Advertisement

Dynamic Role of Ubiquitination in the Management of Misfolded Proteins Associated with Neurodegenerative Diseases

  • Esther S. P. Wong
  • Jeanne M. M. Tan
  • Kah-Leong Lim
Part of the Focus on Structural Biology book series (FOSB, volume 7)

Abstract

Protein aggregation as a result of misfolding is a common theme underlying neurodegenerative diseases. Although a subject of intense research, how misfolded proteins bypass sophisticated protein quality control measures in the cell to be deposited as ubiquitin-enriched inclusion bodies remains poorly understood. Whilst proteasome dysfunction could account for this phenomenon, emerging evidence suggests otherwise. We have previously hypothesized that under conditions of proteolytic stress, the cell may switch to a non-proteolytic form of ubiquitination to help divert misfolded proteins away from an overloaded proteasome. In this way, the cell could preserve its proteasome function over prolonged periods of stress and recover thereafter. Supporting this, we recently found that non-proteolytic lysine (K) 63-linked ubiquitin modification promotes the formation of protein inclusions associated with several major neurodegenerative diseases. Importantly, we further found that K63-linked polyubiquitin selectively facilitates the subsequent clearance of inclusions via autophagy. In this chapter, we will discuss the apparent dynamic role of ubiquitination in the management of misfolded proteins.

Keywords

Misfolded Protein Polyubiquitin Chain Protein Inclusion Ubiquitin Chain Ubiquitin Molecule 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770–774PubMedCrossRefGoogle Scholar
  2. 2.
    Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426:895–899PubMedCrossRefGoogle Scholar
  3. 3.
    Goldberg AL (1972) Degradation of abnormal proteins in Escherichia coli (protein breakdown-protein structure-mistranslation-amino acid analogs-puromycin). Proc Natl Acad Sci USA 69:422–426PubMedCrossRefGoogle Scholar
  4. 4.
    Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479PubMedCrossRefGoogle Scholar
  5. 5.
    Chau V, Tobias JW, Bachmair A, Marriott D, Ecker DJ, Gonda DK, Varshavsky A (1989) A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 243:1576–1583PubMedCrossRefGoogle Scholar
  6. 6.
    Pickart CM, Cohen RE (2004) Proteasomes and their kin: proteases in the machine age. Nat Rev Mol Cell Biol 5:177–187PubMedCrossRefGoogle Scholar
  7. 7.
    Braun BC, Glickman M, Kraft R, Dahlmann B, Kloetzel PM, Finley D, Schmidt M (1999) The base of the proteasome regulatory particle exhibits chaperone-like activity. Nat Cell Biol 1:221–226PubMedCrossRefGoogle Scholar
  8. 8.
    Glickman MH, Rubin DM, Coux O, Wefes I, Pfeifer G, Cjeka Z, Baumeister W, Fried VA, Finley D (1998) A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3. Cell 94:615–623PubMedCrossRefGoogle Scholar
  9. 9.
    Navon A, Goldberg AL (2001) Proteins are unfolded on the surface of the ATPase ring before transport into the proteasome. Mol Cell 8:1339–1349PubMedCrossRefGoogle Scholar
  10. 10.
    Wilkinson KD (1997) Regulation of ubiquitin-dependent processes by deubiquitinating enzymes. Faseb J 11:1245–1256PubMedGoogle Scholar
  11. 11.
    Smith DM, Benaroudj N, Goldberg A (2006) Proteasomes and their associated ATPases: a destructive combination. J Struct Biol 156:72–83PubMedGoogle Scholar
  12. 12.
    Forman MS, Trojanowski JQ, Lee VM (2004) Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med 10:1055–1063PubMedCrossRefGoogle Scholar
  13. 13.
    Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10 (Suppl):S10–S17Google Scholar
  14. 14.
    Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555PubMedCrossRefGoogle Scholar
  15. 15.
    Bennett EJ, Shaler TA, Woodman B, Ryu KY, Zaitseva TS, Becker CH, Bates GP, Schulman H, Kopito RR (2007) Global changes to the ubiquitin system in Huntington’s disease. Nature 448:704–708PubMedCrossRefGoogle Scholar
  16. 16.
    Sherman MY, Goldberg AL (2001) Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 29:15–32PubMedCrossRefGoogle Scholar
  17. 17.
    McNaught KS, Belizaire R, Isacson O, Jenner P, Olanow CW (2003) Altered proteasomal function in sporadic Parkinson’s disease. Exp Neurol 179:38–46PubMedCrossRefGoogle Scholar
  18. 18.
    McNaught KS, Jenner P (2001) Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci Lett 297:191–194PubMedCrossRefGoogle Scholar
  19. 19.
    Lam YA, Pickart CM, Alban A, Landon M, Jamieson C, Ramage R, Mayer RJ, Layfield R (2000) Inhibition of the ubiquitin-proteasome system in Alzheimer’s disease. Proc Natl Acad Sci USA 97:9902–9906PubMedCrossRefGoogle Scholar
  20. 20.
    Keller JN, Hanni KB, Markesbery WR (2000) Impaired proteasome function in Alzheimer’s disease. J Neurochem 75:436–439PubMedCrossRefGoogle Scholar
  21. 21.
    McNaught KS, Perl DP, Brownell AL, Olanow CW (2004) Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann Neurol 56:149–162PubMedCrossRefGoogle Scholar
  22. 22.
    Miwa H, Kubo T, Suzuki A, Nishi K, Kondo T (2005) Retrograde dopaminergic neuron degeneration following intrastriatal proteasome inhibition. Neurosci Lett 380:93–98PubMedCrossRefGoogle Scholar
  23. 23.
    Venkatraman P, Wetzel R, Tanaka M, Nukina N, Goldberg AL (2004) Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol Cell 14:95–104PubMedCrossRefGoogle Scholar
  24. 24.
    Verhoef LG, Lindsten K, Masucci MG, Dantuma NP (2002) Aggregate formation inhibits proteasomal degradation of polyglutamine proteins. Hum Mol Genet 11:2689–2700PubMedCrossRefGoogle Scholar
  25. 25.
    Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608PubMedCrossRefGoogle Scholar
  26. 26.
    Imai Y, Soda M, Takahashi R (2000) Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin–protein ligase activity. J Biol Chem 275:35661–35664PubMedCrossRefGoogle Scholar
  27. 27.
    Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K et al. (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin–protein ligase. Nat Genet 25:302–305PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM (2000) Parkin functions as an E2-dependent ubiquitin–protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci USA 97:13354–13359PubMedCrossRefGoogle Scholar
  29. 29.
    Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105:891–902PubMedCrossRefGoogle Scholar
  30. 30.
    Ko HS, Kim SW, Sriram SR, Dawson VL, Dawson TM (2006) Identification of far upstream element-binding protein-1 as an authentic Parkin substrate. J Biol Chem 281:16193–16196PubMedCrossRefGoogle Scholar
  31. 31.
    Ko HS, von Coelln R, Sriram SR, Kim SW, Chung KK, Pletnikova O, Troncoso J, Johnson B, Saffary R, Goh EL et al. (2005) Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death. J Neurosci 25:7968–7978PubMedCrossRefGoogle Scholar
  32. 32.
    Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A (2003) Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron 37:735–749PubMedCrossRefGoogle Scholar
  33. 33.
    Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T et al. (1998) The ubiquitin pathway in Parkinson’s disease. Nature 395:451–452PubMedCrossRefGoogle Scholar
  34. 34.
    Healy DG, Abou-Sleiman PM, Wood NW (2004) Genetic causes of Parkinson’s disease: UCHL-1. Cell Tissue Res 318:189–194PubMedCrossRefGoogle Scholar
  35. 35.
    Bowman AB, Yoo SY, Dantuma NP, Zoghbi HY (2005) Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum Mol Genet 14:679–691PubMedCrossRefGoogle Scholar
  36. 36.
    Tofaris GK, Razzaq A, Ghetti B, Lilley KS, Spillantini MG (2003) Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. J Biol Chem 278:44405–44411PubMedCrossRefGoogle Scholar
  37. 37.
    Pickart CM (2000) Ubiquitin in chains. Trends Biochem Sci 25:544–548PubMedCrossRefGoogle Scholar
  38. 38.
    Baboshina OV, Haas AL (1996) Novel multiubiquitin chain linkages catalyzed by the conjugating enzymes E2EPF and RAD6 are recognized by 26S proteasome subunit 5. J Biol Chem 271:2823–2831PubMedCrossRefGoogle Scholar
  39. 39.
    Arnason T, Ellison MJ (1994) Stress resistance in Saccharomyces cerevisiae is strongly correlated with assembly of a novel type of multiubiquitin chain. Mol Cell Biol 14:7876–7883PubMedGoogle Scholar
  40. 40.
    Peng J, Schwartz D, Elias JE, Thoreen CC, Cheng D, Marsischky G, Roelofs J, Finley D, Gygi SP (2003) A proteomics approach to understanding protein ubiquitination. Nat Biotechnol 21:921–926PubMedCrossRefGoogle Scholar
  41. 41.
    Crosas B, Hanna J, Kirkpatrick DS, Zhang DP, Tone Y, Hathaway NA, Buecker C, Leggett DS, Schmidt M, King RW et al. (2006) Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities. Cell 127:1401–13PubMedCrossRefGoogle Scholar
  42. 42.
    Hanna J, Hathaway NA, Tone Y, Crosas B, Elsasser S, Kirkpatrick DS, Leggett DS, Gygi SP, King RW, Finley D (2006) Deubiquitinating enzyme Ubp6 functions noncatalytically to delay proteasomal degradation. Cell 127:99–111PubMedCrossRefGoogle Scholar
  43. 43.
    Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W (2002) Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416:648–653PubMedCrossRefGoogle Scholar
  44. 44.
    Hicke L, Schubert HL, Hill CP (2005) Ubiquitin-binding domains. Nat Rev Mol Cell Biol 6:610–621PubMedCrossRefGoogle Scholar
  45. 45.
    Aguilar RC, Wendland B (2003) Ubiquitin: not just for proteasomes anymore. Curr Opin Cell Biol 15:184–190PubMedCrossRefGoogle Scholar
  46. 46.
    Lim KL, Dawson VL, Dawson TM (2006) Parkin-mediated lysine 63-linked polyubiquitination: a link to protein inclusions formation in Parkinson’s and other conformational diseases? Neurobiol Aging 27:524–529PubMedCrossRefGoogle Scholar
  47. 47.
    Hayashi S, Wakabayashi K, Ishikawa A, Nagai H, Saito M, Maruyama M, Takahashi T, Ozawa T, Tsuji S, Takahashi H (2000) An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene. Mov Disord 15:884–888Google Scholar
  48. 48.
    Mori H, Kondo T, Yokochi M, Matsumine H, Nakagawa-Hattori Y, Miyake T, Suda K, Mizuno Y (1998) Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. Neurology 51:890–892PubMedGoogle Scholar
  49. 49.
    Takahashi H, Ohama E, Suzuki S, Horikawa Y, Ishikawa A, Morita T, Tsuji S, Ikuta F (1994) Familial juvenile parkinsonism: clinical and pathologic study in a family. Neurology 44:437–441PubMedGoogle Scholar
  50. 50.
    Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (2001) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 7:1144–1150PubMedCrossRefGoogle Scholar
  51. 51.
    Lim KL, Chew KC, Tan JM, Wang C, Chung KK, Zhang Y, Tanaka Y, Smith W, Engelender S, Ross CA et al. (2005) Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation. J Neurosci 25:2002–2009PubMedCrossRefGoogle Scholar
  52. 52.
    Doss-Pepe EW, Chen L, Madura K (2005) Alpha-synuclein and parkin contribute to the assembly of ubiquitin lysine 63-linked multiubiquitin chains. J Biol Chem 280:16619–16624PubMedCrossRefGoogle Scholar
  53. 53.
    Hampe C, Ardila-Osorio H, Fournier M, Brice A, Corti O (2006) Biochemical analysis of Parkinson’s disease-causing variants of Parkin, an E3 ubiquitin–protein ligase with monoubiquitylation capacity. Hum Mol Genet 15:2059–2075PubMedCrossRefGoogle Scholar
  54. 54.
    Matsuda N, Kitami T, Suzuki T, Mizuno Y, Hattori N, Tanaka K (2006) Diverse effects of pathogenic mutations of Parkin that catalyze multiple monoubiquitylation in vitro. J Biol Chem 281:3204–3209PubMedCrossRefGoogle Scholar
  55. 55.
    Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT Jr. (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson’s disease susceptibility. Cell 111:209–218PubMedCrossRefGoogle Scholar
  56. 56.
    Tan JM, Wong ES, Kirkpatrick DS, Pletnikova O, Ko HS, Tay SP, Ho MW, Troncoso J, Gygi SP, Lee MK et al. (2008) Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases. Hum Mol Genet 17:431–439PubMedCrossRefGoogle Scholar
  57. 57.
    Hofmann RM, Pickart CM (1999) Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 96:645–653PubMedCrossRefGoogle Scholar
  58. 58.
    Tan JM, Wong ES, Dawson VL, Dawson TM, Lim KL (2008) Lysine 63-linked polyubiquitin potentially partners with p62 to promote the clearance of protein inclusions by autophagy. Autophagy 4:251–253Google Scholar
  59. 59.
    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 24:8055–8068PubMedCrossRefGoogle Scholar
  60. 60.
    Raasi S, Varadan R, Fushman D, Pickart CM (2005) Diverse polyubiquitin interaction properties of ubiquitin-associated domains. Nat Struct Mol Biol 12:708–714PubMedCrossRefGoogle Scholar
  61. 61.
    Long J, Gallagher TR, Cavey JR, Sheppard PW, Ralston SH, Layfield R, Searle MS (2008) Ubiquitin recognition by the ubiquitin-associated domain of p62 involves a novel conformational switch. J Biol Chem 283:5427–5440PubMedCrossRefGoogle Scholar
  62. 62.
    Johnston JA, Ward CL, Kopito RR (1998) Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143:1883–1898PubMedCrossRefGoogle Scholar
  63. 63.
    Mishra RS, Bose S, Gu Y, Li R, Singh N (2003) Aggresome formation by mutant prion proteins: the unfolding role of proteasomes in familial prion disorders. J Alzheimers Dis 5:15–23PubMedGoogle Scholar
  64. 64.
    Olanow CW, Perl DP, DeMartino GN, McNaught KS (2004) Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol 3:496–503PubMedCrossRefGoogle Scholar
  65. 65.
    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 12:1393–1407PubMedGoogle Scholar
  66. 66.
    Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431:805–810PubMedCrossRefGoogle Scholar
  67. 67.
    Cummings CJ, Reinstein E, Sun Y, Antalffy B, Jiang Y, Ciechanover A, Orr HT, Beaudet AL, Zoghbi HY (1999) Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24:879–892PubMedCrossRefGoogle Scholar
  68. 68.
    Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, Zoghbi HY, Orr HT (1998) Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95:41–53PubMedCrossRefGoogle Scholar
  69. 69.
    Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8:931–937PubMedCrossRefGoogle Scholar
  70. 70.
    Cuervo AM (2006) Autophagy in neurons: it is not all about food. Trends Mol Med 12:461–464PubMedCrossRefGoogle Scholar
  71. 71.
    Rubinsztein DC, Difiglia M, Heintz N, Nixon RA, Qin ZH, Ravikumar B, Stefanis L, Tolkovsky A (2005) Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy 1:11–22PubMedGoogle Scholar
  72. 72.
    Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H et al. (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889PubMedCrossRefGoogle Scholar
  73. 73.
    Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E et al. (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884PubMedCrossRefGoogle Scholar
  74. 74.
    Berger Z, Ravikumar B, Menzies FM, Oroz LG, Underwood BR, Pangalos MN, Schmitt I, Wullner U, Evert BO, O’Kane CJ et al. (2006) Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet 15:433–442PubMedCrossRefGoogle Scholar
  75. 75.
    Ravikumar B, Berger Z, Vacher C, O’Kane CJ, Rubinsztein DC (2006) Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet 15:1209–1216PubMedCrossRefGoogle Scholar
  76. 76.
    Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O’Kane CJ et al. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–595PubMedCrossRefGoogle Scholar
  77. 77.
    Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC (2007) Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 282:5641–5652PubMedCrossRefGoogle Scholar
  78. 78.
    Kopito RR (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10:524–530PubMedCrossRefGoogle Scholar
  79. 79.
    Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278:25009–25013PubMedCrossRefGoogle Scholar
  80. 80.
    Fortun J, Dunn WA Jr., Joy S, Li J, Notterpek L (2003) Emerging role for autophagy in the removal of aggresomes in Schwann cells. J Neurosci 23:10672–10680PubMedGoogle Scholar
  81. 81.
    Iwata A, Christianson JC, Bucci M, Ellerby LM, Nukina N, Forno LS, Kopito RR (2005) Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc Natl Acad Sci USA 102:13135–13140PubMedCrossRefGoogle Scholar
  82. 82.
    Opazo F, Krenz A, Heermann S, Schulz JB, Falkenburger BH (2008) Accumulation and clearance of alpha-synuclein aggregates demonstrated by time-lapse imaging. J Neurochem. 106:529–540PubMedCrossRefGoogle Scholar
  83. 83.
    Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, Johansen T (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171:603–614PubMedCrossRefGoogle Scholar
  84. 84.
    Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G, Johansen T (2007) p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy. J Biol Chem 282:24131–24145PubMedCrossRefGoogle Scholar
  85. 85.
    Wooten MW, Geetha T, Babu JR, Seibenhener ML, Peng J, Cox N, Diaz-Meco MT, Moscat J (2008) Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins. J Biol Chem 283:6783–6789PubMedCrossRefGoogle Scholar
  86. 86.
    Iwata A, Riley BE, Johnston JA, Kopito RR (2005) HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem 280:40282–40292PubMedCrossRefGoogle Scholar
  87. 87.
    Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115:727–738PubMedCrossRefGoogle Scholar
  88. 88.
    Ravikumar B, Acevedo-Arozena A, Imarisio S, Berger Z, Vacher C, O’Kane CJ, Brown SD, Rubinsztein DC (2005) Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat Genet 37:771–776PubMedCrossRefGoogle Scholar
  89. 89.
    Olzmann JA, Li L, Chudaev MV, Chen J, Perez FA, Palmiter RD, Chin LS (2007) Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J Cell Biol 178:1025–1038PubMedCrossRefGoogle Scholar
  90. 90.
    Rott R, Szargel R, Haskin J, Shani V, Shainskaya A, Manov I, Liani E, Avraham E, Engelender S (2008) Monoubiquitylation of alpha-synuclein by seven in absentia homolog (SIAH) promotes its aggregation in dopaminergic cells. J Biol Chem 283:3316–3328PubMedCrossRefGoogle Scholar
  91. 91.
    Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ (2000) Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103:351–361PubMedCrossRefGoogle Scholar
  92. 92.
    Zhang M, Windheim M, Roe SM, Peggie M, Cohen P, Prodromou C, Pearl LH (2005) Chaperoned ubiquitylation–crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex. Mol Cell 20:525–538PubMedCrossRefGoogle Scholar
  93. 93.
    Shin Y, Klucken J, Patterson C, Hyman BT, McLean PJ (2005) The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways. J Biol Chem 280:23727–23734PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Esther S. P. Wong
  • Jeanne M. M. Tan
  • Kah-Leong Lim
    • 1
  1. 1.Neurodegeneration Research Lab National Neuroscience Institute Singapore and Department of Anatomy and Structural Biology Marion Bessin Liver Research CenterAlbert Einstein College of MedicineUSA

Personalised recommendations