Y and Kondo H (1993) Molecular cloning of rat cDNAs for beta and gamma subtypes of 14-3-3 protein and developmental changes in expression of their mRNAs in the nervous system. Brain Res Mol Brain Res 17, 135-146 https://doi.org/10.1016/0169-328X(93)90082-Z
  43. Xiong XX, Hu DX, Xu L et al (2019) Selective $14-3-3{\gamma}$ upregulation promotes Beclin-1-LC3-Autophagic Influx via ${\beta}$-catenin interaction in starved neurons in vitro and in vivo. Neurochem Res 44, 849-858 https://doi.org/10.1007/s11064-019-02717-4
  44. Gerber KJ, Squires KE and Hepler JR (2018) $14-3-3{\gamma}$ binds regulator of G protein signaling 14 (RGS14) at distinct sites to inhibit the RGS14:$G{\alpha}_{i}-AIF_{4}^{-}$ signaling complex and RGS14 nuclear localization. J Biol Chem 293, 14616-14631 https://doi.org/10.1074/jbc.RA118.002816
  45. Civiero L, Cogo S, Kiekens A et al (2017) PAK6 Phosphorylates $14-3-3{\gamma}$ to Regulate Steady State Phosphorylation of LRRK2. Front Mol Neurosci 10, 417 https://doi.org/10.3389/fnmol.2017.00417
  46. Lee YS, Lee JK, Bae Y et al (2016) Suppression of $14-3-3{\gamma}$-mediated surface expression of ANO1 inhibits cancer progression of glioblastoma cells. Sci Rep 6, 26413 https://doi.org/10.1038/srep26413
  47. Oh SJ, Woo J, Lee YS et al (2016) Direct interaction with $14-3-3{\gamma}$ promotes surface expression of Best1 channel in astrocyte. Mol Brain 10, 51
  48. Cho CH, Kim E, Lee YS et al (2014) Depletion of $14-3-3{\gamma}$ reduces the surface expression of Transient Receptor Potential Melastatin 4b (TRPM4b) channels and attenuates TRPM4b-mediated glutamate-induced neuronal cell death. Mol Brain 7, 52 https://doi.org/10.1186/s13041-014-0052-3
  49. Cornell B and Toyo-Oka K (2017) 14-3-3 proteins in brain development: neurogenesis, neuronal migration and neuromorphogenesis. Front Mol Neurosci 10, 318 https://doi.org/10.3389/fnmol.2017.00318
  50. Wachi T, Cornell B, Marshall C, Zhukarev V, Baas PW and Toyo-oka K (2016) Ablation of the 14-3-3gamma protein results in neuronal migration delay and morphological defects in the developing cerebral cortex. Dev Neurobiol 76, 600-614 https://doi.org/10.1002/dneu.22335
  51. JC Yoo, N Park, B Lee et al (2017) $14-3-3{\gamma}$ regulates Copine1-mediated neuronal differentiation in HiB5 hippocampal progenitor cells. Exp Cell Res 356, 85-92 https://doi.org/10.1016/j.yexcr.2017.04.015
  52. Cornell B, Wachi T, Zhukarev V and Toyo-Oka K (2016) Overexpression of the $14-3-3{\gamma}$ protein in embryonic mice results in neuronal migration delay in the developing cerebral cortex. Neurosci Lett 628, 40-46 https://doi.org/10.1016/j.neulet.2016.06.009
  53. Hillier L, Fulton R, Fulton L et al (2003) The DNA sequence of chromosome 7. Nature 424, 157-164 https://doi.org/10.1038/nature01782
  54. Ramocki MB, Bartnik M, Szafranski P et al (2010) Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual disabilities, epilepsy, and neurobehavioral problems. Am J Hum Genet 87, 857-865 https://doi.org/10.1016/j.ajhg.2010.10.019
  55. Fusco C, Micale L, Augello B et al (2014) Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits. Eur J Hum Genet 22, 64-70 https://doi.org/10.1038/ejhg.2013.101
  56. Nicita F, Garone G, Spalice A et al (2016) Epilepsy is a possible feature in Williams-Beuren syndrome patients harboring typical deletions of the 7q11.23 critical region. Am J Med Genet A 170A, 148-155
  57. Morris CM, Mervis CB, Paciorkowski AP et al (2015) Osborne 7q11.23 duplication syndrome: physical characteristics and natural history. Am J Med Genet A 167A, 2916-2935
  58. Schindler CK, Heverin M and Henshall DC (2016) Isoform- and subcellular fraction-specific differences in hippocampal 14-3-3 levels following experimentally evoked seizures and in human temporal lobe epilepsy. J Neurochem 99, 561-569 https://doi.org/10.1111/j.1471-4159.2006.04153.x
  59. Smani D, Sarkar S, Raymick J, Kanungo J, Paule MG and Gu Q (2018) Downregulation of 14-3-3 proteins in a kainic acid-induced neurotoxicity model. Mol Neurobiol 55, 122-129 https://doi.org/10.1007/s12035-017-0724-y
  60. Guella I, McKenzie MB, Evans DM et al (2017) De Novo mutations in YWHAG cause early-onset epilepsy. Am J Hum Genet 101, 300-310 https://doi.org/10.1016/j.ajhg.2017.07.004
  61. Bull MJ (2020) Down syndrome. N Engl J Med 382, 2344-2352 https://doi.org/10.1056/NEJMra1706537
  62. Fountoulakis M, Cairns N and Lubec G (1999) Increased levels of $14-3-3{\gamma}$ and ${\varepsilon}$ proteins in brain of patients with Alzheimer's disease and Down syndrome. J Neural Transm Suppl 57, 323-335
  63. Peyril A, Weitzdoerfer R, Gulesserian T, Fountoulakis M and Lubec G (2002) Aberrant expression of signalingrelated proteins $14-3-3{\gamma}$ and RACK1 in fetal Down syndrome brain (trisomy 21). Electrophoresis 23, 152-157 https://doi.org/10.1002/1522-2683(200201)23:1<152::AID-ELPS152>3.0.CO;2-T
  64. Hughes AJ, Ben-Shlomo Y, Daniel SE and Lees AJ (1992) What features improve the accuracy of clinical diagnosis in Parkinson's disease: a clinicopathologic study. Neurology 42, 1142-1146 https://doi.org/10.1212/WNL.42.6.1142
  65. Chen H, Burton EA, Webster RG et al (2013) Research on the premotor symptoms of Parkinson's disease: clinical and etiological implications. Environ. Health Perspect 121, 11-12
  66. Sveinbjornsdottir S (2016) The clinical symptoms of Parkinson's disease. J Neurochemistry 139, 318-324 https://doi.org/10.1111/jnc.13691
  67. Jellinger KA (2009) Formation and development of Lewy pathology: a critical update. J Neurology 256, 270-279 https://doi.org/10.1007/s00415-009-5243-y
  68. Goedert M, Spillantini MG, Del Tredici K and Braak H (2013) 100 years of Lewy pathology. Nat Rev Neurol 9, 13-24 https://doi.org/10.1038/nrneurol.2012.242
  69. Wong YC and Krainc D (2017) ${\alpha}$-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med 23, 1-13 https://doi.org/10.1038/nm.4269
  70. Ostrerova N, Petrucelli L, Farrer M et al (1999) alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci 19, 5782-5791 https://doi.org/10.1523/JNEUROSCI.19-14-05782.1999
  71. Kawamoto Y, Akiguchi I, Nakamura S, Honjyo Y, Shibasaki H and Budka H (2002) 14-3-3 proteins in Lewy bodies in Parkinson disease and diffuse Lewy body disease brains. J Neuropathol Exp Neurol 61, 245-253 https://doi.org/10.1093/jnen/61.3.245
  72. Berg D, Riess O and Bornemann A (2003) Specification of 14-3-3 proteins in Lewy bodies. Ann Neurol 53, 135
  73. Yacoubian TA, Slone SR, Harrington AJ et al (2010) Differential neuroprotective effects of 14-3-3 proteins in models of Parkinson's disease. Death Dis 1, e2 https://doi.org/10.1038/cddis.2009.4
  74. Ding H, Underwood R, Lavalley N and Yacoubian TA (2015) 14-3-3 inhibition promotes dopaminergic neuron loss and $14-3-3{\theta}$ overexpression promotes recovery in the MPTP mouse model of Parkinson's disease. Neuroscience 307, 73-82 https://doi.org/10.1016/j.neuroscience.2015.08.042
  75. Xu Z, Graham K, Foote M et al (2013) 14-3-3 protein targets misfolded chaperone-associated proteins to aggresomes. J Cell Sci 126, 4173-4186 https://doi.org/10.1242/jcs.126102
  76. Jia B, Wu Y and Zhou Y (2014) 14-3-3 and aggresome formation: implications in neurodegenerative diseases. Prion 8, 173-177 https://doi.org/10.4161/pri.28123
  77. Plotegher N, Kumar D, Tessari I et al (2014) The chaperone-like protein $14-3-3{\eta}$ interacts with human ${\alpha}$-synuclein aggregation intermediates rerouting the amyloidogenic pathway and reducing ${\alpha}$-synuclein cellular toxicity. Hum Mol Genet 23, 5615-5629 https://doi.org/10.1093/hmg/ddu275
  78. Sato S, Chiba T, Sakata E et al (2006) 14-3-3eta is a novel regulator of parkin ubiquitin ligase. EMBO J 25, 211-221 https://doi.org/10.1038/sj.emboj.7600774
  79. Wang J, Lou H, Pedersen CJ, Smith AD and Perez RG (2009) 14-3-3zeta contributes to tyrosine hydroxylase activity in MN9D cells: localization of dopamine regulatory proteins to mitochondria. J Biol Chem 284, 14011-14019 https://doi.org/10.1074/jbc.M901310200
  80. Scheltens P, Blennow K, Breteler MM et al (2016) Alzheimer's disease. Lancet 388, 505-517 https://doi.org/10.1016/S0140-6736(15)01124-1
  81. Selkoe DJ and Hardy J (2016) The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 8, 595-608 https://doi.org/10.15252/emmm.201606210
  82. Iqbal K, Liu F, Gong CX and Grundke-Iqbal I (2010) Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 7, 656-664 https://doi.org/10.2174/156720510793611592
  83. Layfield R. Fergusson J, Aitken A, Lowe J, Landon M and Mayer RJ (1996) Neurofibrillary tangles of Alzheimer's disease brains contain 14-3-3 proteins. Neurosci Lett 209, 57-60 https://doi.org/10.1016/0304-3940(96)12598-2
  84. Fountoulakis M, Cairns N, Lubec G (1999) Increased levels of $14-3-3{\gamma}$ and ${\varepsilon}$ proteins in brain of patients with Alzheimer's disease and Down syndrome. J Neural Transm Suppl 57, 323-335
  85. Gu O, Cuevas E, Raymick J, Kanungo J and Sarkar S (2020) Downregulation of 14-3-3 proteins in Alzheimer's Disease. Mol Neurobiol 57, 32-40 https://doi.org/10.1007/s12035-019-01754-y
  86. National Institute of Neurological Disorders and Stroke (2003) Creutzfeldt-Jakob Disease Fact Sheet. NINDS. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Creutzfeldt-Jakob-Disease-Fact-Sheet
  87. Spero M and Lazibat I (2010) Creutzfeldt-Jakob disease: case report and review of the literature. Acta Clin Croat 49, 181-187
  88. Hsich G, Kenney K, Gibbs CJ, Lee KH and Harrington MG (1996) The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med 335, 24-30
  89. Zerr I, Bodemer M, Gefeller O et al (1998) Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease. Ann Neurol 43, 32-40 https://doi.org/10.1002/ana.410430109
  90. Lemstra AW, van Meegen MT, Vreyling JP et al (2000) 14-3-3 testing in diagnosing Creutzfeldt-Jakob disease: a prospective study in 112 patients. Neurology 55, 514-516 https://doi.org/10.1212/WNL.55.4.514
  91. Burkhard PR, Sanchez JC, Landis T, Hochstrasser DF et al (2001) CSF detection of the 14-3-3 protein in unselected patients with dementia. Neurology 56, 1528-1533 https://doi.org/10.1212/WNL.56.11.1528
  92. Wiltfang J, Otto M, Baxter HC et al (1999) Isoform pattern of 14-3-3 proteins in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. J Neurochem 73, 2485-2490 https://doi.org/10.1046/j.1471-4159.1999.0732485.x
  93. Shiga Y, Wakabayashi H, Miyazawa K, Kido H and Itoyama Y (2006) 14-3-3 protein levels and isoform patterns in the cerebrospinal fluid of Creutzfeldt-Jakob disease patients in the progressive and terminal stages. J Clin Neurosci 13, 661-665 https://doi.org/10.1016/j.jocn.2005.09.004
  94. Matsui Y, Satoh K, Miyazaki T et al (2011) High sensitivity of an ELISA kit for detection of the gammaisoform of 14-3-3 proteins: usefulness in laboratory diagnosis of human prion disease. BMC Neurol 11, 120 https://doi.org/10.1186/1471-2377-11-120
  95. Leitao MJ, Baldeiras I, Almeida MR et al (2016) Sporadic Creutzfeldt-Jakob disease diagnostic accuracy is improved by a new CSF ELISA $14-3-3{\gamma}$ assay. Neuroscience 322, 398-407 https://doi.org/10.1016/j.neuroscience.2016.02.057
  96. Kilani RT, Maksymowych WP, Aitken A et al (2007) Detection of high levels of 2 specific isoforms of 14-3-3 proteins in synovial fluid from patients with joint inflammation. J Rheumatol 34, 1650-1657
  97. Sardari K, Chavez-Munoz C, Kilani RT, Schiller T and Ghahary A (2011) Increased levels of the 14-3-3 ${\eta}$ and ${\gamma}$ proteins in the synovial fluid of dogs with unilateral cranial cruciate ligament rupture. Can J Vet Res 75, 271-277
  98. Lee D, Steinacker P, Seubert S et al (2015) Role of glial 14-3-3 gamma protein in autoimmune demyelination. J Neuroinflammation 6, 187
  99. Dendrou CA, Fugger L and Friese MA (2015) Immunopathology of multiple sclerosis. Nat Rev Immunol 15, 545-558 https://doi.org/10.1038/nri3871
  100. Nakahara J, Maeda M, Aiso S and Suzuki N (2012) Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy. Clin Rev Allergy Immunol 42, 26-34 https://doi.org/10.1007/s12016-011-8287-6
  101. Constantinescu CS, Farooqi N, O'Brien K, Gran B (2011) Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol 164, 1079-1106 https://doi.org/10.1111/j.1476-5381.2011.01302.x
  102. Pirim I (1998) Ischemic rat brains contain immunoreactivity of 14-3-3 proteins. Int J Neurosci 95, 101-106 https://doi.org/10.3109/00207459809000653
  103. Kawamoto Y, Akiguchi I, Tomimoto H, Shirakashi Y, Honjo Y and Budka H (2006) Upregulated expression of 14-3-3 proteins in astrocytes from human cerebrovascular ischemic lesions. Stroke 37, 830-835 https://doi.org/10.1161/01.STR.0000202587.63936.37
  104. Fujii K, Tanabe Y, Kobayashi K, Uchikawa H and Kohno Y (2005) Detection of 14-3-3 protein in the cerebrospinal fluid in mitochondrial encephalopathy with lactic acidosis and stroke-like episodes. J Neurol Sci 239, 115-118 https://doi.org/10.1016/j.jns.2005.08.007
  105. Lai XJ, Ye SQ, Zheng L et al (2014) Selective $14-3-3{\gamma}$ induction quenches p-${\beta}$-catenin Ser37/Bax-enhanced cell death in cerebral cortical neurons during ischemia. Cell Death Dis 5, e1184 https://doi.org/10.1038/cddis.2014.152
  106. Jang SW, Liu X, Fu H et al (2009) Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell cycle and cell death in neurons. J Biol Chem 284, 24512-24525 https://doi.org/10.1074/jbc.M109.026237
  107. Zhou XY, Hu DX, Chen RQ et al (2017) 14-3-3 Isoforms differentially regulate $NF{\kappa}B$ signaling in the brain after ischemia-reperfusion. Neurochem Res 42, 2354-2362 https://doi.org/10.1007/s11064-017-2255-3
  108. Otsuka S, Sakakima H, Terashi T, Takada S, Nakanishi K and Kikuchi K (2019) Preconditioning exercise reduces brain damage and neuronal apoptosis through enhanced endogenous $14-3-3{\gamma}$ after focal brain ischemia in rats. Brain Struct Funct 224, 739-740 https://doi.org/10.1007/s00429-018-1815-x
  109. Dong Y, Liu HD, Zhao R et al (2009) Ischemia activates JNK/c-Jun/AP-1 pathway to up-regulate 14-3-3gamma in astrocyte. J Neurochem 109, 182-188 https://doi.org/10.1111/j.1471-4159.2009.05974.x
  110. Chen XQ and Yu AC (2002) The association of 14-3-3gamma and actin plays a role in cell division and apoptosis in astrocytes. Biochem Biophys Res Commun 296, 657-663 https://doi.org/10.1016/S0006-291X(02)00895-1
  111. Chen XQ, Chen JG, Zhang Y, Hsiao WW and Yu AC (2003) 14-3-3gamma is upregulated by in vitro ischemia and binds to protein kinase Raf in primary cultures of astrocytes. Glia 42, 315-324 https://doi.org/10.1002/glia.10185
  112. Umahara T, Uchihara T, Tsuchiya K et al (2007) Intranuclear localization and isoform-dependent translocation of 14-3-3 proteins in human brain with infarction. J Neurol Sci 260, 159-166 https://doi.org/10.1016/j.jns.2007.04.053
  113. Chen XQ, Fung YW and Yu AC (2005) Association of 14-3-3gamma and phosphorylated bad attenuates injury in ischemic astrocytes. J Cereb Blood Flow Metab 25, 338-347 https://doi.org/10.1038/sj.jcbfm.9600032
  114. Dong Y, Liu HD, Zhao R et al (2009) Ischemia activates JNK/c-Jun/AP-1 pathway to up-regulate 14-3-3gamma in astrocyte. J Neurochem 109, 182-188 https://doi.org/10.1111/j.1471-4159.2009.05974.x
  115. Pang Y, Chai CR, Gao K et al (2015) Ischemia preconditioning protects astrocytes from ischemic injury through $14-3-3{\gamma}$. J Neurosci Res 93, 1507-1518 https://doi.org/10.1002/jnr.23574
  116. Hermeking H and Benzinger A (2006) 14-3-3 proteins in cell cycle regulation. Semin Cancer Biol 16, 183-192 https://doi.org/10.1016/j.semcancer.2006.03.002
  117. Morrison DK (2009) The 14-3-3 proteins: integrators of diverse signaling cues that impact cell fate and cancer development. Trends Cell Biol 19, 16-23 https://doi.org/10.1016/j.tcb.2008.10.003
  118. Gardino AK and Yaffe MB (2011) 14-3-3 proteins as signaling integration points for cell cycle control and apoptosis. Semin Cell Dev Biol 22, 688-695 https://doi.org/10.1016/j.semcdb.2011.09.008
  119. Jin Y, Dai MS, Lu SZ et al (2006) 14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation. EMBO J 25, 1207-1218 https://doi.org/10.1038/sj.emboj.7601010
  120. Lee JH and Lu H (2011) 14-3-3gamma inhibition of MDMX-mediated p21 turnover independent of p53. J Biol Chem 286, 5136-5142 https://doi.org/10.1074/jbc.M110.190470
  121. Cao WD, Zhang X, Zhang JN et al (2006) Immunocytochemical detection of 14-3-3 in primary nervous system tumors. J Neurooncol 77, 125-130 https://doi.org/10.1007/s11060-005-9027-7
  122. Cao L, Cao W, Zhang W et al (2008) Identification of 14-3-3 protein isoforms in human astrocytoma by immunohistochemistry. Neurosci Lett 432, 94-99 https://doi.org/10.1016/j.neulet.2007.11.071
  123. Yang X, Cao W, Lin H et al (2009) Isoform-specific expression of 14-3-3 proteins in human astrocytoma. J Neurol Sci 276, 54-59 https://doi.org/10.1016/j.jns.2008.08.040
  124. Liang S, Xu Y, Shen G et al (2009) Quantitative protein expression profiling of 14-3-3 isoforms in human renal carcinoma shows 14-3-3 epsilon is involved in limitedly increasing renal cell proliferation. Electrophoresis 30, 4152-4162 https://doi.org/10.1002/elps.200900249
  125. Com E, Clavreul A, Lagarrigue M, Michalak S, Menei P and Pineau C (2012) Quantitative proteomic Isotope-Coded Protein Label (ICPL) analysis reveals alteration of several functional processes in the glioblastoma. J Proteomics 75, 3898-3913 https://doi.org/10.1016/j.jprot.2012.04.034
  126. Cao W, Yang X, Zhou J et al (2010) Targeting 14-3-3 protein, difopein induces apoptosis of human glioma cells and suppresses tumor growth in mice. Apoptosis 15, 230-241 https://doi.org/10.1007/s10495-009-0437-4
  127. Liu J, Liu Y, Ren Y, Kang L and Zhang L (2014) Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor-kappaB signaling pathway. Mol Med Rep 9, 1068-1074 https://doi.org/10.3892/mmr.2014.1888
  128. Yao ZQ, Zhang X, Zhen Y et al (2018) A novel small-molecule activator of Sirtuin-1 induces autophagic cell death/mitophagy as a potential therapeutic strategy in glioblastoma. Cell Death Dis 9, 767 https://doi.org/10.1038/s41419-018-0799-z
  129. Steinacker P, Schwarz P, Reim K et al (2005) Unchanged Survival Rates of $14-3-3{\gamma}$ Knockout Mice after Inoculation with Pathological Prion Protein. Mol Cell Biol 25, 1339-1346 https://doi.org/10.1128/MCB.25.4.1339-1346.2005
  130. Kim DE, Cho CH, Sim KM et al (2019) $14-3-3{\gamma}$ haploinsufficient mice display hyperactive and stress-sensitive behaviors. Exp Neurobiol 28, 43-45 https://doi.org/10.5607/en.2019.28.1.43
  131. Cheah PS, Ramshaw HS, Thomas PQ et al (2012) Neurodevelopmental and neuropsychiatric behavior defects arise from 14-3-3zeta deficiency. Mol Psychiatry 17, 451-466 https://doi.org/10.1038/mp.2011.158
  132. Xu X, Jaehne EJ, Greenberg Z et al (2015) 14-3-3zeta deficient mice in the BALB/c background display behavioral and anatomical defects associated with neurodevelopmental disorders. Sci Rep 5, 12434 https://doi.org/10.1038/srep12434
  133. Jaehne EJ, Ramshaw H, Xu X et al (2015) In-vivo administration of clozapine affects behaviour but does not reverse dendritic spine deficits in the $14-3-3{\xi}$ KO mouse model of schizophrenia-like disorders. Pharmacol Biochem Behav 138, 1-8 https://doi.org/10.1016/j.pbb.2015.09.006
  134. Ikeda M, Hikita T, Taya S et al (2008) Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. Hum Mol Genet 17, 3212-3222 https://doi.org/10.1093/hmg/ddn217
  135. Wachi T, Cornell B and Toyo-Oka K (2017) Complete ablation of the 14-3-3epsilon protein results in multiple defects in neuropsychiatric behaviors. Behav Brain Res 319, 31-36 https://doi.org/10.1016/j.bbr.2016.11.016