Skip to main content
SpringerLink
Log in

E6AP in the Brain: One Protein, Dual Function, Multiple Diseases

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

E6-Associated Protein (E6AP), the founding member of the HECT (Homologus to E6AP C terminus) family of ubiquitin ligases, has been gaining increased attention from the scientific community. In addition to its ubiquitin ligase function, our laboratory has also identified steroid hormone receptor transcriptional coactivation as yet another essential function of this protein. Furthermore, it has been established that E6AP has a role in numerous diseases including cancers and neurological syndromes. In this review, we delineate genetic and biochemical knowledge of E6AP and we focus on its role in the pathobiology of neuro-developmental and neuro-aging diseases; bringing to light important gaps of knowledge related to the involvement of its well-studied ligase function versus the much less studied nuclear receptor transcriptional coactivation function in the pathogenesis of these diseases. Tackling these gaps of knowledge could reveal novel possible neuro-pathobiological mechanisms and present crucial information for the design of effective treatment modalities for devastating CNS diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM (1993) The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75(3):495–505

    CAS  PubMed  Google Scholar 

  2. Glickman MH, Ciechanover A (2002) The ubiquitin–proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82(2):373–428

    CAS  PubMed  Google Scholar 

  3. Nawaz Z, O'Malley BW (2004) Urban renewal in the nucleus: is protein turnover by proteasomes absolutely required for nuclear receptor-regulated transcription? Mol Endocrinol 18(3):493–499

    CAS  PubMed  Google Scholar 

  4. Etlinger JD, Goldberg AL (1977) A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes. Proc Natl Acad Sci U S A 74(1):54–58

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Ciehanover A, Hod Y, Hershko A (1978) A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. Biochem Biophys Res Commun 81(4):1100–1105

    CAS  PubMed  Google Scholar 

  6. Hershko A, Heller H, Elias S, Ciechanover A (1983) Components of ubiquitin–protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem 258(13):8206–8214

    CAS  PubMed  Google Scholar 

  7. Fang S, Weissman AM (2004) A field guide to ubiquitylation. Cell Mol Life Sci 61(13):1546–1561

    CAS  PubMed  Google Scholar 

  8. Powell SR (2006) The ubiquitin-proteasome system in cardiac physiology and pathology. Am J Physiol Heart Circ Physiol 291(1):H1–H19

    CAS  PubMed  Google Scholar 

  9. Meiners S, Ludwig A, Stangl V, Stangl K (2008) Proteasome inhibitors: poisons and remedies. Med Res Rev 28(2):309–327

    CAS  PubMed  Google Scholar 

  10. Tomaic V, Pim D, Banks L (2009) The stability of the human papillomavirus E6 oncoprotein is E6AP dependent. Virology 393(1):7–10

    CAS  PubMed  Google Scholar 

  11. Yamamoto Y, Huibregtse JM, Howley PM (1997) The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing. Genomics 41(2):263–266

    CAS  PubMed  Google Scholar 

  12. Kishino T, Wagstaff J (1998) Genomic organization of the UBE3A/E6-AP gene and related pseudogenes. Genomics 47(1):101–107

    CAS  PubMed  Google Scholar 

  13. Huibregtse JM, Scheffner M, Howley PM (1993) Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. Mol Cell Biol 13(8):4918–4927

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Nawaz Z, Lonard DM, Smith CL, Lev-Lehman E, Tsai SY, Tsai MJ, O'Malley BW (1999) The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. Mol Cell Biol 19(2):1182–1189

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Huibregtse JM, Scheffner M, Beaudenon S, Howley PM (1995) A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci U S A 92(11):2563–2567

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Scheffner M, Huibregtse JM, Howley PM (1994) Identification of a human ubiquitin-conjugating enzyme that mediates the E6-AP-dependent ubiquitination of p53. Proc Natl Acad Sci U S A 91(19):8797–8801

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Kumar S, Kao WH, Howley PM (1997) Physical interaction between specific E2 and Hect E3 enzymes determines functional cooperativity. J Biol Chem 272(21):13548–13554

    CAS  PubMed  Google Scholar 

  18. Huang L, Kinnucan E, Wang G, Beaudenon S, Howley PM, Huibregtse JM, Pavletich NP (1999) Structure of an E6AP–UbcH7 complex: insights into ubiquitination by the E2–E3 enzyme cascade. Science 286(5443):1321–1326

    CAS  PubMed  Google Scholar 

  19. Zanier K, Charbonnier S, Baltzinger M, Nomine Y, Altschuh D, Trave G (2005) Kinetic analysis of the interactions of human papillomavirus E6 oncoproteins with the ubiquitin ligase E6AP using surface plasmon resonance. J Mol Biol 349(2):401–412

    CAS  PubMed  Google Scholar 

  20. Kishino T, Lalande M, Wagstaff J (1997) UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 15(1):70–73

    CAS  PubMed  Google Scholar 

  21. Talis AL, Huibregtse JM, Howley PM (1998) The role of E6AP in the regulation of p53 protein levels in human papillomavirus (HPV)-positive and HPV-negative cells. J Biol Chem 273(11):6439–6445

    CAS  PubMed  Google Scholar 

  22. Cooper B, Schneider S, Bohl J, Jiang Y, Beaudet A, Vande Pol S (2003) Requirement of E6AP and the features of human papillomavirus E6 necessary to support degradation of p53. Virology 306(1):87–99

    CAS  PubMed  Google Scholar 

  23. Dhananjayan SC, Ramamoorthy S, Khan OY, Ismail A, Sun J, Slingerland J, O'Malley BW, Nawaz Z (2006) WW domain binding protein-2, an E6-associated protein interacting protein, acts as a coactivator of estrogen and progesterone receptors. Mol Endocrinol 20(10):2343–2354

    CAS  PubMed  Google Scholar 

  24. Khan OY, Fu G, Ismail A, Srinivasan S, Cao X, Tu Y, Lu S, Nawaz Z (2006) Multifunction steroid receptor coactivator, E6-associated protein, is involved in development of the prostate gland. Mol Endocrinol 20(3):544–559

    CAS  PubMed  Google Scholar 

  25. Salvat C, Wang G, Dastur A, Lyon N, Huibregtse JM (2004) The −4 phenylalanine is required for substrate ubiquitination catalyzed by HECT ubiquitin ligases. J Biol Chem 279(18):18935–18943

    CAS  PubMed  Google Scholar 

  26. Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R, Benchimol S (2003) Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 112(6):779–791

    CAS  PubMed  Google Scholar 

  27. Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W (2003) Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302(5652):1972–1975

    CAS  PubMed  Google Scholar 

  28. Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P, O'Rourke K, Koeppen H, Dixit VM (2004) The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 429(6987):86–92

    CAS  PubMed  Google Scholar 

  29. Oda H, Kumar S, Howley PM (1999) Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination. Proc Natl Acad Sci U S A 96(17):9557–9562

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Liu X, Yuan H, Fu B, Disbrow GL, Apolinario T, Tomaic V, Kelley ML, Baker CC, Huibregtse J, Schlegel R (2005) The E6AP ubiquitin ligase is required for transactivation of the hTERT promoter by the human papillomavirus E6 oncoprotein. J Biol Chem 280(11):10807–10816

    CAS  PubMed  Google Scholar 

  31. Liu X, Disbrow GL, Yuan H, Tomaic V, Schlegel R (2007) Myc and human papillomavirus type 16 E7 genes cooperate to immortalize human keratinocytes. J Virol 81(22):12689–12695

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Kumar S, Talis AL, Howley PM (1999) Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination. J Biol Chem 274(26):18785–18792

    CAS  PubMed  Google Scholar 

  33. Nuber U, Schwarz SE, Scheffner M (1998) The ubiquitin-protein ligase E6-associated protein (E6-AP) serves as its own substrate. Eur J Biochem 254(3):643–649

    CAS  PubMed  Google Scholar 

  34. Kao WH, Beaudenon SL, Talis AL, Huibregtse JM, Howley PM (2000) Human papillomavirus type 16 E6 induces self-ubiquitination of the E6AP ubiquitin-protein ligase. J Virol 74(14):6408–6417

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Reid G, Hubner MR, Metivier R, Brand H, Denger S, Manu D, Beaudouin J, Ellenberg J, Gannon F (2003) Cyclic, proteasome-mediated turnover of unliganded and liganded ERalpha on responsive promoters is an integral feature of estrogen signaling. Mol Cell 11(3):695–707

    CAS  PubMed  Google Scholar 

  36. James MA, Lee JH, Klingelhutz AJ (2006) HPV16-E6 associated hTERT promoter acetylation is E6AP dependent, increased in later passage cells and enhanced by loss of p300. Int J Cancer 119(8):1878–1885

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Catoe HW, Nawaz Z (2011) E6-AP facilitates efficient transcription at estrogen responsive promoters through recruitment of chromatin modifiers. Steroids 76(9):897–902

    CAS  PubMed  Google Scholar 

  38. Ismail A, Nawaz Z (2005) Nuclear hormone receptor degradation and gene transcription: an update. IUBMB Life 57(7):483–490

    CAS  PubMed  Google Scholar 

  39. Alarid ET (2006) Lives and times of nuclear receptors. Mol Endocrinol 20(9):1972–1981

    CAS  PubMed  Google Scholar 

  40. Nawaz Z, Lonard DM, Dennis AP, Smith CL, O'Malley BW (1999) Proteasome-dependent degradation of the human estrogen receptor. Proc Natl Acad Sci U S A 96(5):1858–1862

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Lonard DM, Nawaz Z, Smith CL, O'Malley BW (2000) The 26S proteasome is required for estrogen receptor-alpha and coactivator turnover and for efficient estrogen receptor-alpha transactivation. Mol Cell 5(6):939–948

    CAS  PubMed  Google Scholar 

  42. Gao X, Mohsin SK, Gatalica Z, Fu G, Sharma P, Nawaz Z (2005) Decreased expression of E6-associated protein in breast and prostate carcinomas. Endocrinology 146(4):1707–1712

    CAS  PubMed  Google Scholar 

  43. Mani A, Oh AS, Bowden ET, Lahusen T, Lorick KL, Weissman AM, Schlegel R, Wellstein A, Riegel AT (2006) E6AP mediates regulated proteasomal degradation of the nuclear receptor coactivator amplified in breast cancer 1 in immortalized cells. Cancer Res 66(17):8680–8686

    CAS  PubMed  Google Scholar 

  44. Rochette-Egly C (2005) Dynamic combinatorial networks in nuclear receptor-mediated transcription. J Biol Chem 280(38):32565–32568

    CAS  PubMed  Google Scholar 

  45. Albrecht U, Sutcliffe JS, Cattanach BM, Beechey CV, Armstrong D, Eichele G, Beaudet AL (1997) Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet 17(1):75–78

    CAS  PubMed  Google Scholar 

  46. Meng L, Person RE, Beaudet AL (2012) Ube3a-ATS is an atypical RNA polymerase II transcript that represses the paternal expression of Ube3a. Hum Mol Genet 21(13):3001–3012

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Daily J, Smith AG, Weeber EJ (2012) Spatial and temporal silencing of the human maternal UBE3A gene. Eur J Paediatr Neurol 16(6):587–591

    PubMed Central  PubMed  Google Scholar 

  48. Jiang YH, Armstrong D, Albrecht U, Atkins CM, Noebels JL, Eichele G, Sweatt JD, Beaudet AL (1998) Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21(4):799–811

    CAS  PubMed  Google Scholar 

  49. Mishra A, Jana NR (2008) Regulation of turnover of tumor suppressor p53 and cell growth by E6-AP, a ubiquitin protein ligase mutated in Angelman mental retardation syndrome. Cell Mol Life Sci 65(4):656–666

    CAS  PubMed  Google Scholar 

  50. Mishra A, Godavarthi SK, Jana NR (2009) UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27. Neurobiol Dis 36(1):26–34

    CAS  PubMed  Google Scholar 

  51. Greer PL, Hanayama R, Bloodgood BL, Mardinly AR, Lipton DM, Flavell SW, Kim TK, Griffith EC, Waldon Z, Maehr R, Ploegh HL, Chowdhury S, Worley PF, Steen J, Greenberg ME (2010) The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140(5):704–716

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Margolis SS, Salogiannis J, Lipton DM, Mandel-Brehm C, Wills ZP, Mardinly AR, Hu L, Greer PL, Bikoff JB, Ho HY, Soskis MJ, Sahin M, Greenberg ME (2010) EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell 143(3):442–455

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Reiter LT, Seagroves TN, Bowers M, Bier E (2006) Expression of the Rho-GEF Pbl/ECT2 is regulated by the UBE3A E3 ubiquitin ligase. Hum Mol Genet 15(18):2825–2835

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Mishra A, Dikshit P, Purkayastha S, Sharma J, Nukina N, Jana NR (2008) E6-AP promotes misfolded polyglutamine proteins for proteasomal degradation and suppresses polyglutamine protein aggregation and toxicity. J Biol Chem 283(12):7648–7656

    CAS  PubMed  Google Scholar 

  55. Mulherkar SA, Sharma J, Jana NR (2009) The ubiquitin ligase E6-AP promotes degradation of alpha-synuclein. J Neurochem 110(6):1955–1964

    CAS  PubMed  Google Scholar 

  56. Mishra A, Godavarthi SK, Maheshwari M, Goswami A, Jana NR (2009) The ubiquitin ligase E6-AP is induced and recruited to aggresomes in response to proteasome inhibition and may be involved in the ubiquitination of Hsp70-bound misfolded proteins. J Biol Chem 284(16):10537–10545

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Takiyama Y (2007) Sacsinopathies: sacsin-related ataxia. Cerebellum 6(4):353–359

    CAS  PubMed  Google Scholar 

  58. Smith CL, DeVera DG, Lamb DJ, Nawaz Z, Jiang YH, Beaudet AL, O'Malley BW (2002) Genetic ablation of the steroid receptor coactivator-ubiquitin ligase, E6-AP, results in tissue-selective steroid hormone resistance and defects in reproduction. Mol Cell Biol 22(2):525–535

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Nishihara E, O'Malley BW, Xu JM (2004) Nuclear receptor coregulators are new players in nervous system development and function. Mol Neurobiol 30(3):307–325

    CAS  PubMed  Google Scholar 

  60. Ferdousy F, Bodeen W, Summers K, Doherty O, Wright O, Elsisi N, Hilliard G, O'Donnell JM, Reiter LT (2011) Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism. Neurobiol Dis 41(3):669–677

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Godavarthi SK, Dey P, Maheshwari M, Jana NR (2012) Defective glucocorticoid hormone receptor signaling leads to increased stress and anxiety in a mouse model of Angelman syndrome. Hum Mol Genet 21(8):1824–1834

    CAS  PubMed  Google Scholar 

  62. Low D, Chen KS (2010) Genome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation. Eur J Hum Genet 18(11):1228–1235

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Wu Y, Bolduc FV, Bell K, Tully T, Fang Y, Sehgal A, Fischer JA (2008) A Drosophila model for Angelman syndrome. Proc Natl Acad Sci U S A 105(34):12399–12404

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Lu Y, Wang F, Li Y, Ferris J, Lee JA, Gao FB (2009) The Drosophila homologue of the Angelman syndrome ubiquitin ligase regulates the formation of terminal dendritic branches. Hum Mol Genet 18(3):454–462

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Dindot SV, Antalffy BA, Bhattacharjee MB, Beaudet AL (2008) The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum Mol Genet 17(1):111–118

    CAS  PubMed  Google Scholar 

  66. Yashiro K, Riday TT, Condon KH, Roberts AC, Bernardo DR, Prakash R, Weinberg RJ, Ehlers MD, Philpot BD (2009) Ube3a is required for experience-dependent maturation of the neocortex. Nat Neurosci 12(6):777–783

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Jiang YH, Pan Y, Zhu L, Landa L, Yoo J, Spencer C, Lorenzo I, Brilliant M, Noebels J, Beaudet AL (2010) Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3. PLoS One 5(8):e12278

    PubMed Central  PubMed  Google Scholar 

  68. Condon KH, Ho J, Robinson CG, Hanus C, Ehlers MD (2013) The Angelman syndrome protein Ube3a/E6AP is required for Golgi acidification and surface protein sialylation. J Neurosci 33(9):3799–3814

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Gustin RM, Bichell TJ, Bubser M, Daily J, Filonova I, Mrelashvili D, Deutch AY, Colbran RJ, Weeber EJ, Haas KF (2010) Tissue-specific variation of Ube3a protein expression in rodents and in a mouse model of Angelman syndrome. Neurobiol Dis 39(3):283–291

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Heck DH, Zhao Y, Roy S, LeDoux MS, Reiter LT (2008) Analysis of cerebellar function in Ube3a-deficient mice reveals novel genotype-specific behaviors. Hum Mol Genet 17(14):2181–2189

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Lossie AC, Whitney MM, Amidon D, Dong HJ, Chen P, Theriaque D, Hutson A, Nicholls RD, Zori RT, Williams CA, Driscoll DJ (2001) Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet 38(12):834–845

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Varela MC, Kok F, Otto PA, Koiffmann CP (2004) Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects. Eur J Hum Genet 12(12):987–992

    CAS  PubMed  Google Scholar 

  73. Dan B, Cheron G (2004) Postural rhythmic muscle bursting activity in Angelman syndrome. Brain Dev 26(6):389–393

    PubMed  Google Scholar 

  74. Cheron G, Servais L, Dan B, Gall D, Roussel C, Schiffmann SN (2005) Fast oscillation in the cerebellar cortex of calcium binding protein-deficient mice: a new sensorimotor arrest rhythm. Prog Brain Res 148:165–180

    PubMed  Google Scholar 

  75. Mulherkar SA, Jana NR (2010) Loss of dopaminergic neurons and resulting behavioural deficits in mouse model of Angelman syndrome. Neurobiol Dis 40(3):586–592

    CAS  PubMed  Google Scholar 

  76. Harbord M (2001) Levodopa responsive Parkinsonism in adults with Angelman syndrome. J Clin Neurosci 8(5):421–422

    CAS  PubMed  Google Scholar 

  77. Sato M, Stryker MP (2010) Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a. Proc Natl Acad Sci U S A 107(12):5611–5616

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Dorrn AL, Yuan K, Barker AJ, Schreiner CE, Froemke RC (2010) Developmental sensory experience balances cortical excitation and inhibition. Nature 465(7300):932–936

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Weeber EJ, Jiang YH, Elgersma Y, Varga AW, Carrasquillo Y, Brown SE, Christian JM, Mirnikjoo B, Silva A, Beaudet AL, Sweatt JD (2003) Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome. J Neurosci 23(7):2634–2644

    CAS  PubMed  Google Scholar 

  80. van Woerden GM, Harris KD, Hojjati MR, Gustin RM, Qiu S, de Avila Freire R, Jiang YH, Elgersma Y, Weeber EJ (2007) Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of alphaCaMKII inhibitory phosphorylation. Nat Neurosci 10(3):280–282

    PubMed  Google Scholar 

  81. Jay V, Becker LE, Chan FW, Perry TL Sr (1991) Puppet-like syndrome of Angelman: a pathologic and neurochemical study. Neurology 41(3):416–422

    CAS  PubMed  Google Scholar 

  82. Cao C, Rioult-Pedotti MS, Migani P, Yu CJ, Tiwari R, Parang K, Spaller MR, Goebel DJ, Marshall J (2013) Impairment of TrkB-PSD-95 signaling in Angelman syndrome. PLoS Biol 11(2):e1001478

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Engert JC, Berube P, Mercier J, Dore C, Lepage P, Ge B, Bouchard JP, Mathieu J, Melancon SB, Schalling M, Lander ES, Morgan K, Hudson TJ, Richter A (2000) ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nat Genet 24(2):120–125

    CAS  PubMed  Google Scholar 

  84. Parfitt DA, Michael GJ, Vermeulen EG, Prodromou NV, Webb TR, Gallo JM, Cheetham ME, Nicoll WS, Blatch GL, Chapple JP (2009) The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1. Hum Mol Genet 18(9):1556–1565

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Ramamoorthy S, Nawaz Z (2008) E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors. Nucl Recept Signal 6:e006

    PubMed Central  PubMed  Google Scholar 

  86. Miura K, Kishino T, Li E, Webber H, Dikkes P, Holmes GL, Wagstaff J (2002) Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. Neurobiol Dis 9(2):149–159

    CAS  PubMed  Google Scholar 

  87. Clayton-Smith J, Laan L (2003) Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet 40(2):87–95

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Pelc K, Cheron G, Boyd SG, Dan B (2008) Are there distinctive sleep problems in Angelman syndrome? Sleep Med 9(4):434–441

    PubMed  Google Scholar 

  89. Yamasaki K, Joh K, Ohta T, Masuzaki H, Ishimaru T, Mukai T, Niikawa N, Ogawa M, Wagstaff J, Kishino T (2003) Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a. Hum Mol Genet 12(8):837–847

    CAS  PubMed  Google Scholar 

  90. Mardirossian S, Rampon C, Salvert D, Fort P, Sarda N (2009) Impaired hippocampal plasticity and altered neurogenesis in adult Ube3a maternal deficient mouse model for Angelman syndrome. Exp Neurol 220(2):341–348

    CAS  PubMed  Google Scholar 

  91. Smith SE, Zhou YD, Zhang G, Jin Z, Stoppel DC, Anderson MP (2011) Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Sci Transl Med 3(103):103ra97

    PubMed Central  PubMed  Google Scholar 

  92. Williams CA (2005) Neurological aspects of the Angelman syndrome. Brain Dev 27(2):88–94

    PubMed  Google Scholar 

  93. Lalande M, Calciano MA (2007) Molecular epigenetics of Angelman syndrome. Cell Mol Life Sci 64(7–8):947–960

    CAS  PubMed  Google Scholar 

  94. Matsuura T, Sutcliffe JS, Fang P, Galjaard RJ, Jiang YH, Benton CS, Rommens JM, Beaudet AL (1997) De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet 15(1):74–77

    CAS  PubMed  Google Scholar 

  95. Sutcliffe JS, Jiang YH, Galijaard RJ, Matsuura T, Fang P, Kubota T, Christian SL, Bressler J, Cattanach B, Ledbetter DH, Beaudet AL (1997) The E6-Ap ubiquitin-protein ligase (UBE3A) gene is localized within a narrowed Angelman syndrome critical region. Genome Res 7(4):368–377

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23(2):185–188

    CAS  PubMed  Google Scholar 

  97. Matijevic T, Knezevic J, Slavica M, Pavelic J (2009) Rett syndrome: from the gene to the disease. Eur Neurol 61(1):3–10

    CAS  PubMed  Google Scholar 

  98. Samaco RC, Hogart A, LaSalle JM (2005) Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet 14(4):483–492

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Moretti P, Zoghbi HY (2006) MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev 16(3):276–281

    PubMed  Google Scholar 

  100. Makedonski K, Abuhatzira L, Kaufman Y, Razin A, Shemer R (2005) MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression. Hum Mol Genet 14(8):1049–1058

    CAS  PubMed  Google Scholar 

  101. Jordan C, Francke U (2006) Ube3a expression is not altered in Mecp2 mutant mice. Hum Mol Genet 15(14):2210–2215

    CAS  PubMed  Google Scholar 

  102. Jiang Y, Tsai TF, Bressler J, Beaudet AL (1998) Imprinting in Angelman and Prader–Willi syndromes. Curr Opin Genet Dev 8(3):334–342

    CAS  PubMed  Google Scholar 

  103. Mann MR, Bartolomei MS (1999) Towards a molecular understanding of Prader–Willi and Angelman syndromes. Hum Mol Genet 8(10):1867–1873

    CAS  PubMed  Google Scholar 

  104. Peters SU, Beaudet AL, Madduri N, Bacino CA (2004) Autism in Angelman syndrome: implications for autism research. Clin Genet 66(6):530–536

    CAS  PubMed  Google Scholar 

  105. Veltman MW, Craig EE, Bolton PF (2005) Autism spectrum disorders in Prader–Willi and Angelman syndromes: a systematic review. Psychiatr Genet 15(4):243–254

    PubMed  Google Scholar 

  106. Hughes JR (2009) Update on autism: a review of 1300 reports published in 2008. Epilepsy Behav 16(4):569–589

    PubMed  Google Scholar 

  107. O'Hare A (2009) Autism spectrum disorder: diagnosis and management. Arch Dis Child Educ Pract Ed 94(6):161–168

    PubMed  Google Scholar 

  108. Verhoeven JS, De Cock P, Lagae L, Sunaert S (2010) Neuroimaging of autism. Neuroradiology 52(1):3–14

    PubMed  Google Scholar 

  109. Cook EH Jr, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E (1997) Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet 60(4):928–934

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Sutcliffe JS, Nurmi EL, Lombroso PJ (2003) Genetics of childhood disorders: XLVII. Autism: Part 6. Duplication and inherited susceptibility of chromosome 15q11–q13 genes in autism. J Am Acad Child Adolesc Psychiatry 42(2):253–256

    PubMed  Google Scholar 

  111. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459(7246):569–573

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, Mizuno Y, Kosik KS, Selkoe DJ (2001) Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293(5528):263–269

    CAS  PubMed  Google Scholar 

  113. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) alpha-Synuclein locus triplication causes Parkinson's disease. Science 302(5646):841

    CAS  PubMed  Google Scholar 

  114. The Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72(6):971–983

    Google Scholar 

  115. Orr HT, Zoghbi HY (2007) Trinucleotide repeat disorders. Annu Rev Neurosci 30:575–621

    CAS  PubMed  Google Scholar 

  116. Landles C, Bates GP (2004) Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series. EMBO Rep 5(10):958–963

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Maheshwari M, Samanta A, Godavarthi SK, Mukherjee R, Jana NR (2012) Dysfunction of the ubiquitin ligase Ube3a may be associated with synaptic pathophysiology in a mouse model of Huntington disease. J Biol Chem 287(35):29949–29957

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

Jimmy El Hokayem is supported by the Lois Pope LIFE Fellows Program. This work is supported by a grant from the Foundation for Angelman Syndrome Therapeutics (FAST).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, 1501 N.W. 10th Avenue, Miami, FL, 33136, USA

    Jimmy El Hokayem & Zafar Nawaz

  2. Braman Family Breast Cancer Institute/Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, BRB Building, Room 723 (C-227), 1501 NW 10th Avenue, Miami, FL, 33136, USA

    Zafar Nawaz

Authors
  1. Jimmy El Hokayem
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zafar Nawaz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zafar Nawaz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

El Hokayem, J., Nawaz, Z. E6AP in the Brain: One Protein, Dual Function, Multiple Diseases. Mol Neurobiol 49, 827–839 (2014). https://doi.org/10.1007/s12035-013-8563-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-013-8563-y

Keywords

Search

Navigation