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Sumoylation in neurodegenerative diseases

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Abstract

The yeast SUMO (small ubiquitin-like modifier) orthologue SMT3 was initially discovered in a genetic suppressors screen for the centromeric protein Mif2 (Meluh and Koshland in Mol Bio Cell 6:793–807, 1). Later, it turned out that the homologous mammalian proteins SUMO1 to SUMO4 are reversible protein modifiers that can form isopeptide bonds with lysine residues of respective target proteins (Mahajan et al. in Cell 88:97–107, 2). This was the discovery of a post-translational modification called sumoylation, which enzymatically resembles ubiquitination. However, very soon it became clear that SUMO attachments served a far more diverse role than ubiquitination. Meanwhile, numerous cellular processes are known to be subject to the impact of SUMO modification, including transcription, protein targeting, protein solubility, apoptosis or activity of various enzymes. In many instances, SUMO proteins create new protein interaction surfaces or block existing interaction domains (Geiss-Friedlander and Melchior in Nat Rev in Mol Cell Biol 8:947–956, 3). For the past few years, sumoylation attracted increasing attention as a versatile regulator of toxic protein properties in neurodegenerative diseases. In this review, we summarize the growing knowledge about the involvement of sumoylation in neurodegeneration, and discuss the underlying molecular principles affected by this multifaceted and intriguing post-translational modification.

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References

  1. Meluh PB, Koshland D (1995) Evidence that the MIF2 gene of Saccharomyces cerevisiae encodes a centromere protein with homology to the mammalian centromere protein CENP-C. Mol Biol Cell 6:793–807

    PubMed  CAS  Google Scholar 

  2. Mahajan R, Delphin C, Guan T, Gerace L, Melchior F (1997) A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell 88:97–107

    Article  PubMed  CAS  Google Scholar 

  3. Geiss-Friedlander R, Melchior F (2007) Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 8:947–956

    Article  PubMed  CAS  Google Scholar 

  4. Kamitani T, Kito K, Nguyen HP, Yeh ET (1997) Characterization of NEDD8, a developmentally down-regulated ubiquitin-like protein. J Biol Chem 272:28557–28562

    Article  PubMed  CAS  Google Scholar 

  5. Kessler DS, Levy DE, Darnell JE Jr (1988) Two interferon-induced nuclear factors bind a single promoter element in interferon-stimulated genes. Proc Natl Acad Sci USA 85:8521–8525

    Article  PubMed  CAS  Google Scholar 

  6. Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, Ishihara N, Mizushima N, Tanida I, Kominami E, Ohsumi M, Noda T, Ohsumi Y (2000) A ubiquitin-like system mediates protein lipidation. Nature 408:488–492

    Article  PubMed  CAS  Google Scholar 

  7. Matunis MJ, Coutavas E, Blobel G (1996) A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. J Cell Biol 135:1457–1470

    Article  PubMed  CAS  Google Scholar 

  8. Melchior F (2000) SUMO–nonclassical ubiquitin. Annu Rev Cell Dev Biol 16:591–626

    Article  PubMed  CAS  Google Scholar 

  9. Bohren KM, Nadkarni V, Song JH, Gabbay KH, Owerbach D (2004) A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. J Biol Chem 279:27233–27238

    Article  PubMed  CAS  Google Scholar 

  10. Guo D, Li M, Zhang Y, Yang P, Eckenrode S, Hopkins D, Zheng W, Purohit S, Podolsky RH, Muir A, Wang J, Dong Z, Brusko T, Atkinson M, Pozzilli P, Zeidler A, Raffel LJ, Jacob CO, Park Y, Serrano-Rios M, Larrad MT, Zhang Z, Garchon HJ, Bach JF, Rotter JI, She JX, Wang CY (2004) A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat Genet 36:837–841

    Article  PubMed  CAS  Google Scholar 

  11. Nacerddine K, Lehembre F, Bhaumik M, Artus J, Cohen-Tannoudji M, Babinet C, Pandolfi PP, Dejean A (2005) The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice. Dev Cell 9:769–779

    Article  PubMed  CAS  Google Scholar 

  12. Saracco SA, Miller MJ, Kurepa J, Vierstra RD (2007) Genetic analysis of SUMOylation in Arabidopsis: conjugation of SUMO1 and SUMO2 to nuclear proteins is essential. Plant Physiol 145:119–134

    Article  PubMed  CAS  Google Scholar 

  13. Tanaka K, Nishide J, Okazaki K, Kato H, Niwa O, Nakagawa T, Matsuda H, Kawamukai M, Murakami Y (1999) Characterization of a fission yeast SUMO-1 homologue, pmt3p, required for multiple nuclear events, including the control of telomere length and chromosome segregation. Mol Cell Biol 19:8660–8672

    PubMed  CAS  Google Scholar 

  14. Wong KH, Todd RB, Oakley BR, Oakley CE, Hynes MJ, Davis MA (2008) Sumoylation in Aspergillus nidulans: SUMO inactivation, overexpression and live-cell imaging. Fungal Genet Biol 45:728–737

    Article  PubMed  CAS  Google Scholar 

  15. Alkuraya FS, Saadi I, Lund JJ, Turbe-Doan A, Morton CC, Maas RL (2006) SUMO1 haploinsufficiency leads to cleft lip and palate. Science 313:1751

    Article  PubMed  Google Scholar 

  16. Zhang FP, Mikkonen L, Toppari J, Palvimo JJ, Thesleff I, Janne OA (2008) Sumo-1 function is dispensable in normal mouse development. Mol Cell Biol 28:5381–5390

    Article  PubMed  CAS  Google Scholar 

  17. Bayer P, Arndt A, Metzger S, Mahajan R, Melchior F, Jaenicke R, Becker J (1998) Structure determination of the small ubiquitin-related modifier SUMO-1. J Mol Biol 280:275–286

    Article  PubMed  CAS  Google Scholar 

  18. Song J, Durrin LK, Wilkinson TA, Krontiris TG, Chen Y (2004) Identification of a SUMO-binding motif that recognizes SUMO-modified proteins. Proc Natl Acad Sci USA 101:14373–14378

    Article  PubMed  CAS  Google Scholar 

  19. Hecker CM, Rabiller M, Haglund K, Bayer P, Dikic I (2006) Specification of SUMO1- and SUMO2-interacting motifs. J Biol Chem 281:16117–16127

    Article  PubMed  CAS  Google Scholar 

  20. Lin DY, Huang YS, Jeng JC, Kuo HY, Chang CC, Chao TT, Ho CC, Chen YC, Lin TP, Fang HI, Hung CC, Suen CS, Hwang MJ, Chang KS, Maul GG, Shih HM (2006) Role of SUMO-interacting motif in Daxx SUMO modification, subnuclear localization, and repression of sumoylated transcription factors. Mol Cell 24:341–354

    Article  PubMed  CAS  Google Scholar 

  21. Rodriguez MS, Dargemont C, Hay RT (2001) SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting. J Biol Chem 276:12654–12659

    Article  PubMed  CAS  Google Scholar 

  22. Sampson DA, Wang M, Matunis MJ (2001) The small ubiquitin-like modifier-1 (SUMO-1) consensus sequence mediates Ubc9 binding and is essential for SUMO-1 modification. J Biol Chem 276:21664–21669

    Article  PubMed  CAS  Google Scholar 

  23. Pichler A, Knipscheer P, Oberhofer E, van Dijk WJ, Korner R, Olsen JV, Jentsch S, Melchior F, Sixma TK (2005) SUMO modification of the ubiquitin-conjugating enzyme E2-25K. Nat Struct Mol Biol 12:264–269

    Article  PubMed  CAS  Google Scholar 

  24. Macauley MS, Errington WJ, Scharpf M, Mackereth CD, Blaszczak AG, Graves BJ, McIntosh LP (2006) Beads-on-a-string, characterization of ETS-1 sumoylated within its flexible N-terminal sequence. J Biol Chem 281:4164–4172

    Article  PubMed  CAS  Google Scholar 

  25. Yang SH, Galanis A, Witty J, Sharrocks AD (2006) An extended consensus motif enhances the specificity of substrate modification by SUMO. EMBO J 25:5083–5093

    Article  PubMed  CAS  Google Scholar 

  26. Hietakangas V, Anckar J, Blomster HA, Fujimoto M, Palvimo JJ, Nakai A, Sistonen L (2006) PDSM, a motif for phosphorylation-dependent SUMO modification. Proc Natl Acad Sci USA 103:45–50

    Article  PubMed  CAS  Google Scholar 

  27. Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S (2002) RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419:135–141

    Article  PubMed  CAS  Google Scholar 

  28. Rui HL, Fan E, Zhou HM, Xu Z, Zhang Y, Lin SC (2002) SUMO-1 modification of the C-terminal KVEKVD of Axin is required for JNK activation but has no effect on Wnt signaling. J Biol Chem 277:42981–42986

    Article  PubMed  CAS  Google Scholar 

  29. Johnson ES, Gupta AA (2001) An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell 106:735–744

    Article  PubMed  CAS  Google Scholar 

  30. Takahashi Y, Kahyo T, Toh E, Yasuda H, Kikuchi Y (2001) Yeast Ull1/Siz1 is a novel SUMO1/Smt3 ligase for septin components and functions as an adaptor between conjugating enzyme and substrates. J Biol Chem 276:48973–48977

    Article  PubMed  CAS  Google Scholar 

  31. Schmidt D, Muller S (2002) Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc Natl Acad Sci USA 99:2872–2877

    Article  PubMed  CAS  Google Scholar 

  32. Andrews EA, Palecek J, Sergeant J, Taylor E, Lehmann AR, Watts FZ (2005) Nse2, a component of the Smc5-6 complex, is a SUMO ligase required for the response to DNA damage. Mol Cell Biol 25:185–196

    Article  PubMed  CAS  Google Scholar 

  33. Potts PR, Yu H (2005) Human MMS21/NSE2 is a SUMO ligase required for DNA repair. Mol Cell Biol 25:7021–7032

    Article  PubMed  CAS  Google Scholar 

  34. Zhao X, Blobel G (2005) A SUMO ligase is part of a nuclear multiprotein complex that affects DNA repair and chromosomal organization. Proc Natl Acad Sci USA 102:4777–4782

    Article  PubMed  CAS  Google Scholar 

  35. Pichler A, Gast A, Seeler JS, Dejean A, Melchior F (2002) The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell 108:109–120

    Article  PubMed  CAS  Google Scholar 

  36. Wotton D, Merrill JC (2007) Pc2 and SUMOylation. Biochem Soc Trans 35:1401–1404

    Article  PubMed  CAS  Google Scholar 

  37. Melchior F, Schergaut M, Pichler A (2003) SUMO: ligases, isopeptidases and nuclear pores. Trends Biochem Sci 28:612–618

    Article  PubMed  CAS  Google Scholar 

  38. Tatham MH, Jaffray E, Vaughan OA, Desterro JM, Botting CH, Naismith JH, Hay RT (2001) Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem 276:35368–35374

    Article  PubMed  CAS  Google Scholar 

  39. Saitoh H, Hinchey J (2000) Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem 275:6252–6258

    Article  PubMed  CAS  Google Scholar 

  40. Vertegaal AC, Andersen JS, Ogg SC, Hay RT, Mann M, Lamond AI (2006) Distinct and overlapping sets of SUMO-1 and SUMO-2 target proteins revealed by quantitative proteomics. Mol Cell Proteomics 5:2298–2310

    Article  PubMed  CAS  Google Scholar 

  41. Gong L, Yeh ET (2006) Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3. J Biol Chem 281:15869–15877

    Article  PubMed  CAS  Google Scholar 

  42. Cheng CH, Lo YH, Liang SS, Ti SC, Lin FM, Yeh CH, Huang HY, Wang TF (2006) SUMO modifications control assembly of synaptonemal complex and polycomplex in meiosis of Saccharomyces cerevisiae. Genes Dev 20:2067–2081

    Article  PubMed  CAS  Google Scholar 

  43. Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, Palvimo JJ, Hay RT (2008) RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol 10:538–546

    Article  PubMed  CAS  Google Scholar 

  44. Di BA, Ouyang J, Lee HY, Catic A, Ploegh H, Gill G (2006) The SUMO-specific protease SENP5 is required for cell division. Mol Cell Biol 26:4489–4498

    Article  CAS  Google Scholar 

  45. Di BA, Gill G (2006) SUMO-specific proteases and the cell cycle. An essential role for SENP5 in cell proliferation. Cell Cycle 5:2310–2313

    Article  Google Scholar 

  46. Kim KI, Baek SH, Jeon YJ, Nishimori S, Suzuki T, Uchida S, Shimbara N, Saitoh H, Tanaka K, Chung CH (2000) A new SUMO-1-specific protease, SUSP1, that is highly expressed in reproductive organs. J Biol Chem 275:14102–14106

    Article  PubMed  CAS  Google Scholar 

  47. Gong L, Millas S, Maul GG, Yeh ET (2000) Differential regulation of sentrinized proteins by a novel sentrin-specific protease. J Biol Chem 275:3355–3359

    Article  PubMed  CAS  Google Scholar 

  48. Nishida T, Tanaka H, Yasuda H (2000) A novel mammalian Smt3-specific isopeptidase 1 (SMT3IP1) localized in the nucleolus at interphase. Eur J Biochem 267:6423–6427

    Article  PubMed  CAS  Google Scholar 

  49. Best JL, Ganiatsas S, Agarwal S, Changou A, Salomoni P, Shirihai O, Meluh PB, Pandolfi PP, Zon LI (2002) SUMO-1 protease-1 regulates gene transcription through PML. Mol Cell 10:843–855

    Article  PubMed  CAS  Google Scholar 

  50. Zhang H, Saitoh H, Matunis MJ (2002) Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex. Mol Cell Biol 22:6498–6508

    Article  PubMed  CAS  Google Scholar 

  51. Loriol C, Parisot J, Poupon G, Gwizdek C, Martin S (2012) Developmental regulation and spatiotemporal redistribution of the sumoylation machinery in the rat central nervous system. PLoS ONE 7:e33757

    Article  PubMed  CAS  Google Scholar 

  52. Shin EJ, Shin HM, Nam E, Kim WS, Kim JH, Oh BH, Yun Y (2012) DeSUMOylating isopeptidase: a second class of SUMO protease. EMBO Rep 13:339–346

    Article  PubMed  CAS  Google Scholar 

  53. Martin S, Nishimune A, Mellor JR, Henley JM (2007) SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature 447:321–325

    Article  PubMed  CAS  Google Scholar 

  54. Benson MD, Li QJ, Kieckhafer K, Dudek D, Whorton MR, Sunahara RK, Iniguez-Lluhi JA, Martens JR (2007) SUMO modification regulates inactivation of the voltage-gated potassium channel Kv1.5. Proc Natl Acad Sci USA 104:1805–1810

    Article  PubMed  CAS  Google Scholar 

  55. Martin S, Wilkinson KA, Nishimune A, Henley JM (2007) Emerging extranuclear roles of protein SUMOylation in neuronal function and dysfunction. Nat Rev Neurosci 8:948–959

    Article  PubMed  CAS  Google Scholar 

  56. Plant LD, Dementieva IS, Kollewe A, Olikara S, Marks JD, Goldstein SA (2010) One SUMO is sufficient to silence the dimeric potassium channel K2P1. Proc Natl Acad Sci USA 107:10743–10748

    Article  PubMed  CAS  Google Scholar 

  57. Plant LD, Dowdell EJ, Dementieva IS, Marks JD, Goldstein SA (2011) SUMO modification of cell surface Kv2.1 potassium channels regulates the activity of rat hippocampal neurons. J Gen Physiol 137:441–454

    Article  PubMed  CAS  Google Scholar 

  58. Takashima H, Boerkoel CF, John J, Saifi GM, Salih MA, Armstrong D, Mao Y, Quiocho FA, Roa BB, Nakagawa M, Stockton DW, Lupski JR (2002) Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet 32:267–272

    Article  PubMed  CAS  Google Scholar 

  59. Hudson JJ, Chiang SC, Wells OS, Rookyard C, El-Khamisy SF (2012) SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair. Nat Commun 3:733

    Article  PubMed  CAS  Google Scholar 

  60. Mao Y, Sun M, Desai SD, Liu LF (2000) SUMO-1 conjugation to topoisomerase I: a possible repair response to topoisomerase-mediated DNA damage. Proc Natl Acad Sci USA 97:4046–4051

    Article  PubMed  CAS  Google Scholar 

  61. van Niekerk EA, Willis DE, Chang JH, Reumann K, Heise T, Twiss JL (2007) Sumoylation in axons triggers retrograde transport of the RNA-binding protein La. Proc Natl Acad Sci USA 104:12913–12918

    Article  PubMed  CAS  Google Scholar 

  62. Ivankovic-Dikic I, Gronroos E, Blaukat A, Barth BU, Dikic I (2000) Pyk2 and FAK regulate neurite outgrowth induced by growth factors and integrins. Nat Cell Biol 2:574–581

    Article  PubMed  CAS  Google Scholar 

  63. Ren XR, Ming GL, Xie Y, Hong Y, Sun DM, Zhao ZQ, Feng Z, Wang Q, Shim S, Chen ZF, Song HJ, Mei L, Xiong WC (2004) Focal adhesion kinase in netrin-1 signaling. Nat Neurosci 7:1204–1212

    Article  PubMed  CAS  Google Scholar 

  64. Kadare G, Toutant M, Formstecher E, Corvol JC, Carnaud M, Boutterin MC, Girault JA (2003) PIAS1-mediated sumoylation of focal adhesion kinase activates its autophosphorylation. J Biol Chem 278:47434–47440

    Article  PubMed  CAS  Google Scholar 

  65. Vekrellis K, Xilouri M, Emmanouilidou E, Rideout HJ, Stefanis L (2011) Pathological roles of alpha-synuclein in neurological disorders. Lancet Neurol 10:1015–1025

    Article  PubMed  CAS  Google Scholar 

  66. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC (2011) Amyotrophic lateral sclerosis. Lancet 377:942–955

    Article  PubMed  CAS  Google Scholar 

  67. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931

    Article  PubMed  Google Scholar 

  68. 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

    Article  PubMed  CAS  Google Scholar 

  69. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de BJ, 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

    Article  PubMed  CAS  Google Scholar 

  70. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de BJ, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211

    Article  PubMed  CAS  Google Scholar 

  71. Schulz JB, Dichgans J (1999) Molecular pathogenesis of movement disorders: are protein aggregates a common link in neuronal degeneration? Curr Opin Neurol 12:433–439

    Article  PubMed  CAS  Google Scholar 

  72. Kabashi E, Durham HD (2006) Failure of protein quality control in amyotrophic lateral sclerosis. Biochim Biophys Acta 1762:1038–1050

    Article  PubMed  CAS  Google Scholar 

  73. Riley BE, Zoghbi HY, Orr HT (2005) SUMOylation of the polyglutamine repeat protein, ataxin-1, is dependent on a functional nuclear localization signal. J Biol Chem 280:21942–21948

    Article  PubMed  CAS  Google Scholar 

  74. Shinbo Y, Niki T, Taira T, Ooe H, Takahashi-Niki K, Maita C, Seino C, Iguchi-Ariga SM, Ariga H (2006) Proper SUMO-1 conjugation is essential to DJ-1 to exert its full activities. Cell Death Differ 13:96–108

    Article  PubMed  CAS  Google Scholar 

  75. Krumova P, Meulmeester E, Garrido M, Tirard M, Hsiao HH, Bossis G, Urlaub H, Zweckstetter M, Kugler S, Melchior F, Bahr M, Weishaupt JH (2011) Sumoylation inhibits alpha-synuclein aggregation and toxicity. J Cell Biol 194:49–60

    Article  PubMed  CAS  Google Scholar 

  76. Steffan JS, Agrawal N, Pallos J, Rockabrand E, Trotman LC, Slepko N, Illes K, Lukacsovich T, Zhu YZ, Cattaneo E, Pandolfi PP, Thompson LM, Marsh JL (2004) SUMO modification of Huntingtin and Huntington’s disease pathology. Science 304:100–104

    Article  PubMed  CAS  Google Scholar 

  77. Li Y, Wang H, Wang S, Quon D, Liu YW, Cordell B (2003) Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc Natl Acad Sci USA 100:259–264

    Article  PubMed  CAS  Google Scholar 

  78. Fei E, Jia N, Yan M, Ying Z, Sun Q, Wang H, Zhang T, Ma X, Ding H, Yao X, Shi Y, Wang G (2006) SUMO-1 modification increases human SOD1 stability and aggregation. Biochem Biophys Res Commun 347:406–412

    Article  PubMed  CAS  Google Scholar 

  79. Ahn K, Song JH, Kim DK, Park MH, Jo SA, Koh YH (2009) Ubc9 gene polymorphisms and late-onset Alzheimer’s disease in the Korean population: a genetic association study. Neurosci Lett 465:272–275

    Article  PubMed  CAS  Google Scholar 

  80. Karpinar DP, Balija MB, Kugler S, Opazo F, Rezaei-Ghaleh N, Wender N, Kim HY, Taschenberger G, Falkenburger BH, Heise H, Kumar A, Riedel D, Fichtner L, Voigt A, Braus GH, Giller K, Becker S, Herzig A, Baldus M, Jackle H, Eimer S, Schulz JB, Griesinger C, Zweckstetter M (2009) Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson’s disease models. EMBO J 28:3256–3268

    Article  PubMed  CAS  Google Scholar 

  81. 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 302:841

    Article  PubMed  CAS  Google Scholar 

  82. Paleologou KE, Oueslati A, Shakked G, Rospigliosi CC, Kim HY, Lamberto GR, Fernandez CO, Schmid A, Chegini F, Gai WP, Chiappe D, Moniatte M, Schneider BL, Aebischer P, Eliezer D, Zweckstetter M, Masliah E, Lashuel HA (2010) Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. J Neurosci 30:3184–3198

    Article  PubMed  CAS  Google Scholar 

  83. Gorbatyuk OS, Li S, Sullivan LF, Chen W, Kondrikova G, Manfredsson FP, Mandel RJ, Muzyczka N (2008) The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease. Proc Natl Acad Sci USA 105:763–768

    Article  PubMed  CAS  Google Scholar 

  84. Sato H, Arawaka S, Hara S, Fukushima S, Koga K, Koyama S, Kato T (2011) Authentically phosphorylated alpha-synuclein at Ser129 accelerates neurodegeneration in a rat model of familial Parkinson’s disease. J Neurosci 31:16884–16894

    Article  PubMed  CAS  Google Scholar 

  85. Marblestone JG, Edavettal SC, Lim Y, Lim P, Zuo X, Butt TR (2006) Comparison of SUMO fusion technology with traditional gene fusion systems: enhanced expression and solubility with SUMO. Protein Sci 15:182–189

    Article  PubMed  CAS  Google Scholar 

  86. Butt TR, Edavettal SC, Hall JP, Mattern MR (2005) SUMO fusion technology for difficult-to-express proteins. Protein Expr Purif 43:1–9

    Article  PubMed  CAS  Google Scholar 

  87. Kaminsky R, Denison C, Bening-Abu-Shach U, Chisholm AD, Gygi SP, Broday L (2009) SUMO regulates the assembly and function of a cytoplasmic intermediate filament protein in C. elegans. Dev Cell 17:724–735

    Article  PubMed  CAS  Google Scholar 

  88. Droescher M, Begitt A, Vinkemeier U (2011) Paracrystals of STAT proteins and their dissolution by SUMO: how reduced transcription factor solubility increases cytokine signaling. Oncotarget. 2:527–528

    PubMed  Google Scholar 

  89. Droescher M, Begitt A, Marg A, Zacharias M, Vinkemeier U (2011) Cytokine-induced paracrystals prolong the activity of signal transducers and activators of transcription (STAT) and provide a model for the regulation of protein solubility by small ubiquitin-like modifier (SUMO). J Biol Chem 286:18731–18746

    Article  PubMed  CAS  Google Scholar 

  90. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840

    Article  PubMed  CAS  Google Scholar 

  91. Dorval V, Fraser PE (2006) Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein. J Biol Chem 281:9919–9924

    Article  PubMed  CAS  Google Scholar 

  92. Crowther RA, Daniel SE, Goedert M (2000) Characterisation of isolated alpha-synuclein filaments from substantia nigra of Parkinson’s disease brain. Neurosci Lett 292:128–130

    Article  PubMed  CAS  Google Scholar 

  93. Serpell LC, Berriman J, Jakes R, Goedert M, Crowther RA (2000) Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation. Proc Natl Acad Sci USA 97:4897–4902

    Article  PubMed  CAS  Google Scholar 

  94. Pountney DL, Chegini F, Shen X, Blumbergs PC, Gai WP (2005) SUMO-1 marks subdomains within glial cytoplasmic inclusions of multiple system atrophy. Neurosci Lett 381:74–79

    Article  PubMed  CAS  Google Scholar 

  95. Um JW, Chung KC (2006) Functional modulation of parkin through physical interaction with SUMO-1. J Neurosci Res 84:1543–1554

    Article  PubMed  CAS  Google Scholar 

  96. La Spada AR, Paulson HL, Fischbeck KH (1994) Trinucleotide repeat expansion in neurological disease. Ann Neurol 36:814–822

    Article  PubMed  Google Scholar 

  97. Orr HT (2012) Cell biology of spinocerebellar ataxia. J Cell Biol 197:167–177

    Article  PubMed  CAS  Google Scholar 

  98. Ueda H, Goto J, Hashida H, Lin X, Oyanagi K, Kawano H, Zoghbi HY, Kanazawa I, Okazawa H (2002) Enhanced SUMOylation in polyglutamine diseases. Biochem Biophys Res Commun 293:307–313

    Article  PubMed  CAS  Google Scholar 

  99. Ryu J, Cho S, Park BC, Lee dH (2010) Oxidative stress-enhanced SUMOylation and aggregation of ataxin-1: implication of JNK pathway. Biochem Biophys Res Commun 393:280–285

    Article  PubMed  CAS  Google Scholar 

  100. Janer A, Werner A, Takahashi-Fujigasaki J, Daret A, Fujigasaki H, Takada K, Duyckaerts C, Brice A, Dejean A, Sittler A (2010) SUMOylation attenuates the aggregation propensity and cellular toxicity of the polyglutamine expanded ataxin-7. Hum Mol Genet 19:181–195

    Article  PubMed  CAS  Google Scholar 

  101. Chan HY, Warrick JM, Andriola I, Merry D, Bonini NM (2002) Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum Mol Genet 11:2895–2904

    Article  PubMed  CAS  Google Scholar 

  102. Selkoe DJ (1998) The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol 8:447–453

    Article  PubMed  CAS  Google Scholar 

  103. Dorval V, Mazzella MJ, Mathews PM, Hay RT, Fraser PE (2007) Modulation of Abeta generation by small ubiquitin-like modifiers does not require conjugation to target proteins. Biochem. J. 404:309–316

    Article  PubMed  CAS  Google Scholar 

  104. Zhang YQ, Sarge KD (2008) Sumoylation of amyloid precursor protein negatively regulates Abeta aggregate levels. Biochem Biophys Res Commun 374:673–678

    Article  PubMed  CAS  Google Scholar 

  105. Gibb SL, Boston-Howes W, Lavina ZS, Gustincich S, Brown RH Jr, Pasinelli P, Trotti D (2007) A caspase-3-cleaved fragment of the glial glutamate transporter EAAT2 is sumoylated and targeted to promyelocytic leukemia nuclear bodies in mutant SOD1-linked amyotrophic lateral sclerosis. J Biol Chem 282:32480–32490

    Article  PubMed  CAS  Google Scholar 

  106. Boston-Howes W, Gibb SL, Williams EO, Pasinelli P, Brown RH Jr, Trotti D (2006) Caspase-3 cleaves and inactivates the glutamate transporter EAAT2. J Biol Chem 281:14076–14084

    Article  PubMed  CAS  Google Scholar 

  107. Foran E, Bogush A, Goffredo M, Roncaglia P, Gustincich S, Pasinelli P, Trotti D (2011) Motor neuron impairment mediated by a sumoylated fragment of the glial glutamate transporter EAAT2. Glia 59:1719–1731

    Article  PubMed  Google Scholar 

  108. 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

    Article  PubMed  CAS  Google Scholar 

  109. Mackenzie IR, Rademakers R, Neumann M (2010) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9:995–1007

    Article  PubMed  CAS  Google Scholar 

  110. Geser F, Lee VM, Trojanowski JQ (2010) Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies. Neuropathology 30:103–112

    Article  PubMed  Google Scholar 

  111. Lieberman AP, Robitaille Y, Trojanowski JQ, Dickson DW, Fischbeck KH (1998) Polyglutamine-containing aggregates in neuronal intranuclear inclusion disease. Lancet 351:884

    Article  PubMed  CAS  Google Scholar 

  112. Pountney DL, Huang Y, Burns RJ, Haan E, Thompson PD, Blumbergs PC, Gai WP (2003) SUMO-1 marks the nuclear inclusions in familial neuronal intranuclear inclusion disease. Exp Neurol 184:436–446

    Article  PubMed  CAS  Google Scholar 

  113. Takahashi-Fujigasaki J, Arai K, Funata N, Fujigasaki H (2006) SUMOylation substrates in neuronal intranuclear inclusion disease. Neuropathol Appl Neurobiol 32:92–100

    Article  PubMed  CAS  Google Scholar 

  114. Weishaupt JH, Bahr M (2001) Degeneration of axotomized retinal ganglion cells as a model for neuronal apoptosis in the central nervous system—molecular death and survival pathways. Restor Neurol Neurosci 19:19–27

    PubMed  CAS  Google Scholar 

  115. Kermer P, Liman J, Weishaupt JH, Bahr M (2004) Neuronal apoptosis in neurodegenerative diseases: from basic research to clinical application. Neurodegener Dis 1:9–19

    Article  PubMed  Google Scholar 

  116. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1:515–525

    Article  PubMed  CAS  Google Scholar 

  117. Meuer K, Suppanz IE, Lingor P, Planchamp V, Goricke B, Fichtner L, Braus GH, Dietz GP, Jakobs S, Bahr M, Weishaupt JH (2007) Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis. Cell Death Differ 14:651–661

    Article  PubMed  CAS  Google Scholar 

  118. Harder Z, Zunino R, McBride H (2004) Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr Biol 14:340–345

    PubMed  CAS  Google Scholar 

  119. Zunino R, Schauss A, Rippstein P, Andrade-Navarro M, McBride HM (2007) The SUMO protease SENP5 is required to maintain mitochondrial morphology and function. J Cell Sci 120:1178–1188

    Article  PubMed  CAS  Google Scholar 

  120. Braschi E, Zunino R, McBride HM (2009) MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission. EMBO Rep 10:748–754

    Article  PubMed  CAS  Google Scholar 

  121. Wasiak S, Zunino R, McBride HM (2007) Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J Cell Biol 177:439–450

    Article  PubMed  CAS  Google Scholar 

  122. Besnault-Mascard L, Leprince C, Auffredou MT, Meunier B, Bourgeade MF, Camonis J, Lorenzo HK, Vazquez A (2005) Caspase-8 sumoylation is associated with nuclear localization. Oncogene 24:3268–3273

    Article  PubMed  CAS  Google Scholar 

  123. Hayashi N, Shirakura H, Uehara T, Nomura Y (2006) Relationship between SUMO-1 modification of caspase-7 and its nuclear localization in human neuronal cells. Neurosci Lett 397:5–9

    Article  PubMed  CAS  Google Scholar 

  124. Lee Y-J, Mou Y, Maric D, Klimanis D, Auh S, Hallenbeck JM (2011) Elevated global SUMOylation in Ubc9 transgenic mice protects their brains against focal cerebral ischemic damage. PLoS ONE 6(10):e25852

    Article  PubMed  CAS  Google Scholar 

  125. Andersen PM, Al-Chalabi A (2011) Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol 7:603–615

    Article  PubMed  CAS  Google Scholar 

  126. Bossis G, Melchior F (2006) Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes. Mol Cell 21:349–357

    Article  PubMed  CAS  Google Scholar 

  127. Han Y, Huang C, Sun X, Xiang B, Wang M, Yeh ET, Chen Y, Li H, Shi G, Cang H, Sun Y, Wang J, Wang W, Gao F, Yi J (2010) SENP3-mediated de-conjugation of SUMO2/3 from promyelocytic leukemia is correlated with accelerated cell proliferation under mild oxidative stress. J Biol Chem 285:12906–12915

    Article  PubMed  CAS  Google Scholar 

  128. Cimarosti H, Lindberg C, Bomholt SF, Ronn LC, Henley JM (2008) Increased protein SUMOylation following focal cerebral ischemia. Neuropharmacology 54:280–289

    Article  PubMed  CAS  Google Scholar 

  129. Chan JY, Tsai CY, Wu CH, Li FC, Dai KY, Sun EY, Chan SH, Chang AY (2011) Sumoylation of hypoxia-inducible factor-1alpha ameliorates failure of brain stem cardiovascular regulation in experimental brain death. PLoS ONE 6:e17375

    Article  PubMed  CAS  Google Scholar 

  130. Poukka H, Karvonen U, Janne OA, Palvimo JJ (2000) Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1). Proc Natl Acad Sci USA 97(26):14145–14150. PMID:11121022

    Google Scholar 

  131. Mukherjee S, Thomas M, Dadgar N, Lieberman AP, Iñiguez-Lluhí JA ( 2009) Small ubiquitin-like modifier (SUMO) modification of the androgen receptor attenuates polyglutamine-mediated aggregation. J Biol Chem 284(32):21296–21306. PMID:19497852

    Google Scholar 

  132. Terashima T, Kawai H, Fujitani M, Maeda K, Yasuda H (2002) SUMO-1 co-localized with mutant atrophin-1 with expanded polyglutamines accelerates intranuclear aggregation and cell death. Neuroreport 13(17):2359–2364. PMID:12488827

    Google Scholar 

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Acknowledgments

This work was supported by the Charcot Foundation for ALS Research (JHW).

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Authors and Affiliations

  1. Neuroscience, Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002, Basel, Switzerland

    Petranka Krumova

  2. Neurology Department, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany

    Jochen H. Weishaupt

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  1. Petranka Krumova
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  2. Jochen H. Weishaupt
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Correspondence to Jochen H. Weishaupt.

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Krumova, P., Weishaupt, J.H. Sumoylation in neurodegenerative diseases. Cell. Mol. Life Sci. 70, 2123–2138 (2013). https://doi.org/10.1007/s00018-012-1158-3

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