Skip to main content
SpringerLink
Log in

Sumoylation: Implications for Neurodegenerative Diseases

  • Chapter
  • First Online:
SUMO Regulation of Cellular Processes

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 963))

Abstract

The covalent posttranslational modifications of proteins are critical events in signaling cascades that enable cells to efficiently, rapidly and reversibly respond to extracellular stimuli. This is especially important in the CNS where the processes affecting synaptic communication between neurons are highly complex and very tightly regulated. Sumoylation regulates the function and fate of a diverse array of proteins and participates in the complex cell signaling pathways required for cell survival. One of the most complex signaling pathways is synaptic transmission.

Correct synaptic function is critical to the working of the brain and its alteration through synaptic plasticity mediates learning, mental disorders and stroke. The investigation of neuronal sumoylation is a new and exciting field and the functional and pathophysiological implications are far-reaching. Sumoylation has already been implicated in a diverse array of neurological disorders. Here we provide an overview of current literature highlighting recent insights into the role of sumoylation in neurodegeneration. In addition we present a brief assessment of drug discovery in the analogous ubiquitin system and extrapolate on the potential for development of novel therapies that might target SUMO-associated mechanisms of neurodegenerative disease.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abeywardana T, Pratt MR (2015) Extent of inhibition of α-synuclein aggregation in vitro by SUMOylation is conjugation site- and SUMO isoform-selective. Biochemist 54:959–961

    Article  CAS  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152:879–884

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bae SH, Jeong JW, Park JA, Kim SH, Bae MK, Choi SJ, Kim KW (2004) Sumoylation increases HIF-1alpha stability and its transcriptional activity. Biochem Biophys Res Commun 324:394–400

    Article  CAS  PubMed  Google Scholar 

  • Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8:663–672

    Article  CAS  PubMed  Google Scholar 

  • Capili AD, Lima CD (2007) Structure and analysis of a complex between SUMO and Ubc9 illustrates features of a conserved E2-Ubl interaction. J Mol Biol 369:608–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carbia-Nagashima A, Gerez J, Perez-Castro C, Paez-Pereda M, Silberstein S, Stalla GK, Holsboer F, Arzt E (2007) RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia. Cell 131:309–323

    Article  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123:383–396

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Qi L (2010) SUMO modification regulates the transcriptional activity of XBP1. Biochem J 429:95–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng J, Kang X, Zhang S, Yeh ET (2007) SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell 131:584–595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho SJ, Yun SM, Jo C, Lee DH, Choi KJ, Song JC, Park SI, Kim YJ, Koh YH (2015a) SUMO1 promotes Aβ production via the modulation of autophagy. Autophagy 11:100–112

    Article  PubMed  Google Scholar 

  • Cho SJ, Yun SM, Lee DH, Jo C, Ho Park M, Han C, Ho Koh Y (2015b) Plasma SUMO1 protein is elevated in Alzheimer’s disease. J Alzheimers Dis 47:639–643

    Article  CAS  PubMed  Google Scholar 

  • Chua JP, Reddy SL, Yu Z, Giorgetti E, Montie HL, Mukherjee S, Higgins J, McEachin RC, Robins DM, Merry DE, Iñiguez-Lluhí JA, Lieberman AP (2015) Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease. J Clin Invest 2:831–845

    Article  Google Scholar 

  • Ciechanover A, Brundin P (2003) The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40:427–446

    Article  CAS  PubMed  Google Scholar 

  • Cimarosti H, Henley JM (2008) Investigating the mechanisms underlying neuronal death in ischaemia using in vitro oxygen-glucose deprivation: potential involvement of protein SUMOylation. Neuroscientist 14:626–636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Cimarosti H, Ashikaga E, Jaafari N, Dearden L, Rubin P, Wilkinson KA, Henley JM (2012) Enhanced SUMOylation and SENP-1 protein levels following oxygen and glucose deprivation in neurons. J Cereb Blood Flow Metab 32:17–22

    Article  CAS  PubMed  Google Scholar 

  • Craig TJ, Henley JM (2015) Fighting polyglutamine disease by wrestling with SUMO. J Clin Invest 125:498–500

    Article  PubMed  PubMed Central  Google Scholar 

  • Datwyler AL, Lättig-Tünnemann G, Yang W, Paschen W, Lee SLL, Dirnagl U, Endres M, Harms C (2011) SUMO2/3 conjugation is an endogenous neuroprotective mechanism. J Cereb Blood Flow Metab 31:2152–2159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • David G, Neptune MA, DePinho RA (2002) SUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities. J Biol Chem 277:23658–23663

    Article  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • Dorval V, Fraser PE (2007) SUMO on the road to neurodegeneration. Biochim Biophys Acta 1773:694–706

    Article  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  PubMed Central  Google Scholar 

  • Eckermann K (2013) SUMO and Parkinson ’s disease. NeuroMolecular Med 15:737–759

    Article  CAS  PubMed  Google Scholar 

  • Ehrnhoefer DE, Sutton L, Hayden MR (2011) Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease. Neuroscientist 17:475–492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang H, Du X, Meng FT, Zhou JN (2011) SUMO negatively regulates BACE expression. Neuro Endocrinol Lett 32:313–316

    CAS  PubMed  Google Scholar 

  • Fei E, Jia N, Yan M, Zing Z, Sun Z, 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  CAS  PubMed  Google Scholar 

  • Feligioni M, Brambilla E, Camassa A, Sclip A, Arnaboldi A, Morelli F, Antoniou X, Borsello T (2012) Crosstalk between JNK and SUMO signaling pathways: deSUMOylation is protective against H2O2-induced cell injury. PLoS One 6:e28185

    Article  CAS  Google Scholar 

  • 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  PubMed Central  Google Scholar 

  • Foran E, Rosenblum L, Bogush AI, Trotti D (2013) Sumoylation of critical proteins in amyotrophic lateral sclerosis: emerging pathways of pathogenesis. NeuroMolecular Med 15:1–18

    Article  CAS  Google Scholar 

  • Foran E, Rosenblum L, Bogush A, Pasinelli P, Trotti D (2014) SUMOylation of the astroglial glutamate transporter EAAT2 governs its intracellular compartmentalization. Glia 2:1241–1253

    Article  Google Scholar 

  • Gatchel JR, Zoghbi HY (2005) Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet 6:743–755

    Article  CAS  PubMed  Google Scholar 

  • Gil JM, Rego AC (2008) Mechanisms of neurodegeneration in Huntington’s disease. Eur J Neurosci 27:2803–2820

    Article  PubMed  Google Scholar 

  • Gocke CB, Yu H, Kang J (2005) Systematic identification and analysis of mammalian small ubiquitin-like modifier substrates. J Biol Chem 280:5004–5012

    Article  CAS  PubMed  Google Scholar 

  • Guedat P, Colland F (2007) Patented small molecule inhibitors in the ubiquitin proteasome system. BMC Biochem 8:S14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Guerra de Souza AC, Prediger RD, Cimarosti H (2016) SUMO-regulated mitochondrial function in Parkinson’s disease. J. Neurochem 137(5):673–686

    Article  CAS  PubMed  Google Scholar 

  • Guo C, Hildick KL, Luo J, Dearden L, Wilkinson KA, Henley JM (2013) SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia. EMBO J 32:1514–1528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo L, Giasson BI, Bloom AG, Brewer MD, Shorter J, Gitler AD, Yang X (2014) A cellular system that degrades misfolded proteins and protects against neurodegeneration. Mol Cell 55:15–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han Y, Huang C, Sun X, Xiang B, Wang M, Yeh ETH, Chen Y, Li H, Shi G, Cang H, Sun YP, 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  CAS  PubMed  PubMed Central  Google Scholar 

  • Henley JM, Craig TJ, Wilkinson KA (2014) Neuronal sumoylation: mechanisms, physiology, and roles in neuronal dysfunction. Physiol Rev 94:1249–1285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heun P (2007) SUMOrganization of the nucleus. Curr Opin Cell Biol 19:350–355

    Article  CAS  PubMed  Google Scholar 

  • Hoppe JB, Rattray M, Tu H, Salbego CG, Cimarosti H (2013) SUMO-1 conjugation blocks beta-amyloid-induced astrocyte reactivity. Neurosci Lett 546:51–56

    Article  CAS  PubMed  Google Scholar 

  • Hoppe JB, Salbego CG, Cimarosti H (2015) SUMOylation: novel neuroprotective approach for Alzheimer’s disease? Aging Dis 6:322–330

    Article  PubMed  PubMed Central  Google Scholar 

  • Huang C, Han Y, Wang Y, Sun X, Yan S, Yeh ETH, Chen Y, Cang H, Li H, Shi G, Cheng J, Tang X, Yi J (2009) SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation. EMBO J 28:2748–2762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, Masucci M, Pramanik A, Selivanova G (2004) Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 10:1321–1328

    Article  CAS  PubMed  Google Scholar 

  • 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 9:181–195

    Article  CAS  Google Scholar 

  • Jiang Z, Fan Q, Zhang Z, Zou Y, Cai R, Wang Q, Zuo Y, Cheng J (2012) SENP1 deficiency promotes ER stress-induced apoptosis by increasing XBP1 SUMOylation. Cell Cycle 11:1118–1122

    Article  CAS  PubMed  Google Scholar 

  • Johnson F, Giulivi C (2005) Superoxide dismutases and their impact upon human health. Mol Asp Med 26:340–352

    Article  CAS  Google Scholar 

  • Kerscher O (2007) SUMO junction-what’s your function? New insights through SUMO interacting motifs. EMBO Rep 8:550–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim YM, Jang WH, Quezado MM, Oh Y, Chung KC, Junn E, Mouradian MM (2011) Proteasome inhibition induces α-synuclein SUMOylation and aggregate formation. J Neurol Sci 307:157–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krumova P, Weishaupt JH (2013) Sumoylation in neurodegenerative diseases. Cell Mol Life Sci 70:2123–2138

    Article  CAS  PubMed  Google Scholar 

  • Krumova P, Meulmeester E, Garrido M, Tirard M, Hsiao HH, Bossis G, Urlaub H, Zweckstetter M, Kügler S, Melchior F, Bähr M, Weishaupt JH (2011) SUMOylation inhibits α-synuclein aggregation and toxicity. J Cell Biol 194:49–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar A, Ito A, Takemoto M, Yoshida M, Zhang KYJ (2014) Identification of 1,2,5-oxadiazoles as a new class of SENP2 inhibitors using structure based virtual screening. J Chem Inf Model 54:870–880

    Article  CAS  PubMed  Google Scholar 

  • Kumar A, Ito A, Hirohama M, Yoshida M, Zhang KYJ (2016) Identification of new SUMO activating enzyme 1 inhibitors using virtual screening and scaffold hopping. Bioorg Med Chem Lett 26:1218–1223

    Article  CAS  PubMed  Google Scholar 

  • Kunadt M, Eckermann K, Stuendl A, Gong J, Russo B, Strauss K, Rai S, Kügler S, Lockhart LF, Schwalbe M, Krumova P, Oliveira LMA, Bahr M, Mobius W, Levin J, Giese A, Kruse N, Mollenhauer B, Friedlander RG, Ludolph AC, Freischmidt A, Feiler MS, Danzer KM, Zweckstetter M, Jovin TM, Simons M, Weishaupt JH, Schneider A (2015) Extracellular vesicle sorting of α-synuclein is regulated by SUMOylation. Acta Neuropathol 129:695–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee YJ, Hallenbeck JM (2006) Insights into cytoprotection from ground squirrel hibernation, a natural model of tolerance to profound brain oligaemia. Biochem Soc Trans 34:1295–1298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee YJ, Hallenbeck JM (2013) SUMO and ischemic tolerance. Neuromolecular Med 15:771–781

    Article  CAS  PubMed  Google Scholar 

  • Lee YJ, Miyake S, Wakita H, McMullen DC, Azuma Y, Auh S, Hallenbeck JM (2007) Protein SUMOylation is massively increased in hibernation torpor and is critical for the cytoprotection provided by ischemic preconditioning and hypothermia in SHSY5Y cells. J Cereb Blood Flow Metab 27:950–962

    Article  CAS  PubMed  Google Scholar 

  • Lee Y, Castri P, Bembry J, Maric D, Auh S, Hallenbeck JM (2009) SUMOylation participates in induction of ischemic tolerance. J Neurochem 109:257–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee Y, 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:e25852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee L, Dale E, Staniszewski A, Zhang H, Saeed F, Sakurai M, Fá M, Orozco I, Michelassi F, Akpan N, Lehrer H, Arancio O (2014a) Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer’s disease. Sci Rep 4:7190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee Y, Mou Y, Klimanis D, Bernstock JD, Hallenbeck JM (2014b) Global SUMOylation is a molecular mechanism underlying hypothermia-induced ischemic tolerance. Front Cell Neurosci 8:416

    PubMed  PubMed Central  Google Scholar 

  • Leitao BB, Jones MC, Brosens JJ (2011) The SUMO E3-ligase PIAS1 couples reactive oxygen species-dependent JNK activation to oxidative cell death. FASEB J 25:3416–3425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 U S A 100:259–264

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lieberman AP, Trojanowski JQ, Leonard DG, Chen KL, Barnett JL, Leverenz JB, Bird TD, Robitaille Y, Malandrini A, Fischbeck KH (1999) Ataxin 1 and ataxin 3 in neuronal intranuclear inclusion disease. Ann Neurol 46:271–273

    Article  CAS  PubMed  Google Scholar 

  • Liu B, Shuai K (2008) Targeting the PIAS1 SUMO ligase pathway to control inflammation. Trends Pharmacol Sci 29:505–509

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Loftus LT, Gala R, Yang T, Jessick VJ, Ashley MD, Ordonez AN, Thompson SJ, Simon RP, Meller R (2009) SUMO-2/3-ylation following in vitro modeled ischemia is reduced in delayed ischemic tolerance. Brain Res 1272:71–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lois LM, Lima CD (2005) Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1. EMBO J 24:439–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo HB, Xia YY, Shu XJ, Liu ZC, Feng Y, Liu XH, Yu G, Yin G, Xiong YS, Zeng K, Jiang J, Ye K, Wang XC, Wang JZ (2014) SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination. Proc Natl Acad Sci U S A 18:16586–16591

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martins WC, Tasca CI, Cimarosti H (2016) Battling Alzheimer’s disease: targeting SUMOylation-mediated pathways. Neurochem Res 41:568–578

    Article  CAS  PubMed  Google Scholar 

  • McCoy MK, Tansey MG (2008) TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 5:45

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • McFadden K, Hamilton RL, Insalaco SJ, Lavine L, Al-Mateen M, Wang G, Wiley CA (2005) Neuronal intranuclear inclusion disease without polyglutamine inclusions in a child. J Neuropathol Exp Neurol 64:545–552

    Article  PubMed  PubMed Central  Google Scholar 

  • McMillan LE, Brown JT, Henley JM, Cimarosti H (2011) Profiles of SUMO and ubiquitin conjugation in an Alzheimer’s disease model. Neurosci Lett 502:201–208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michels G, Hoppe UC (2008) Rapid actions of androgens. Front Neuroendocrinol 29:182–198

    Article  CAS  PubMed  Google Scholar 

  • Moore DJ, Zhang L, Dawson TM, Dawson VL (2003) A missense mutation (L166P) in DJ-1, linked to familial Parkinson’s disease, confers reduced protein stability and impairs homo-oligomerization. J Neurochem 87:1558–1567

    Article  CAS  PubMed  Google Scholar 

  • 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 284:21296–21306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mukhopadhyay D, Dasso M (2007) Modification in reverse: the SUMO proteases. Trends Biochem Sci 32:286–295

    Article  CAS  PubMed  Google Scholar 

  • Nalepa G, Rolfe M, Harper JW (2006) Drug discovery in the ubiquitin-proteasome system. Nat Rev Drug Discov 5:596–613

    Article  CAS  PubMed  Google Scholar 

  • Navascues J, Bengoechea R, Tapia O, Casafont I, Berciano MT, Lafarga M (2008) SUMO-1 transiently localizes to Cajal bodies in mammalian neurons. J Struct Biol 163:137–146

    Article  CAS  PubMed  Google Scholar 

  • Niikura T, Kita Y, Abe Y (2014) SUMO3 modification accelerates the aggregation of LS-linked SOD1 mutants. PLoS One 9:e101080

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nisticò R, Ferraina C, Marconi V, Blandini F, Negri L, Egebjerg J, Feligioni M (2014) Age-related changes of protein SUMOylation balance in the AβPP Tg2576 mouse model of Alzheimer’s disease. Front Pharmacol 5:63

    PubMed  PubMed Central  Google Scholar 

  • Oh Y, Kim YM, Mouradian MM, Chung KC (2011) Human polycomb protein 2 promotes α-synuclein aggregate formation through covalent SUMOylation. Brain Res 1381:78–89

    Article  CAS  PubMed  Google Scholar 

  • Olzmann JA, Brown K, Wilkinson KD, Rees HD, Huai Q, Ke H, Levey AI, Li L, Chin LS (2004) Familial Parkinson’s disease-associated L166P mutation disrupts DJ-1 protein folding and function. J Biol Chem 279:8506–8515

    Article  CAS  PubMed  Google Scholar 

  • 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 U S A 97:14145–14150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • Pountney DL, Raftery MJ, Chegini F, Blumbergs PC, Gai WP (2008) NSF, Unc- 18-1, dynamin-1 and HSP90 are inclusion body components in neuronal intranuclear inclusion disease identified by anti-SUMO-1-immunocapture. Acta Neuropathol 116:603–614

    Article  CAS  PubMed  Google Scholar 

  • Ren R (2005) Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 5:172–183

    Article  CAS  PubMed  Google Scholar 

  • Reverter D, Lima CD (2005) Insights into E3 ligase activity revealed by a SUMORanGAP1- Ubc9-Nup358 complex. Nature 435:687–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reverter D, Lima CD (2006) Structural basis for SENP2 protease interactions with SUMO precursors and conjugated substrates. Nat Struct Mol Biol 13:1060–1068

    Article  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10:S10–S17

    Article  PubMed  CAS  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • Schilling G, Wood JD, Duan K, Slunt HH, Gonzales V, Yamada M, Cooper JK, Margolis RL, Jenkins NA, Copeland NG, Takahashi H, Tsuji S, Price DL, Borchelt DR, Ross CA (1999) Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA. Neuron 24:275–286

    Article  CAS  PubMed  Google Scholar 

  • Seeler JS, Dejean A (2003) Nuclear and unclear functions of SUMO. Nat Rev Cell Biol 4:690–699

    Article  CAS  Google Scholar 

  • Shahpasandzadeh H, Popova B, Kleinknecht A, Fraser PE, Outeiro TF, Braus GH (2014) Interplay between Sumoylation and phosphorylation for protection against α-synuclein inclusions. J Biol Chem 289:31224–31240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shao R, Zhang FP, Tian F, Anders Friberg P, Wang X, Sjoland H, Billig H (2004) Increase of SUMO-1 expression in response to hypoxia: direct interaction with HIF-1alpha in adult mouse brain and heart in vivo. FEBS Lett 569:293–300

    Article  CAS  PubMed  Google Scholar 

  • Shen L, Tatham MH, Dong C, Zagorska A, Naismith JH, Hay RT (2006) SUMO protease SENP1 induces isomerization of the scissile peptide bond. Nat Struct Mol Biol 13:1069–1077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • Silveirinha V, Stephens GJ, Cimarosti H (2013) Molecular targets underlying SUMO-mediated neuroprotection in brain ischemia. J Neurochem 127:580–591

    Article  CAS  PubMed  Google Scholar 

  • Sone J, Tanaka F, Koike H, Inukai A, Katsuno M, Yoshida M, Watanabe H, Sobue G (2011) Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease. Neurology 76:1372–1376

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Sramko M, Markus J, Kabat J, Wolff L, Bies J (2006) Stress-induced inactivation of the c-Myb transcription factor through conjugation of SUMO-2/3 proteins. J Biol Chem 281:40065–40075

    Article  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • Subramaniam S, Sixt KM, Barrow R, Snyder SH (2009) Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 324:1327–1330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Subramaniam S, Mealer RG, Sixt KM, Barrow RK, Usiello A, Snyder SH (2010) Rhes, a physiologic regulator of sumoylation, enhances cross-sumoylation between the basic sumoylation enzymes E1 and Ubc9. J Biol Chem 285:20428–20432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H (2004) DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep 5:213–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takahashi K, Taira T, Niki T, Seino C, Iguchi-Ariga SM, Ariga H (2001) DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor. J Biol Chem 276:37556–37563

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Ishida M, Komano H, Takahashi H (2008) SUMO-1 immunoreactivity colocalizes with phospho-Tau in APP transgenic mice but not in mutant Tau transgenic mice. Neurosci Lett 441:90–93

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Tan EK, Skipper LM (2007) Pathogenic mutations in Parkinson disease. Hum Mutat 28:641–653

    Article  CAS  PubMed  Google Scholar 

  • Tempe D, Piechaczyk M, Bossis G (2008) SUMO under stress. Biochem Soc Trans 36:874–878

    Article  CAS  PubMed  Google Scholar 

  • 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 13:2359–2364

    Article  CAS  PubMed  Google Scholar 

  • Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J (2004) The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 62:1984–1989

    Article  CAS  PubMed  Google Scholar 

  • Tong L, Wu Z, Ran M, Chen Y, Yang L, Zhang H, Zhang L, Dong H, Xiong L (2015) The role of SUMO-conjugating enzyme ubc9 in the neuroprotection of isoflurane preconditioning against ischemic neuronal injury. Mol Neurobiol 51:1221–1231

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Um JW, Min DS, Rhim H, Kim J, Paik SR, Chung KC (2006) Parkin ubiquitinates and promotes the degradation of RanBP2. J Biol Chem 281:3595–3603

    Article  CAS  PubMed  Google Scholar 

  • Uno M, Koma Y, Ban HS, Nakamura H (2012) Discovery of 1-[4-(N-benzylamino)phenyl]-3-phenylurea derivatives as non-peptidic selective SUMO-sentrin specific protease (SENP)1 inhibitors. Bioorg Med Chem Lett 22:5169–5173

    Article  CAS  PubMed  Google Scholar 

  • Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–848

    Article  CAS  PubMed  Google Scholar 

  • Vijayakumaran S, Wong MB, Antony H, Pountney DL (2015) Direct and/or indirect roles for SUMO in modulating Alpha-Synuclein toxicity. Biomolecules 5:1697–1716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wakabayashi K, Tanji K, Mori F, Takahashi H (2007) The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates. Neuropathology 27:494–506

    Article  PubMed  Google Scholar 

  • Wang L, Charroux B, Kerridge S, Tsai CC (2008) Atrophin recruits HDAC1/2 and G9a to modify histone H3K9 and to determine cell fates. EMBO Rep 9:555–562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Ma Q, Yang W, Mackensen GB, Paschen W (2012) Moderate hypothermia induces marked increase in levels and nuclear accumulation of SUMO2/3-conjugated proteins in neurons. J Neurochem 123:349–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weetman J, Wong MB, Sharry S, Rcom-H’cheo-Gauthier A, Gai WP, Meedeniya A, Pountney DL (2013) Increased SUMO-1 expression in the unilateral rotenone-lesioned mouse model of Parkinson’s disease. Neurosci Lett 544:119–124

    Article  CAS  PubMed  Google Scholar 

  • Wiltshire KM, Dunham C, Reid S, Auer RN, Suchowersky O (2010) Neuronal intranuclear inclusion disease presenting as juvenile Parkinsonism. Can J Neurol Sci 37:213–218

    Article  PubMed  Google Scholar 

  • Wolfe MS (2006) The gamma-secretase complex: membrane-embedded proteolytic ensemble. Biochemist 45:7931–7939

    Article  CAS  Google Scholar 

  • Wuerzberger-Davis SM, Nakamura Y, Seufzer BJ, Miyamoto S (2007) NF-kappaB activation by combinations of NEMO SUMOylation and ATM activation stresses in the absence of DNA damage. Oncogene 26:641–651

    Article  CAS  PubMed  Google Scholar 

  • Yang W, Sheng H, Homi HM, Warner DS, Paschen W (2008a) Cerebral ischemia/stroke and small ubiquitin-like modifier (SUMO) conjugation – a new target for therapeutic intervention? J Neurochem 106:989–999

    Article  CAS  PubMed  Google Scholar 

  • Yang W, Sheng H, Warner DS, Paschen W (2008b) Transient focal cerebral ischemia induces a dramatic activation of small ubiquitin-like modifier conjugation. J Cereb Blood Flow Metab 28:892–896

    Article  PubMed  CAS  Google Scholar 

  • Yang W, Sheng H, Warner DS, Paschen W (2008c) Transient global cerebral ischemia induces a massive increase in protein sumoylation. J Cereb Blood Flow Metab 28:269–279

    Article  PubMed  CAS  Google Scholar 

  • Yang W, Thompson JW, Wang Z, Wang L, Sheng H, Foster MW, Moseley MA, Paschen W (2012a) Analysis of oxygen/glucose-deprivation-induced changes in SUMO3 conjugation using SILAC-based quantitative proteomics. J Proteome Res 11:1108–1117

    Article  CAS  PubMed  Google Scholar 

  • Yang QG, Wang F, Zhang Q, Xu WR, Chen YP, Chen GH (2012b) Correlation of increased hippocampal Sumo3 with spatial learning ability in old C57BL/6 mice. Neurosci Lett 518:75–79

    Article  CAS  PubMed  Google Scholar 

  • Yazawa I, Nukina N, Hashida H, Goto J, Yamada M, Kanazawa I (1995) Abnormal gene product identified in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) brain. Nat Genet 10:99–103

    Article  CAS  PubMed  Google Scholar 

  • Yun SM, Cho SJ, Song JC, Song SY, Jo SA, Jo C, Yoon K, Tanzi RE, Choi EJ, Koh YH (2013) SUMO1 modulates Aβ generation via BACE1 accumulation. Neurobiol Aging 34:650–662

    Article  CAS  PubMed  Google Scholar 

  • Yunus AA, Lima CD (2006) Lysine activation and functional analysis of E2-mediated conjugation in the SUMO pathway. Nat Struct Mol Biol 13:491–499

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Goodson ML, Hong Y, Sarge KD (2008) MEL-18 interacts with HSF2 and the SUMO E2 UBC9 to inhibit HSF2 sumoylation. J Biol Chem 283:7464–7469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao X, Sternsdorf T, Bolger TA, Evans RM, Yao TP (2005) Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol Cell Biol 25:8456–8464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou YF, Liao SS, Luo YY, Tang JG, Wang JL, Lei LF, Chi JW, Du J, Jiang H, Xia K, Tang BS, Shen L (2013) SUMO-1 modification on K166 of polyQ-expanded ataxin-3 strengthens its stability and increases its cytotoxicity. PLoS One 8:e54214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zoghbi HY, Orr HT (2000) Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23:217–247

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Camila Zanella is a PhD student funded by CNPq. We are grateful to the Welcome Trust, BBSRC, MRC, ERC, Newton Fund/Royal Society, IBRO and ISN-CAEN for financial support.

Author information

Authors and Affiliations

  1. Ipsen Bioinnovation Ltd, Units 4-10 The Quadrant, Barton Lane, Abingdon, OX14 3YS, UK

    Dina B. Anderson

  2. Department of Pharmacology, Federal University of Santa Catarina, Campus Universitario – Trindade, Florianopolis, CEP, 88040-900, Brazil

    Camila A. Zanella & Helena Cimarosti

  3. MRC Centre for Synaptic Plasticity, School of Biochemistry, University of Bristol, University Walk, Bristol, BS8 1TD, UK

    Jeremy M. Henley

Authors
  1. Dina B. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Camila A. Zanella
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeremy M. Henley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Helena Cimarosti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helena Cimarosti .

Editor information

Editors and Affiliations

  1. Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M Health Science Center, Bryan, Texas, USA

    Van G. Wilson

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Anderson, D.B., Zanella, C.A., Henley, J.M., Cimarosti, H. (2017). Sumoylation: Implications for Neurodegenerative Diseases. In: Wilson, V. (eds) SUMO Regulation of Cellular Processes. Advances in Experimental Medicine and Biology, vol 963. Springer, Cham. https://doi.org/10.1007/978-3-319-50044-7_16

Download citation

Publish with us

Policies and ethics

Search

Navigation