Molecular Neurobiology

, Volume 53, Issue 8, pp 5229–5251 | Cite as

Inhibition of Protein Ubiquitination by Paraquat and 1-Methyl-4-Phenylpyridinium Impairs Ubiquitin-Dependent Protein Degradation Pathways

  • Juliana Navarro-Yepes
  • Annadurai Anandhan
  • Erin Bradley
  • Iryna Bohovych
  • Bo Yarabe
  • Annemieke de Jong
  • Huib Ovaa
  • You Zhou
  • Oleh Khalimonchuk
  • Betzabet Quintanilla-Vega
  • Rodrigo Franco


Intracytoplasmic inclusions of protein aggregates in dopaminergic cells (Lewy bodies) are the pathological hallmark of Parkinson’s disease (PD). Ubiquitin (Ub), alpha (α)-synuclein, p62/sequestosome 1, and oxidized proteins are the major components of Lewy bodies. However, the mechanisms involved in the impairment of misfolded/oxidized protein degradation pathways in PD are still unclear. PD is linked to mitochondrial dysfunction and environmental pesticide exposure. In this work, we evaluated the effects of the pesticide paraquat (PQ) and the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+) on Ub-dependent protein degradation pathways. No increase in the accumulation of Ub-bound proteins or aggregates was observed in dopaminergic cells (SK-N-SH) treated with PQ or MPP+, or in mice chronically exposed to PQ. PQ decreased Ub protein content, but not its mRNA transcription. Protein synthesis inhibition with cycloheximide depleted Ub levels and potentiated PQ-induced cell death. The inhibition of proteasomal activity by PQ was found to be a late event in cell death progression and had neither effect on the toxicity of either MPP+ or PQ, nor on the accumulation of oxidized sulfenylated, sulfonylated (DJ-1/PARK7 and peroxiredoxins), and carbonylated proteins induced by PQ. PQ- and MPP+-induced Ub protein depletion prompted the dimerization/inactivation of the Ub-binding protein p62 that regulates the clearance of ubiquitinated proteins by autophagy. We confirmed that PQ and MPP+ impaired autophagy flux and that the blockage of autophagy by the overexpression of a dominant-negative form of the autophagy protein 5 (dnAtg5) stimulated their toxicity, but there was no additional effect upon inhibition of the proteasome. PQ induced an increase in the accumulation of α-synuclein in dopaminergic cells and membrane-associated foci in yeast cells. Our results demonstrate that the inhibition of protein ubiquitination by PQ and MPP+ is involved in the dysfunction of Ub-dependent protein degradation pathways.


Ubiquitin-proteasome system Sequestosome 1 SQSTM1 MPP+ Ubiquitylation Autophagy Pesticides Parkinson’s disease 

Supplementary material

12035_2015_9414_MOESM1_ESM.pdf (283 kb)
ESM 1(PDF 283 kb)


  1. 1.
    Tanaka K, Matsuda N (2014) Proteostasis and neurodegeneration: the roles of proteasomal degradation and autophagy. Biochim Biophys Acta 1843(1):197–204. doi:10.1016/j.bbamcr.2013.03.012 PubMedCrossRefGoogle Scholar
  2. 2.
    Cook C, Stetler C, Petrucelli L (2012) Disruption of protein quality control in Parkinson’s disease. Cold Spring Harb Perspect Med 2(5):a009423. doi:10.1101/cshperspect.a009423 PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Wakabayashi K, Tanji K, Odagiri S, Miki Y, Mori F, Takahashi H (2013) The Lewy body in Parkinson’s disease and related neurodegenerative disorders. Mol Neurobiol 47(2):495–508. doi:10.1007/s12035-012-8280-y PubMedCrossRefGoogle Scholar
  4. 4.
    Zatloukal K, Stumptner C, Fuchsbichler A, Heid H, Schnoelzer M, Kenner L, Kleinert R, Prinz M et al (2002) p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases. Am J Pathol 160(1):255–263. doi:10.1016/S0002-9440(10)64369-6 PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Kuzuhara S, Mori H, Izumiyama N, Yoshimura M, Ihara Y (1988) Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. Acta Neuropathol 75(4):345–353PubMedCrossRefGoogle Scholar
  6. 6.
    Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A 95(11):6469–6473PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Gomez-Tortosa E, Newell K, Irizarry MC, Sanders JL, Hyman BT (2000) alpha-Synuclein immunoreactivity in dementia with Lewy bodies: morphological staging and comparison with ubiquitin immunostaining. Acta Neuropathol 99(4):352–357PubMedCrossRefGoogle Scholar
  8. 8.
    Choi AM, Ryter SW, Levine B (2013) Autophagy in human health and disease. N Engl J Med 368(7):651–662. doi:10.1056/NEJMra1205406 PubMedCrossRefGoogle Scholar
  9. 9.
    Navarro-Yepes J, Burns M, Anandhan A, Khalimonchuk O, del Razo LM, Quintanilla-Vega B, Pappa A, Panayiotidis MI et al (2014) Oxidative stress, redox signaling, and autophagy: cell death versus survival. Antioxid Redox Signal 21(1):66–85. doi:10.1089/ars.2014.5837 PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Shaid S, Brandts CH, Serve H, Dikic I (2013) Ubiquitination and selective autophagy. Cell Death Differ 20(1):21–30. doi:10.1038/cdd.2012.72 PubMedCrossRefGoogle Scholar
  11. 11.
    Rogov V, Dotsch V, Johansen T, Kirkin V (2014) Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol Cell 53(2):167–178. doi:10.1016/j.molcel.2013.12.014 PubMedCrossRefGoogle Scholar
  12. 12.
    Ahmed I, Liang Y, Schools S, Dawson VL, Dawson TM, Savitt JM (2012) Development and characterization of a new Parkinson’s disease model resulting from impaired autophagy. J Neurosci 32(46):16503–16509. doi:10.1523/JNEUROSCI.0209-12.2012 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z (2012) Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain. J Neurosci 32(22):7585–7593. doi:10.1523/JNEUROSCI.5809-11.2012 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Komatsu M, Kageyama S, Ichimura Y (2012) p62/SQSTM1/A170: physiology and pathology. Pharmacol Res 66(6):457–462. doi:10.1016/j.phrs.2012.07.004 PubMedCrossRefGoogle Scholar
  15. 15.
    Watanabe Y, Tanaka M (2011) p62/SQSTM1 in autophagic clearance of a non-ubiquitylated substrate. J Cell Sci 124(Pt 16):2692–2701. doi:10.1242/jcs.081232 PubMedCrossRefGoogle Scholar
  16. 16.
    Gal J, Strom AL, Kwinter DM, Kilty R, Zhang J, Shi P, Fu W, Wooten MW et al (2009) Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism. J Neurochem 111(4):1062–1073. doi:10.1111/j.1471-4159.2009.06388.x PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, Wooten MW (2004) Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol 24(18):8055–8068. doi:10.1128/MCB.24.18.8055-8068.2004 PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Babu JR, Geetha T, Wooten MW (2005) Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem 94(1):192–203. doi:10.1111/j.1471-4159.2005.03181.x PubMedCrossRefGoogle Scholar
  19. 19.
    Dunlop RA, Brunk UT, Rodgers KJ (2009) Oxidized proteins: mechanisms of removal and consequences of accumulation. IUBMB Life 61(5):522–527. doi:10.1002/iub.189 PubMedCrossRefGoogle Scholar
  20. 20.
    Chondrogianni N, Petropoulos I, Grimm S, Georgila K, Catalgol B, Friguet B, Grune T, Gonos ES (2012) Protein damage, repair and proteolysis. Mol Asp Med. doi:10.1016/j.mam.2012.09.001 Google Scholar
  21. 21.
    Wang L, Cano M, Handa JT (2014) p62 Provides dual cytoprotection against oxidative stress in the retinal pigment epithelium. Biochim Biophys Acta 1843(7):1248–1258. doi:10.1016/j.bbamcr.2014.03.016 PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Marques C, Pereira P, Taylor A, Liang JN, Reddy VN, Szweda LI, Shang F (2004) Ubiquitin-dependent lysosomal degradation of the HNE-modified proteins in lens epithelial cells. FASEB J 18(12):1424–1426. doi:10.1096/fj.04-1743fje PubMedPubMedCentralGoogle Scholar
  23. 23.
    Klein C, Westenberger A (2012) Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med 2(1):a008888. doi:10.1101/cshperspect.a008888 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, Marras C, Bhudhikanok GS et al (2011) Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect 119(6):866–872. doi:10.1289/ehp.1002839 PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Kamel F (2013) Epidemiology. Paths from pesticides to Parkinson’s. Science 341(6147):722–723. doi:10.1126/science.1243619 PubMedCrossRefGoogle Scholar
  26. 26.
    van der Mark M, Brouwer M, Kromhout H, Nijssen P, Huss A, Vermeulen R (2012) Is pesticide use related to Parkinson disease? Some clues to heterogeneity in study results. Environ Health Perspect 120(3):340–347. doi:10.1289/ehp.1103881 PubMedCrossRefGoogle Scholar
  27. 27.
    Caudle WM, Guillot TS, Lazo CR, Miller GW (2012) Industrial toxicants and Parkinson’s disease. Neurotoxicology 33(2):178–188. doi:10.1016/j.neuro.2012.01.010 PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Jang H, Boltz DA, Webster RG, Smeyne RJ (2009) Viral parkinsonism. Biochim Biophys Acta 1792(7):714–721. doi:10.1016/j.bbadis.2008.08.001 PubMedCrossRefGoogle Scholar
  29. 29.
    Gorell JM, Rybicki BA, Cole Johnson C, Peterson EL (1999) Occupational metal exposures and the risk of Parkinson’s disease. Neuroepidemiology 18(6):303–308PubMedCrossRefGoogle Scholar
  30. 30.
    Caneda-Ferron B, De Girolamo LA, Costa T, Beck KE, Layfield R, Billett EE (2008) Assessment of the direct and indirect effects of MPP+ and dopamine on the human proteasome: implications for Parkinson’s disease aetiology. J Neurochem 105(1):225–238. doi:10.1111/j.1471-4159.2007.05130.x PubMedCrossRefGoogle Scholar
  31. 31.
    Yang W, Tiffany-Castiglioni E (2007) The bipyridyl herbicide paraquat induces proteasome dysfunction in human neuroblastoma SH-SY5Y cells. J Toxic Environ Health A 70(21):1849–1857. doi:10.1080/15287390701459262 CrossRefGoogle Scholar
  32. 32.
    Fornai F, Schluter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL et al (2005) Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci U S A 102(9):3413–3418. doi:10.1073/pnas.0409713102 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Garcia-Garcia A, Anandhan A, Burns M, Chen H, Zhou Y, Franco R (2013) Impairment of Atg5-dependent autophagic flux promotes paraquat- and MPP+-induced apoptosis but not rotenone or 6-hydroxydopamine toxicity. Toxicol Sci 136(1):166–182. doi:10.1093/toxsci/kft188 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Wills J, Credle J, Oaks AW, Duka V, Lee JH, Jones J, Sidhu A (2012) Paraquat, but not maneb, induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways. PLoS One 7(1):e30745. doi:10.1371/journal.pone.0030745 PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA et al (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447(7146):859–863. doi:10.1038/nature05853 PubMedCrossRefGoogle Scholar
  36. 36.
    Janen SB, Chaachouay H, Richter-Landsberg C (2010) Autophagy is activated by proteasomal inhibition and involved in aggresome clearance in cultured astrocytes. Glia 58(14):1766–1774. doi:10.1002/glia.21047 PubMedCrossRefGoogle Scholar
  37. 37.
    Lei S, Zavala-Flores L, Garcia-Garcia A, Nandakumar R, Huang Y, Madayiputhiya N, Stanton RC, Dodds ED et al (2014) Alterations in energy/redox metabolism induced by mitochondrial and environmental toxins: a specific role for glucose-6-phosphate-dehydrogenase and the pentose phosphate pathway in paraquat toxicity. ACS Chem Biol. doi:10.1021/cb400894a PubMedCentralGoogle Scholar
  38. 38.
    Scholz D, Poltl D, Genewsky A, Weng M, Waldmann T, Schildknecht S, Leist M (2011) Rapid, complete and large-scale generation of post-mitotic neurons from the human LUHMES cell line. J Neurochem 119(5):957–971. doi:10.1111/j.1471-4159.2011.07255.x PubMedCrossRefGoogle Scholar
  39. 39.
    Rodriguez-Rocha H, Garcia-Garcia A, Zavala-Flores L, Li S, Madayiputhiya N, Franco R (2012) Glutaredoxin 1 protects dopaminergic cells by increased protein glutathionylation in experimental Parkinson’s disease. Antioxid Redox Signal. doi:10.1089/ars.2011.4474 Google Scholar
  40. 40.
    Seo YH, Carroll KS (2009) Profiling protein thiol oxidation in tumor cells using sulfenic acid-specific antibodies. Proc Natl Acad Sci U S A 106(38):16163–16168. doi:10.1073/pnas.0903015106 PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Luo S, Wehr NB (2009) Protein carbonylation: avoiding pitfalls in the 2,4-dinitrophenylhydrazine assay. Redox Rep 14(4):159–166. doi:10.1179/135100009X392601 PubMedCrossRefGoogle Scholar
  42. 42.
    Levine RL, Williams JA, Stadtman ER, Shacter E (1994) Carbonyl assays for determination of oxidatively modified proteins. Methods Enzymol 233:346–357PubMedCrossRefGoogle Scholar
  43. 43.
    Anandhan A, Rodriguez-Rocha H, Bohovych I, Griggs AM, Zavala-Flores L, Reyes-Reyes EM, Seravalli J, Stanciu LA et al (2014) Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways. Neurobiol Dis. doi:10.1016/j.nbd.2014.11.018 PubMedPubMedCentralGoogle Scholar
  44. 44.
    Myeku N, Metcalfe MJ, Huang Q, Figueiredo-Pereira M (2011) Assessment of proteasome impairment and accumulation/aggregation of ubiquitinated proteins in neuronal cultures. Methods Mol Biol 793:273–296. doi:10.1007/978-1-61779-328-8_18 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Rodriguez-Rocha H, Garcia-Garcia A, Pickett C, Li S, Jones J, Chen H, Webb B, Choi J et al (2013) Compartmentalized oxidative stress in dopaminergic cell death induced by pesticides and complex I inhibitors: distinct roles of superoxide anion and superoxide dismutases. Free Radic Biol Med 61C:370–383. doi:10.1016/j.freeradbiomed.2013.04.021 CrossRefGoogle Scholar
  46. 46.
    Bence NF, Bennett EJ, Kopito RR (2005) Application and analysis of the GFPu family of ubiquitin-proteasome system reporters. Methods Enzymol 399:481–490. doi:10.1016/S0076-6879(05)99033-2 PubMedCrossRefGoogle Scholar
  47. 47.
    Berkers CR, van Leeuwen FW, Groothuis TA, Peperzak V, van Tilburg EW, Borst J, Neefjes JJ, Ovaa H (2007) Profiling proteasome activity in tissue with fluorescent probes. Mol Pharm 4(5):739–748. doi:10.1021/mp0700256 PubMedCrossRefGoogle Scholar
  48. 48.
    de Jong A, Schuurman KG, Rodenko B, Ovaa H, Berkers CR (2012) Fluorescence-based proteasome activity profiling. Methods Mol Biol 803:183–204. doi:10.1007/978-1-61779-364-6_13 PubMedCrossRefGoogle Scholar
  49. 49.
    Yang L, Li P, Fu S, Calay ES, Hotamisligil GS (2010) Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab 11(6):467–478. doi:10.1016/j.cmet.2010.04.005 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Liu F, Hindupur J, Nguyen JL, Ruf KJ, Zhu J, Schieler JL, Bonham CC, Wood KV et al (2008) Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson’s disease-related insults. Free Radic Biol Med 45(3):242–255. doi:10.1016/j.freeradbiomed.2008.03.022 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Barde I, Salmon P, Trono D (2010) Production and titration of lentiviral vectors. Curr Protoc Neurosci Chapter 4:Unit 4 21. doi:10.1002/0471142301.ns0421s53
  52. 52.
    Srivastava G, Dixit A, Yadav S, Patel DK, Prakash O, Singh MP (2012) Resveratrol potentiates cytochrome P450 2 d22-mediated neuroprotection in maneb- and paraquat-induced parkinsonism in the mouse. Free Radic Biol Med 52(8):1294–1306. doi:10.1016/j.freeradbiomed.2012.02.005 PubMedCrossRefGoogle Scholar
  53. 53.
    Goldman SM (2014) Environmental toxins and Parkinson’s disease. Annu Rev Pharmacol Toxicol 54:141–164. doi:10.1146/annurev-pharmtox-011613-135937 PubMedCrossRefGoogle Scholar
  54. 54.
    Subramaniam SR, Chesselet MF (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol 106–107:17–32. doi:10.1016/j.pneurobio.2013.04.004 PubMedCrossRefGoogle Scholar
  55. 55.
    Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3(12):1301–1306. doi:10.1038/81834 PubMedCrossRefGoogle Scholar
  56. 56.
    Sun F, Kanthasamy A, Anantharam V, Kanthasamy AG (2007) Environmental neurotoxic chemicals-induced ubiquitin proteasome system dysfunction in the pathogenesis and progression of Parkinson’s disease. Pharmacol Ther 114(3):327–344. doi:10.1016/j.pharmthera.2007.04.001 PubMedCrossRefGoogle Scholar
  57. 57.
    Corcoran LJ, Mitchison TJ, Liu Q (2004) A novel action of histone deacetylase inhibitors in a protein aggresome disease model. Curr Biol 14(6):488–492. doi:10.1016/j.cub.2004.03.003 PubMedCrossRefGoogle Scholar
  58. 58.
    Waelter S, Boeddrich A, Lurz R, Scherzinger E, Lueder G, Lehrach H, Wanker EE (2001) Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell 12(5):1393–1407PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Stack JH, Whitney M, Rodems SM, Pollok BA (2000) A ubiquitin-based tagging system for controlled modulation of protein stability. Nat Biotechnol 18(12):1298–1302. doi:10.1038/82422 PubMedCrossRefGoogle Scholar
  60. 60.
    Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292(5521):1552–1555. doi:10.1126/science.292.5521.1552 PubMedCrossRefGoogle Scholar
  61. 61.
    Li X, Zhao X, Fang Y, Jiang X, Duong T, Fan C, Huang CC, Kain SR (1998) Generation of destabilized green fluorescent protein as a transcription reporter. J Biol Chem 273(52):34970–34975PubMedCrossRefGoogle Scholar
  62. 62.
    Corish P, Tyler-Smith C (1999) Attenuation of green fluorescent protein half-life in mammalian cells. Protein Eng 12(12):1035–1040PubMedCrossRefGoogle Scholar
  63. 63.
    Shamoto-Nagai M, Maruyama W, Kato Y, Isobe K, Tanaka M, Naoi M, Osawa T (2003) An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells. J Neurosci Res 74(4):589–597. doi:10.1002/jnr.10777 PubMedCrossRefGoogle Scholar
  64. 64.
    Yamamuro A, Yoshioka Y, Ogita K, Maeda S (2006) Involvement of endoplasmic reticulum stress on the cell death induced by 6-hydroxydopamine in human neuroblastoma SH-SY5Y cells. Neurochem Res 31(5):657–664. doi:10.1007/s11064-006-9062-6 PubMedCrossRefGoogle Scholar
  65. 65.
    Endo R, Saito T, Asada A, Kawahara H, Ohshima T, Hisanaga S (2009) Commitment of 1-methyl-4-phenylpyrinidinium ion-induced neuronal cell death by proteasome-mediated degradation of p35 cyclin-dependent kinase 5 activator. J Biol Chem 284(38):26029–26039. doi:10.1074/jbc.M109.026443 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Sawada H, Kohno R, Kihara T, Izumi Y, Sakka N, Ibi M, Nakanishi M, Nakamizo T et al (2004) Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes alpha-synuclein inclusions. J Biol Chem 279(11):10710–10719. doi:10.1074/jbc.M308434200 PubMedCrossRefGoogle Scholar
  67. 67.
    Prasad K, Winnik B, Thiruchelvam MJ, Buckley B, Mirochnitchenko O, Richfield EK (2007) Prolonged toxicokinetics and toxicodynamics of paraquat in mouse brain. Environ Health Perspect 115(10):1448–1453. doi:10.1289/ehp.9932 PubMedPubMedCentralGoogle Scholar
  68. 68.
    Seufert W, Jentsch S (1990) Ubiquitin-conjugating enzymes UBC4 and UBC5 mediate selective degradation of short-lived and abnormal proteins. EMBO J 9(2):543–550PubMedPubMedCentralGoogle Scholar
  69. 69.
    Oh C, Park S, Lee EK, Yoo YJ (2013) Downregulation of ubiquitin level via knockdown of polyubiquitin gene Ubb as potential cancer therapeutic intervention. Sci Rep 3:2623. doi:10.1038/srep02623 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Hanna J, Leggett DS, Finley D (2003) Ubiquitin depletion as a key mediator of toxicity by translational inhibitors. Mol Cell Biol 23(24):9251–9261PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Shringarpure R, Grune T, Mehlhase J, Davies KJ (2003) Ubiquitin conjugation is not required for the degradation of oxidized proteins by proteasome. J Biol Chem 278(1):311–318. doi:10.1074/jbc.M206279200 PubMedCrossRefGoogle Scholar
  72. 72.
    Kastle M, Reeg S, Rogowska-Wrzesinska A, Grune T (2012) Chaperones, but not oxidized proteins, are ubiquitinated after oxidative stress. Free Radic Biol Med 53(7):1468–1477. doi:10.1016/j.freeradbiomed.2012.05.039 PubMedCrossRefGoogle Scholar
  73. 73.
    Long J, Garner TP, Pandya MJ, Craven CJ, Chen P, Shaw B, Williamson MP, Layfield R et al (2010) Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and regulates NF-kappaB signalling. J Mol Biol 396(1):178–194. doi:10.1016/j.jmb.2009.11.032 PubMedCrossRefGoogle Scholar
  74. 74.
    Yang Y, Kitagaki J, Dai RM, Tsai YC, Lorick KL, Ludwig RL, Pierre SA, Jensen JP et al (2007) Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer Res 67(19):9472–9481. doi:10.1158/0008-5472.CAN-07-0568 PubMedCrossRefGoogle Scholar
  75. 75.
    Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, Agholme L, Agnello M et al (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8(4):445–544PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Bang Y, Kang BY, Choi HJ (2014) Preconditioning stimulus of proteasome inhibitor enhances aggresome formation and autophagy in differentiated SH-SY5Y cells. Neurosci Lett 566:263–268. doi:10.1016/j.neulet.2014.02.056 PubMedCrossRefGoogle Scholar
  77. 77.
    Lan D, Wang W, Zhuang J, Zhao Z (2015) Proteasome inhibitor-induced autophagy in PC12 cells overexpressing A53T mutant alpha-synuclein. Mol Med Rep 11(3):1655–1660. doi:10.3892/mmr.2014.3011 PubMedGoogle Scholar
  78. 78.
    Lim J, Lee Y, Jung S, Youdim MB, Oh YJ (2014) Impaired autophagic flux is critically involved in drug-induced dopaminergic neuronal death. Parkinsonism Relat Disord 20(Suppl 1):S162–S166. doi:10.1016/S1353-8020(13)70039-7 PubMedCrossRefGoogle Scholar
  79. 79.
    Myeku N, Figueiredo-Pereira ME (2011) Dynamics of the degradation of ubiquitinated proteins by proteasomes and autophagy: association with sequestosome 1/p62. J Biol Chem 286(25):22426–22440. doi:10.1074/jbc.M110.149252 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Kageyama S, Sou YS, Uemura T, Kametaka S, Saito T, Ishimura R, Kouno T, Bedford L et al (2014) Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway. J Biol Chem 289(36):24944–24955. doi:10.1074/jbc.M114.580357 PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Korolchuk VI, Mansilla A, Menzies FM, Rubinsztein DC (2009) Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell 33(4):517–527. doi:10.1016/j.molcel.2009.01.021 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Rubinsztein DC (2007) Autophagy induction rescues toxicity mediated by proteasome inhibition. Neuron 54(6):854–856. doi:10.1016/j.neuron.2007.06.005 PubMedCrossRefGoogle Scholar
  83. 83.
    Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z, Rockenstein E, Masliah E, Hyman BT, McLean PJ, Unni VK (2011) Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of alpha-synuclein. J Neurosci 31(41):14508–14520. doi:10.1523/JNEUROSCI.1560-11.2011 PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278(27):25009–25013. doi:10.1074/jbc.M300227200 PubMedCrossRefGoogle Scholar
  85. 85.
    Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305(5688):1292–1295. doi:10.1126/science.1101738 PubMedCrossRefGoogle Scholar
  86. 86.
    Chorfa A, Betemps D, Morignat E, Lazizzera C, Hogeveen K, Andrieu T, Baron T (2013) Specific pesticide-dependent increases in alpha-synuclein levels in human neuroblastoma (SH-SY5Y) and melanoma (SK-MEL-2) cell lines. Toxicol Sci 133(2):289–297. doi:10.1093/toxsci/kft076 PubMedCrossRefGoogle Scholar
  87. 87.
    Chorfa A, Lazizzera C, Betemps D, Morignat E, Dussurgey S, Andrieu T, Baron T (2014) A variety of pesticides trigger in vitro alpha-synuclein accumulation, a key event in Parkinson’s disease. Arch Toxicol. doi:10.1007/s00204-014-1388-2 Google Scholar
  88. 88.
    Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 277(3):1641–1644. doi:10.1074/jbc.C100560200 PubMedCrossRefGoogle Scholar
  89. 89.
    Mitra S, Chakrabarti N, Bhattacharyya A (2011) Differential regional expression patterns of alpha-synuclein, TNF-alpha, and IL-1beta; and variable status of dopaminergic neurotoxicity in mouse brain after Paraquat treatment. J Neuroinflammation 8:163. doi:10.1186/1742-2094-8-163 PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Fauvet B, Mbefo MK, Fares MB, Desobry C, Michael S, Ardah MT, Tsika E, Coune P et al (2012) Alpha-synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J Biol Chem 287(19):15345–15364. doi:10.1074/jbc.M111.318949 PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Lashuel HA, Overk CR, Oueslati A, Masliah E (2013) The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 14(1):38–48. doi:10.1038/nrn3406 PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT Jr (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 35(43):13709–13715. doi:10.1021/bi961799n PubMedCrossRefGoogle Scholar
  93. 93.
    Dettmer U, Newman AJ, Luth ES, Bartels T, Selkoe D (2013) In vivo cross-linking reveals principally oligomeric forms of alpha-synuclein and beta-synuclein in neurons and non-neural cells. J Biol Chem 288(9):6371–6385. doi:10.1074/jbc.M112.403311 PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Bartels T, Choi JG, Selkoe DJ (2011) Alpha-synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477(7362):107–110. doi:10.1038/nature10324 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Khurana V, Lindquist S (2010) Modelling neurodegeneration in Saccharomyces cerevisiae: why cook with baker’s yeast? Nat Rev Neurosci 11(6):436–449. doi:10.1038/nrn2809 PubMedCrossRefGoogle Scholar
  96. 96.
    Trinh J, Farrer M (2013) Advances in the genetics of Parkinson disease. Nat Rev Neurol 9(8):445–454. doi:10.1038/nrneurol.2013.132 PubMedCrossRefGoogle Scholar
  97. 97.
    Chung KK, Dawson VL, Dawson TM (2001) The role of the ubiquitin-proteasomal pathway in Parkinson’s disease and other neurodegenerative disorders. Trends Neurosci 24(11 Suppl):S7–S14PubMedCrossRefGoogle Scholar
  98. 98.
    Clague MJ, Urbe S (2010) Ubiquitin: same molecule, different degradation pathways. Cell 143(5):682–685. doi:10.1016/j.cell.2010.11.012 PubMedCrossRefGoogle Scholar
  99. 99.
    McNaught KS, Jenner P (2001) Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci Lett 297(3):191–194PubMedCrossRefGoogle Scholar
  100. 100.
    McNaught KS, Belizaire R, Jenner P, Olanow CW, Isacson O (2002) Selective loss of 20S proteasome alpha-subunits in the substantia nigra pars compacta in Parkinson’s disease. Neurosci Lett 326(3):155–158PubMedCrossRefGoogle Scholar
  101. 101.
    McNaught KS, Belizaire R, Isacson O, Jenner P, Olanow CW (2003) Altered proteasomal function in sporadic Parkinson’s disease. Exp Neurol 179(1):38–46PubMedCrossRefGoogle Scholar
  102. 102.
    Martins-Branco D, Esteves AR, Santos D, Arduino DM, Swerdlow RH, Oliveira CR, Januario C, Cardoso SM (2012) Ubiquitin proteasome system in Parkinson’s disease: a keeper or a witness? Exp Neurol 238(2):89–99. doi:10.1016/j.expneurol.2012.08.008 PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Wang XF, Li S, Chou AP, Bronstein JM (2006) Inhibitory effects of pesticides on proteasome activity: implication in Parkinson’s disease. Neurobiol Dis 23(1):198–205. doi:10.1016/j.nbd.2006.02.012 PubMedCrossRefGoogle Scholar
  104. 104.
    Zeng BY, Iravani MM, Lin ST, Irifune M, Kuoppamaki M, Al-Barghouthy G, Smith L, Jackson MJ et al (2006) MPTP treatment of common marmosets impairs proteasomal enzyme activity and decreases expression of structural and regulatory elements of the 26S proteasome. Eur J Neurosci 23(7):1766–1774. doi:10.1111/j.1460-9568.2006.04718.x PubMedCrossRefGoogle Scholar
  105. 105.
    Kadoguchi N, Umeda M, Kato H, Araki T (2008) Proteasome inhibitor does not enhance MPTP neurotoxicity in mice. Cell Mol Neurobiol 28(7):971–979. doi:10.1007/s10571-008-9271-4 PubMedCrossRefGoogle Scholar
  106. 106.
    Carvalho AN, Marques C, Rodrigues E, Henderson CJ, Wolf CR, Pereira P, Gama MJ (2013) Ubiquitin-proteasome system impairment and MPTP-induced oxidative stress in the brain of C57BL/6 wild-type and GSTP knockout mice. Mol Neurobiol 47(2):662–672. doi:10.1007/s12035-012-8368-4 PubMedCrossRefGoogle Scholar
  107. 107.
    Xu Q, Farah M, Webster JM, Wojcikiewicz RJ (2004) Bortezomib rapidly suppresses ubiquitin thiolesterification to ubiquitin-conjugating enzymes and inhibits ubiquitination of histones and type I inositol 1,4,5-trisphosphate receptor. Mol Cancer Ther 3(10):1263–1269PubMedGoogle Scholar
  108. 108.
    Ding Q, Dimayuga E, Markesbery WR, Keller JN (2006) Proteasome inhibition induces reversible impairments in protein synthesis. FASEB J 20(8):1055–1063. doi:10.1096/fj.05-5495com PubMedCrossRefGoogle Scholar
  109. 109.
    Giordano S, Lee J, Darley-Usmar VM, Zhang J (2012) Distinct effects of rotenone, 1-methyl-4-phenylpyridinium and 6-hydroxydopamine on cellular bioenergetics and cell death. PLoS One 7(9):e44610. doi:10.1371/journal.pone.0044610 PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Yacoubian TA, Slone SR, Harrington AJ, Hamamichi S, Schieltz JM, Caldwell KA, Caldwell GA, Standaert DG (2010) Differential neuroprotective effects of 14-3-3 proteins in models of Parkinson’s disease. Cell Death Dis 1:e2. doi:10.1038/cddis.2009.4 PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Song JX, Shaw PC, Wong NS, Sze CW, Yao XS, Tang CW, Tong Y, Zhang YB (2012) Chrysotoxine, a novel bibenzyl compound selectively antagonizes MPP(+), but not rotenone, neurotoxicity in dopaminergic SH-SY5Y cells. Neurosci Lett 521(1):76–81. doi:10.1016/j.neulet.2012.05.063 PubMedCrossRefGoogle Scholar
  112. 112.
    Huang Y, Xu J, Liang M, Hong X, Suo H, Liu J, Yu M, Huang F (2013) RESP18 is involved in the cytotoxicity of dopaminergic neurotoxins in MN9D cells. Neurotox Res 24(2):164–175. doi:10.1007/s12640-013-9375-6 PubMedCrossRefGoogle Scholar
  113. 113.
    Martins JB, Bastos Mde L, Carvalho F, Capela JP (2013) Differential effects of methyl-4-phenylpyridinium ion, rotenone, and paraquat on differentiated SH-SY5Y cells. J Toxicol 2013:347312. doi:10.1155/2013/347312 PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Zhu M, Li WW, Lu CZ (2014) Histone decacetylase inhibitors prevent mitochondrial fragmentation and elicit early neuroprotection against MPP+. CNS Neurosci Ther 20(4):308–316. doi:10.1111/cns.12217 PubMedCrossRefGoogle Scholar
  115. 115.
    Zhang X, Zhou J, Fernandes AF, Sparrow JR, Pereira P, Taylor A, Shang F (2008) The proteasome: a target of oxidative damage in cultured human retina pigment epithelial cells. Invest Ophthalmol Vis Sci 49(8):3622–3630. doi:10.1167/iovs.07-1559 PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Jahngen-Hodge J, Obin MS, Gong X, Shang F, Nowell TR Jr, Gong J, Abasi H, Blumberg J et al (1997) Regulation of ubiquitin-conjugating enzymes by glutathione following oxidative stress. J Biol Chem 272(45):28218–28226PubMedCrossRefGoogle Scholar
  117. 117.
    Obin M, Shang F, Gong X, Handelman G, Blumberg J, Taylor A (1998) Redox regulation of ubiquitin-conjugating enzymes: mechanistic insights using the thiol-specific oxidant diamide. FASEB J 12(7):561–569PubMedGoogle Scholar
  118. 118.
    Yao D, Gu Z, Nakamura T, Shi ZQ, Ma Y, Gaston B, Palmer LA, Rockenstein EM et al (2004) Nitrosative stress linked to sporadic Parkinson’s disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proc Natl Acad Sci U S A 101(29):10810–10814. doi:10.1073/pnas.0404161101 PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Ishii T, Sakurai T, Usami H, Uchida K (2005) Oxidative modification of proteasome: identification of an oxidation-sensitive subunit in 26 S proteasome. Biochemistry 44(42):13893–13901. doi:10.1021/bi051336u PubMedCrossRefGoogle Scholar
  120. 120.
    Caballero M, Liton PB, Epstein DL, Gonzalez P (2003) Proteasome inhibition by chronic oxidative stress in human trabecular meshwork cells. Biochem Biophys Res Commun 308(2):346–352PubMedCrossRefGoogle Scholar
  121. 121.
    Okada K, Wangpoengtrakul C, Osawa T, Toyokuni S, Tanaka K, Uchida K (1999) 4-Hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress. Identification of proteasomes as target molecules. J Biol Chem 274(34):23787–23793PubMedCrossRefGoogle Scholar
  122. 122.
    Ding Q, Keller JN (2001) Proteasome inhibition in oxidative stress neurotoxicity: implications for heat shock proteins. J Neurochem 77(4):1010–1017PubMedCrossRefGoogle Scholar
  123. 123.
    Cotto-Rios XM, Bekes M, Chapman J, Ueberheide B, Huang TT (2012) Deubiquitinases as a signaling target of oxidative stress. Cell Rep 2(6):1475–1484. doi:10.1016/j.celrep.2012.11.011 PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Lee JG, Baek K, Soetandyo N, Ye Y (2013) Reversible inactivation of deubiquitinases by reactive oxygen species in vitro and in cells. Nat Commun 4:1568. doi:10.1038/ncomms2532 PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Shang F, Taylor A (2011) Ubiquitin-proteasome pathway and cellular responses to oxidative stress. Free Radic Biol Med 51(1):5–16. doi:10.1016/j.freeradbiomed.2011.03.031 PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Shang F, Gong X, Taylor A (1997) Activity of ubiquitin-dependent pathway in response to oxidative stress. Ubiquitin-activating enzyme is transiently up-regulated. J Biol Chem 272(37):23086–23093PubMedCrossRefGoogle Scholar
  127. 127.
    Monia BP, Ecker DJ, Crooke ST (1990) New perspectives on the structure and function of ubiquitin. Nat Biotechnol 8(3):209–215CrossRefGoogle Scholar
  128. 128.
    Buttgereit F, Brand MD (1995) A hierarchy of ATP-consuming processes in mammalian cells. Biochem J 312(Pt 1):163–167PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Notter MF, Irwin I, Langston JW, Gash DM (1988) Neurotoxicity of MPTP and MPP+ in vitro: characterization using specific cell lines. Brain Res 456(2):254–262PubMedCrossRefGoogle Scholar
  130. 130.
    Ling J, Soll D (2010) Severe oxidative stress induces protein mistranslation through impairment of an aminoacyl-tRNA synthetase editing site. Proc Natl Acad Sci U S A 107(9):4028–4033. doi:10.1073/pnas.1000315107 PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Wei N, Shi Y, Truong LN, Fisch KM, Xu T, Gardiner E, Fu G, Hsu YS et al (2014) Oxidative stress diverts tRNA synthetase to nucleus for protection against DNA damage. Mol Cell 56(2):323–332. doi:10.1016/j.molcel.2014.09.006 PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Tanaka M, Chock PB, Stadtman ER (2007) Oxidized messenger RNA induces translation errors. Proc Natl Acad Sci U S A 104(1):66–71. doi:10.1073/pnas.0609737104 PubMedCrossRefGoogle Scholar
  133. 133.
    Shan X, Tashiro H, Lin CL (2003) The identification and characterization of oxidized RNAs in Alzheimer’s disease. J Neurosci 23(12):4913–4921PubMedGoogle Scholar
  134. 134.
    Shan X, Chang Y, Lin CL (2007) Messenger RNA oxidation is an early event preceding cell death and causes reduced protein expression. FASEB J 21(11):2753–2764. doi:10.1096/fj.07-8200com PubMedCrossRefGoogle Scholar
  135. 135.
    Chang Y, Kong Q, Shan X, Tian G, Ilieva H, Cleveland DW, Rothstein JD, Borchelt DR et al (2008) Messenger RNA oxidation occurs early in disease pathogenesis and promotes motor neuron degeneration in ALS. PLoS One 3(8):e2849. doi:10.1371/journal.pone.0002849 PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Simms CL, Hudson BH, Mosior JW, Rangwala AS, Zaher HS (2014) An active role for the ribosome in determining the fate of oxidized mRNA. Cell Rep 9(4):1256–1264. doi:10.1016/j.celrep.2014.10.042 PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Ding Q, Dimayuga E, Keller JN (2007) Oxidative stress alters neuronal RNA- and protein-synthesis: implications for neural viability. Free Radic Res 41(8):903–910. doi:10.1080/10715760701416996 PubMedCrossRefGoogle Scholar
  138. 138.
    Alam ZI, Daniel SE, Lees AJ, Marsden DC, Jenner P, Halliwell B (1997) A generalised increase in protein carbonyls in the brain in Parkinson’s but not incidental Lewy body disease. J Neurochem 69(3):1326–1329PubMedCrossRefGoogle Scholar
  139. 139.
    Saito Y, Hamakubo T, Yoshida Y, Ogawa Y, Hara Y, Fujimura H, Imai Y, Iwanari H et al (2009) Preparation and application of monoclonal antibodies against oxidized DJ-1. Significant elevation of oxidized DJ-1 in erythrocytes of early-stage Parkinson disease patients. Neurosci Lett 465(1):1–5. doi:10.1016/j.neulet.2009.08.074 PubMedCrossRefGoogle Scholar
  140. 140.
    Choi J, Sullards MC, Olzmann JA, Rees HD, Weintraub ST, Bostwick DE, Gearing M, Levey AI et al (2006) Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. J Biol Chem 281(16):10816–10824. doi:10.1074/jbc.M509079200 PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Fang J, Nakamura T, Cho DH, Gu Z, Lipton SA (2007) S-nitrosylation of peroxiredoxin 2 promotes oxidative stress-induced neuronal cell death in Parkinson’s disease. Proc Natl Acad Sci U S A 104(47):18742–18747. doi:10.1073/pnas.0705904104 PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Cho CS, Yoon HJ, Kim JY, Woo HA, Rhee SG (2014) Circadian rhythm of hyperoxidized peroxiredoxin II is determined by hemoglobin autoxidation and the 20S proteasome in red blood cells. Proc Natl Acad Sci U S A 111(33):12043–12048. doi:10.1073/pnas.1401100111 PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Li X, Lu D, He F, Zhou H, Liu Q, Wang Y, Shao C, Gong Y (2011) Cullin 4B protein ubiquitin ligase targets peroxiredoxin III for degradation. J Biol Chem 286(37):32344–32354. doi:10.1074/jbc.M111.249003 PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Miller DW, Ahmad R, Hague S, Baptista MJ, Canet-Aviles R, McLendon C, Carter DM, Zhu PP et al (2003) L166P mutant DJ-1, causative for recessive Parkinson’s disease, is degraded through the ubiquitin-proteasome system. J Biol Chem 278(38):36588–36595. doi:10.1074/jbc.M304272200 PubMedCrossRefGoogle Scholar
  145. 145.
    Ravid T, Hochstrasser M (2008) Diversity of degradation signals in the ubiquitin-proteasome system. Nat Rev Mol Cell Biol 9(9):679–690. doi:10.1038/nrm2468 PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Asher G, Reuven N, Shaul Y (2006) 20S proteasomes and protein degradation “by default”. BioEssays 28(8):844–849. doi:10.1002/bies.20447 PubMedCrossRefGoogle Scholar
  147. 147.
    Sohal RS, Mockett RJ, Orr WC (2002) Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free Radic Biol Med 33(5):575–586PubMedCrossRefGoogle Scholar
  148. 148.
    da Cunha FM, Demasi M, Kowaltowski AJ (2011) Aging and calorie restriction modulate yeast redox state, oxidized protein removal, and the ubiquitin-proteasome system. Free Radic Biol Med 51(3):664–670. doi:10.1016/j.freeradbiomed.2011.05.035 PubMedCrossRefGoogle Scholar
  149. 149.
    Shang F, Gong X, Palmer HJ, Nowell TR Jr, Taylor A (1997) Age-related decline in ubiquitin conjugation in response to oxidative stress in the lens. Exp Eye Res 64(1):21–30. doi:10.1006/exer.1996.0176 PubMedCrossRefGoogle Scholar
  150. 150.
    Yang F, Yang YP, Mao CJ, Liu L, Zheng HF, Hu LF, Liu CF (2013) Crosstalk between the proteasome system and autophagy in the clearance of alpha-synuclein. Acta Pharmacol Sin 34(5):674–680. doi:10.1038/aps.2013.29 PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Petroi D, Popova B, Taheri-Talesh N, Irniger S, Shahpasandzadeh H, Zweckstetter M, Outeiro TF, Braus GH (2012) Aggregate clearance of alpha-synuclein in Saccharomyces cerevisiae depends more on autophagosome and vacuole function than on the proteasome. J Biol Chem 287(33):27567–27579. doi:10.1074/jbc.M112.361865 PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Korolchuk VI, Menzies FM, Rubinsztein DC (2010) Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett 584(7):1393–1398. doi:10.1016/j.febslet.2009.12.047 PubMedCrossRefGoogle Scholar
  153. 153.
    Bove J, Zhou C, Jackson-Lewis V, Taylor J, Chu Y, Rideout HJ, Wu DC, Kordower JH et al (2006) Proteasome inhibition and Parkinson’s disease modeling. Ann Neurol 60(2):260–264. doi:10.1002/ana.20937 PubMedCrossRefGoogle Scholar
  154. 154.
    Kim YM, Jang WH, Quezado MM, Oh Y, Chung KC, Junn E, Mouradian MM (2011) Proteasome inhibition induces alpha-synuclein SUMOylation and aggregate formation. J Neurol Sci 307(1–2):157–161. doi:10.1016/j.jns.2011.04.015 PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Kordower JH, Kanaan NM, Chu Y, Suresh Babu R, Stansell J 3rd, Terpstra BT, Sortwell CE, Steece-Collier K et al (2006) Failure of proteasome inhibitor administration to provide a model of Parkinson’s disease in rats and monkeys. Ann Neurol 60(2):264–268. doi:10.1002/ana.20935 PubMedCrossRefGoogle Scholar
  156. 156.
    Manning-Bog AB, Reaney SH, Chou VP, Johnston LC, McCormack AL, Johnston J, Langston JW, Di Monte DA (2006) Lack of nigrostriatal pathology in a rat model of proteasome inhibition. Ann Neurol 60(2):256–260. doi:10.1002/ana.20938 PubMedCrossRefGoogle Scholar
  157. 157.
    Sun F, Anantharam V, Zhang D, Latchoumycandane C, Kanthasamy A, Kanthasamy AG (2006) Proteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models. Neurotoxicology 27(5):807–815. doi:10.1016/j.neuro.2006.06.006 PubMedCrossRefGoogle Scholar
  158. 158.
    Xie W, Li X, Li C, Zhu W, Jankovic J, Le W (2010) Proteasome inhibition modeling nigral neuron degeneration in Parkinson’s disease. J Neurochem 115(1):188–199. doi:10.1111/j.1471-4159.2010.06914.x PubMedCrossRefGoogle Scholar
  159. 159.
    Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441(7095):885–889. doi:10.1038/nature04724 PubMedCrossRefGoogle Scholar
  160. 160.
    Kuusisto E, Salminen A, Alafuzoff I (2001) Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. Neuroreport 12(10):2085–2090PubMedCrossRefGoogle Scholar
  161. 161.
    Odagiri S, Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K (2012) Autophagic adapter protein NBR1 is localized in Lewy bodies and glial cytoplasmic inclusions and is involved in aggregate formation in alpha-synucleinopathy. Acta Neuropathol 124(2):173–186. doi:10.1007/s00401-012-0975-7 PubMedCrossRefGoogle Scholar
  162. 162.
    Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K (2011) Alteration of autophagosomal proteins (LC3, GABARAP and GATE-16) in Lewy body disease. Neurobiol Dis 43(3):690–697. doi:10.1016/j.nbd.2011.05.022 PubMedCrossRefGoogle Scholar
  163. 163.
    Watanabe Y, Tatebe H, Taguchi K, Endo Y, Tokuda T, Mizuno T, Nakagawa M, Tanaka M (2012) p62/SQSTM1-dependent autophagy of Lewy body-like alpha-synuclein inclusions. PLoS One 7(12):e52868. doi:10.1371/journal.pone.0052868 PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Kuusisto E, Salminen A, Alafuzoff I (2002) Early accumulation of p62 in neurofibrillary tangles in Alzheimer’s disease: possible role in tangle formation. Neuropathol Appl Neurobiol 28(3):228–237PubMedCrossRefGoogle Scholar
  165. 165.
    Nagaoka U, Kim K, Jana NR, Doi H, Maruyama M, Mitsui K, Oyama F, Nukina N (2004) Increased expression of p62 in expanded polyglutamine-expressing cells and its association with polyglutamine inclusions. J Neurochem 91(1):57–68. doi:10.1111/j.1471-4159.2004.02692.x PubMedCrossRefGoogle Scholar
  166. 166.
    Wooten MW, Geetha T, Seibenhener ML, Babu JR, Diaz-Meco MT, Moscat J (2005) The p62 scaffold regulates nerve growth factor-induced NF-kappaB activation by influencing TRAF6 polyubiquitination. J Biol Chem 280(42):35625–35629. doi:10.1074/jbc.C500237200 PubMedCrossRefGoogle Scholar
  167. 167.
    Linares JF, Duran A, Yajima T, Pasparakis M, Moscat J, Diaz-Meco MT (2013) K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Mol Cell 51(3):283–296. doi:10.1016/j.molcel.2013.06.020 PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T, Jiang T, Sun Z, White E et al (2010) A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol 30(13):3275–3285. doi:10.1128/MCB.00248-10 PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Tofaris GK, Kim HT, Hourez R, Jung JW, Kim KP, Goldberg AL (2011) Ubiquitin ligase Nedd4 promotes alpha-synuclein degradation by the endosomal-lysosomal pathway. Proc Natl Acad Sci U S A 108(41):17004–17009. doi:10.1073/pnas.1109356108 PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Zucchelli S, Codrich M, Marcuzzi F, Pinto M, Vilotti S, Biagioli M, Ferrer I, Gustincich S (2010) TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson’s disease brains. Hum Mol Genet 19(19):3759–3770. doi:10.1093/hmg/ddq290 PubMedCrossRefGoogle Scholar
  171. 171.
    Mulherkar SA, Sharma J, Jana NR (2009) The ubiquitin ligase E6-AP promotes degradation of alpha-synuclein. J Neurochem 110(6):1955–1964. doi:10.1111/j.1471-4159.2009.06293.x PubMedCrossRefGoogle Scholar
  172. 172.
    Lee FK, Wong AK, Lee YW, Wan OW, Chan HY, Chung KK (2009) The role of ubiquitin linkages on alpha-synuclein induced-toxicity in a Drosophila model of Parkinson’s disease. J Neurochem 110(1):208–219. doi:10.1111/j.1471-4159.2009.06124.x PubMedCrossRefGoogle Scholar
  173. 173.
    Lee JT, Wheeler TC, Li L, Chin LS (2008) Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Hum Mol Genet 17(6):906–917. doi:10.1093/hmg/ddm363 PubMedCrossRefGoogle Scholar
  174. 174.
    Tofaris GK, Layfield R, Spillantini MG (2001) Alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett 509(1):22–26PubMedCrossRefGoogle Scholar
  175. 175.
    Meier F, Abeywardana T, Dhall A, Marotta NP, Varkey J, Langen R, Chatterjee C, Pratt MR (2012) Semisynthetic, site-specific ubiquitin modification of alpha-synuclein reveals differential effects on aggregation. J Am Chem Soc 134(12):5468–5471. doi:10.1021/ja300094r PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Haj-Yahya M, Fauvet B, Herman-Bachinsky Y, Hejjaoui M, Bavikar SN, Karthikeyan SV, Ciechanover A, Lashuel HA et al (2013) Synthetic polyubiquitinated alpha-synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology. Proc Natl Acad Sci U S A 110(44):17726–17731. doi:10.1073/pnas.1315654110 PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Liu C, Fei E, Jia N, Wang H, Tao R, Iwata A, Nukina N, Zhou J et al (2007) Assembly of lysine 63-linked ubiquitin conjugates by phosphorylated alpha-synuclein implies Lewy body biogenesis. J Biol Chem 282(19):14558–14566. doi:10.1074/jbc.M700422200 PubMedCrossRefGoogle Scholar
  178. 178.
    Klucken J, Poehler AM, Ebrahimi-Fakhari D, Schneider J, Nuber S, Rockenstein E, Schlotzer-Schrehardt U, Hyman BT et al (2012) Alpha-synuclein aggregation involves a bafilomycin A 1-sensitive autophagy pathway. Autophagy 8(5):754–766. doi:10.4161/auto.19371 PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Sampathu DM, Giasson BI, Pawlyk AC, Trojanowski JQ, Lee VM (2003) Ubiquitination of alpha-synuclein is not required for formation of pathological inclusions in alpha-synucleinopathies. Am J Pathol 163(1):91–100PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Dixon C, Mathias N, Zweig RM, Davis DA, Gross DS (2005) Alpha-synuclein targets the plasma membrane via the secretory pathway and induces toxicity in yeast. Genetics 170(1):47–59. doi:10.1534/genetics.104.035493 PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Goel P, Manning JA, Kumar S (2015) NEDD4-2 (NEDD4L): the ubiquitin ligase for multiple membrane proteins. Gene 557(1):1–10. doi:10.1016/j.gene.2014.11.051 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Juliana Navarro-Yepes
    • 1
    • 2
    • 4
  • Annadurai Anandhan
    • 1
    • 2
  • Erin Bradley
    • 1
  • Iryna Bohovych
    • 1
    • 3
  • Bo Yarabe
    • 1
  • Annemieke de Jong
    • 5
  • Huib Ovaa
    • 5
  • You Zhou
    • 3
  • Oleh Khalimonchuk
    • 1
    • 3
  • Betzabet Quintanilla-Vega
    • 4
  • Rodrigo Franco
    • 1
    • 2
  1. 1.Redox Biology CenterUniversity of Nebraska-LincolnLincolnUSA
  2. 2.School of Veterinary Medicine and Biomedical SciencesUniversity of Nebraska-LincolnLincolnUSA
  3. 3.Department of BiochemistryUniversity of Nebraska-LincolnLincolnUSA
  4. 4.Department of ToxicologyCINVESTAV-IPNMexico CityMexico
  5. 5.Division of Cell Biology IIThe Netherlands Cancer InstituteAmsterdamThe Netherlands

Personalised recommendations