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Ubiquitin/proteasome pathway impairment in neurodegeneration: therapeutic implications

  • Apoptosis in the aging brain
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Abstract

The ubiquitin/proteasome pathway is the major proteolytic quality control system in cells. In this review we discuss the impact of a deregulation of this pathway on neuronal function and its causal relationship to the intracellular deposition of ubiquitin protein conjugates in pathological inclusion bodies in all the major chronic neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and Huntington’s diseases as well as amyotrophic lateral sclerosis. We describe the intricate nature of the ubiquitin/proteasome pathway and discuss the paradox of protein aggregation, i.e. its potential toxic/protective effect in neurodegeneration. The relations between some of the dysfunctional components of the pathway and neurodegeneration are presented. We highlight possible ubiquitin/proteasome pathway-targeting therapeutic approaches, such as activating the proteasome, enhancing ubiquitination and promoting SUMOylation that might be important to slow/treat the progression of neurodegeneration. Finally, a model time line is presented for neurodegeneration starting at the initial injurious events up to protein aggregation and cell death, with potential time points for therapeutic intervention.

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Abbreviations

AD:

Alzheimer’s disease

AIRAP:

Arsenite-inducible RNA-associated protein

ALS:

Amyotrophic lateral sclerosis

CDDO:

2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid

CHIP:

Carboxyl terminus of Hsc 70-interacting protein

CNS:

Central nervous system

DALIS:

Dendritic cell aggresome-like induced structures

DriPs:

Defective ribosomal products

E1:

Ubiquitin-activating enzyme

E2:

Ubiquitin-conjugating enzyme

E3:

Ubiquitin ligase

Gad:

Gracile axonal dystrophy

GFP:

Green fluorescent protein

HD:

Huntington’s disease

Hsp:

Heat shock protein

LC3:

Light chain 3

MJD:

Machado-Joseph disease

MTOC:

Microtubule organizing center

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

Nrf2:

Nuclear factor-erythroid 2-related factor 2

PA:

Proteasome activator

PD:

Parkinson’s disease

PGJ2:

Prostaglandin J2

PINK1:

PTEN-induced kinase 1

PolyQ:

Polyglutamine

POMP:

Proteasome maturation protein

PROTACS:

Proteolysis targeting chimera molecules

Rpn:

19S Regulatory particle, non ATP-dependent

UBA:

Ubiquitin-associated domain

UBL:

Ubiquitin-like domain

UCH-L1:

Ubiquitin carboxyl-terminal hydrolase-L1

UDP:

Ubiquitin-domain proteins

UIM:

Ubiquitin-interacting motif

UPP:

Ubiquitin/proteasome pathway

References

  1. Ciechanover A (2005) Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Cell Death Differ 12:1178–1190

    CAS  PubMed  Google Scholar 

  2. Lee DH, Goldberg AL (1998) Proteasome inhibitors: valuable new tools for cell biologists. Trends Cell Biol 8:397–403

    CAS  PubMed  Google Scholar 

  3. Yewdell JW (2001) Not such a dismal science: the economics of protein synthesis, folding, degradation and antigen processing. Trends Cell Biol 11:294–297

    CAS  PubMed  Google Scholar 

  4. Haas AL, Bright PM (1985) The immunochemical detection and quantitation of intracellular ubiquitin-protein conjugates. J Biol Chem 260:12464–12473

    CAS  PubMed  Google Scholar 

  5. Gronostajski RM, Pardee AB, Goldberg AL (1985) The ATP dependence of the degradation of short- and long-lived proteins in growing fibroblasts. J Biol Chem 260:3344–3349

    CAS  PubMed  Google Scholar 

  6. Hendil KB (1988) The 19 S multicatalytic “prosome” proteinase is a constitutive enzyme in HeLa cells. Biochem Int 17:471–477

    CAS  PubMed  Google Scholar 

  7. Princiotta MF, Finzi D, Qian SB, Gibbs J, Schuchmann S, Buttgereit F, Bennink JR, Yewdell JW (2003) Quantitating protein synthesis, degradation, and endogenous antigen processing. Immunity 18:343–354

    CAS  PubMed  Google Scholar 

  8. Alves-Rodrigues A, Gregori L, Figueiredo-Pereira ME (1998) Ubiquitin, cellular inclusions and their role in neurodegeneration. Trends Neurosci 21:516–520

    CAS  PubMed  Google Scholar 

  9. Jung T, Catalgol B, Grune T (2009) The proteasomal system. Mol Aspects Med 30:191–296

    CAS  PubMed  Google Scholar 

  10. Segref A, Hoppe T (2009) Think locally: control of ubiquitin-dependent protein degradation in neurons. EMBO Rep 10:44–50

    CAS  PubMed  Google Scholar 

  11. Beal R, Deveraux Q, Xia G, Rechsteiner M, Pickart C (1996) Surface hydrophobic residues of multiubiquitin chains essential for proteolytic targeting. Proc Natl Acad Sci USA 93:861–866

    CAS  PubMed  Google Scholar 

  12. Hochstrasser M (2009) Origin and function of ubiquitin-like proteins. Nature 458:422–429

    CAS  PubMed  Google Scholar 

  13. Deshaies RJ, Joazeiro CA (2009) RING domain E3 ubiquitin ligases. Annu Rev Biochem 78:399–434

    CAS  PubMed  Google Scholar 

  14. Koegl M, Hoppe T, Schlenker S, Ulrich HD, Mayer TU, Jentsch S (1999) A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell 96:635–644

    CAS  PubMed  Google Scholar 

  15. Reyes-Turcu FE, Ventii KH, Wilkinson KD (2009) Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 78:363–397

    CAS  PubMed  Google Scholar 

  16. Tanaka K (2009) The proteasome: overview of structure and functions. Proc Jpn Acad Ser B Phys Biol Sci 85:12–36

    CAS  PubMed  Google Scholar 

  17. Finley D (2009) Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu Rev Biochem 78:477–513

    CAS  PubMed  Google Scholar 

  18. Rechsteiner M, Realini C, Ustrell V (2000) The proteasome activator 11 S REG (PA28) and class I antigen presentation. Biochem J 345(Pt 1):1–15

    CAS  PubMed  Google Scholar 

  19. Marques AJ, Palanimurugan R, Matias AC, Ramos PC, Dohmen RJ (2009) Catalytic mechanism and assembly of the proteasome. Chem Rev 109:1509–1536

    CAS  PubMed  Google Scholar 

  20. Groll M, Ditzel L, Lowe J, Stock D, Bochtler M, Bartunik HD, Huber R (1997) Structure of 20S proteasome from yeast at 2.4 A resolution. Nature 386:463–471

    CAS  PubMed  Google Scholar 

  21. Benaroudj N, Zwickl P, Seemuller E, Baumeister W, Goldberg AL (2003) ATP hydrolysis by the proteasome regulatory complex PAN serves multiple functions in protein degradation. Mol Cell 11:69–78

    CAS  PubMed  Google Scholar 

  22. Bech-Otschir D, Helfrich A, Enenkel C, Consiglieri G, Seeger M, Holzhutter HG, Dahlmann B, Kloetzel PM (2009) Polyubiquitin substrates allosterically activate their own degradation by the 26S proteasome. Nat Struct Mol Biol 16:219–225

    CAS  PubMed  Google Scholar 

  23. Babbitt SE, Kiss A, Deffenbaugh AE, Chang YH, Bailly E, Erdjument-Bromage H, Tempst P, Buranda T, Sklar LA, Baumler J, Gogol E, Skowyra D (2005) ATP hydrolysis-dependent disassembly of the 26S proteasome is part of the catalytic cycle. Cell 121:553–565

    CAS  PubMed  Google Scholar 

  24. Orlowski M, Wilk S (2003) Ubiquitin-independent proteolytic functions of the proteasome. Arch Biochem Biophys 415:1–5

    CAS  PubMed  Google Scholar 

  25. Grune T, Davies KJ (2003) The proteasomal system and HNE-modified proteins. Mol Aspects Med 24:195–204

    CAS  PubMed  Google Scholar 

  26. Thrower JS, Hoffman L, Rechsteiner M, Pickart CM (2000) Recognition of the polyubiquitin proteolytic signal. EMBO J 19:94–102

    CAS  PubMed  Google Scholar 

  27. Young P, Deveraux Q, Beal RE, Pickart CM, Rechsteiner M (1998) Characterization of two polyubiquitin binding sites in the 26 S protease subunit 5a. J Biol Chem 273:5461–5467

    CAS  PubMed  Google Scholar 

  28. Husnjak K, Elsasser S, Zhang N, Chen X, Randles L, Shi Y, Hofmann K, Walters KJ, Finley D, Dikic I (2008) Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature 453:481–488

    CAS  PubMed  Google Scholar 

  29. Johnston JA, Ward CL, Kopito RR (1998) Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143:1883–1898

    CAS  PubMed  Google Scholar 

  30. Wojcik C, DeMartino GN (2003) Intracellular localization of proteasomes. Int J Biochem Cell Biol 35:579–589

    CAS  PubMed  Google Scholar 

  31. Reits EAJ, Benham AM, Plougastel B, Neefjes J, Trowsdale J (1997) Dynamics of proteasome distribution in living cells. EMBO J 16:6087–6094

    CAS  PubMed  Google Scholar 

  32. Welchman RL, Gordon C, Mayer RJ (2005) Ubiquitin and ubiquitin-like proteins as multifunctional signals. Nat Rev Mol Cell Biol 6:599–609

    CAS  PubMed  Google Scholar 

  33. Elsasser S, Finley D (2005) Delivery of ubiquitinated substrates to protein-unfolding machines. Nat Cell Biol 7:742–749

    CAS  PubMed  Google Scholar 

  34. Mayer RJ (2003) From neurodegeneration to neurohomeostasis: the role of ubiquitin. Drug News Perspect 16:103–108

    CAS  PubMed  Google Scholar 

  35. Medicherla B, Goldberg AL (2008) Heat shock and oxygen radicals stimulate ubiquitin-dependent degradation mainly of newly synthesized proteins. J Cell Biol 182:663–673

    CAS  PubMed  Google Scholar 

  36. Szeto J, Kaniuk NA, Canadien V, Nisman R, Mizushima N, Yoshimori T, Bazett-Jones DP, Brumell JH (2006) ALIS are stress-induced protein storage compartments for substrates of the proteasome and autophagy. Autophagy 2:189–199

    CAS  PubMed  Google Scholar 

  37. Katayama H, Yamamoto A, Mizushima N, Yoshimori T, Miyawaki A (2008) GFP-like proteins stably accumulate in lysosomes. Cell Struct Funct 33:1–12

    CAS  PubMed  Google Scholar 

  38. Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555

    CAS  PubMed  Google Scholar 

  39. Wang Y, Martinez-Vicente M, Kruger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E (2009) Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet 18:4153–4170

    CAS  PubMed  Google Scholar 

  40. Tanaka M, Kim YM, Lee G, Junn E, Iwatsubo T, Mouradian MM (2004) Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem 279:4625–4631

    CAS  PubMed  Google Scholar 

  41. Cookson MR, Lockhart PJ, McLendon C, O’Farrell C, Schlossmacher M, Farrer MJ (2003) RING finger 1 mutations in Parkin produce altered localization of the protein. Hum Mol Genet 12:2957–2965

    CAS  PubMed  Google Scholar 

  42. 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 431:805–810

    CAS  PubMed  Google Scholar 

  43. Mitra S, Tsvetkov AS, Finkbeiner S (2009) Protein turnover and inclusion body formation. Autophagy 5:1037–1038

    CAS  PubMed  Google Scholar 

  44. Orr HT (2004) Neurodegenerative disease: neuron protection agency. Nature 431:747–748

    CAS  PubMed  Google Scholar 

  45. Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95:55–66

    CAS  PubMed  Google Scholar 

  46. Wang Z, Figueiredo-Pereira ME (2005) Inhibition of sequestosome 1/p62 up-regulation prevents aggregation of ubiquitinated proteins induced by prostaglandin J2 without reducing its neurotoxicity. Mol Cell Neurosci 29:222–231

    CAS  PubMed  Google Scholar 

  47. Arnaud LT, Myeku N, Figueiredo-Pereira ME (2009) Proteasome-caspase-cathepsin sequence leading to tau pathology induced by prostaglandin J2 in neuronal cells. J Neurochem 110:328–342

    CAS  PubMed  Google Scholar 

  48. Wigley WC, Fabunmi RP, Lee MG, Marino CR, Muallem S, DeMartino GN, Thomas PJ (1999) Dynamic association of proteasomal machinery with the centrosome. J Cell Biol 145:481–490

    CAS  PubMed  Google Scholar 

  49. Garcia-Mata R, Bebok Z, Sorscher EJ, Sztul ES (1999) Characterization and dynamics of aggresome formation by a cytosolic GFP- chimera. J Cell Biol 146:1239–1254

    CAS  PubMed  Google Scholar 

  50. Fabunmi RP, Wigley WC, Thomas PJ, DeMartino GN (2000) Activity and regulation of the centrosome-associated proteasome. J Biol Chem 275:409–413

    CAS  PubMed  Google Scholar 

  51. Ogburn KD, Figueiredo-Pereira ME (2006) Cytoskeleton/endoplasmic reticulum collapse induced by prostaglandin J2 parallels centrosomal deposition of ubiquitinated protein aggregates. J Biol Chem 281:23274–23284

    CAS  PubMed  Google Scholar 

  52. Cappelletti G, Pedrotti B, Maggioni MG, Maci R (2001) Microtubule assembly is directly affected by MPP(+)in vitro. Cell Biol Int 25:981–984

    CAS  PubMed  Google Scholar 

  53. Diaz-Corrales FJ, Asanuma M, Miyazaki I, Miyoshi K, Ogawa N (2005) Rotenone induces aggregation of gamma-tubulin protein and subsequent disorganization of the centrosome: relevance to formation of inclusion bodies and neurodegeneration. Neuroscience 133:117–135

    CAS  PubMed  Google Scholar 

  54. Marshall LE, Himes RH (1978) Rotenone inhibition of tubulin self-assembly. Biochim Biophys Acta 543:590–594

    CAS  PubMed  Google Scholar 

  55. Roy S, Zhang B, Lee VM, Trojanowski JQ (2005) Axonal transport defects: a common theme in neurodegenerative diseases. Acta Neuropathol 109:5–13

    PubMed  Google Scholar 

  56. Lelouard H, Ferrand V, Marguet D, Bania J, Camosseto V, David A, Gatti E, Pierre P (2004) Dendritic cell aggresome-like induced structures are dedicated areas for ubiquitination and storage of newly synthesized defective proteins. J Cell Biol 164:667–675

    CAS  PubMed  Google Scholar 

  57. Ebstein F, Lange N, Urban S, Seifert U, Kruger E, Kloetzel PM (2009) Maturation of human dendritic cells is accompanied by functional remodelling of the ubiquitin-proteasome system. Int J Biochem Cell Biol 41:1205–1215

    CAS  PubMed  Google Scholar 

  58. Hartmann-Petersen R, Semple CA, Ponting CP, Hendil KB, Gordon C (2003) UBA domain containing proteins in fission yeast. Int J Biochem Cell Biol 35:629–636

    CAS  PubMed  Google Scholar 

  59. Su V, Lau AF (2009) Ubiquitin-like and ubiquitin-associated domain proteins: significance in proteasomal degradation. Cell Mol Life Sci 66:2819–2833

    CAS  PubMed  Google Scholar 

  60. Wilkinson CR, Seeger M, Hartmann-Petersen R, Stone M, Wallace M, Semple C, Gordon C (2001) Proteins containing the UBA domain are able to bind to multi-ubiquitin chains. Nat Cell Biol 3:939–943

    CAS  PubMed  Google Scholar 

  61. Madura K (2002) The ubiquitin-associated (UBA) domain: on the path from prudence to prurience. Cell Cycle 1:235–244

    CAS  PubMed  Google Scholar 

  62. Shin J (1998) P62 and the sequestosome, a novel mechanism for protein metabolism. Arch Pharm Res 21:629–633

    CAS  PubMed  Google Scholar 

  63. Kim S, Nollen EA, Kitagawa K, Bindokas VP, Morimoto RI (2002) Polyglutamine protein aggregates are dynamic. Nat Cell Biol 4:826–831

    CAS  PubMed  Google Scholar 

  64. Tran PB, Miller RJ (1999) Aggregates in neurodegenerative disease: crowds and power? Trends Neurosci 22:194–197

    CAS  PubMed  Google Scholar 

  65. Sharma D, Sharma S, Pasha S, Brahmachari SK (1999) Peptide models for inherited neurodegenerative disorders: conformation and aggregation properties of long polyglutamine peptides with and without interruptions. FEBS Lett 456:181–185

    CAS  PubMed  Google Scholar 

  66. Trushina E, Heldebrant MP, Perez-Terzic CM, Bortolon R, Kovtun IV, Badger JD, Terzic A, Estevez A, Windebank AJ, Dyer RB, Yao J, McMurray CT (2003) Microtubule destabilization and nuclear entry are sequential steps leading to toxicity in Huntington’s disease. Proc Natl Acad Sci USA 100:12171–12176

    CAS  PubMed  Google Scholar 

  67. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW (2008) Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 14:504–506

    CAS  PubMed  Google Scholar 

  68. Kordower JH, Chu Y, Hauser RA, Olanow CW, Freeman TB (2008) Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov Disord 23:2303–2306

    PubMed  Google Scholar 

  69. Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A, Widner H, Revesz T, Lindvall O, Brundin P (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501–503

    CAS  PubMed  Google Scholar 

  70. Cicchetti F, Saporta S, Hauser RA, Parent M, Saint-Pierre M, Sanberg PR, Li XJ, Parker JR, Chu Y, Mufson EJ, Kordower JH, Freeman TB (2009) Neural transplants in patients with Huntington’s disease undergo disease-like neuronal degeneration. Proc Natl Acad Sci USA 106:12483–12488

    CAS  PubMed  Google Scholar 

  71. Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR (2009) Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol 11:219–225

    CAS  PubMed  Google Scholar 

  72. Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852

    CAS  PubMed  Google Scholar 

  73. Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA 106:13010–13015

    CAS  PubMed  Google Scholar 

  74. McGeer EG, Klegeris A, McGeer PL (2005) Inflammation, the complement system and the diseases of aging. Neurobiol Aging 26(Suppl 1):94–97

    PubMed  Google Scholar 

  75. Bjorkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, Raibon E, Lee RV, Benn CL, Soulet D, Magnusson A, Woodman B, Landles C, Pouladi MA, Hayden MR, Khalili-Shirazi A, Lowdell MW, Brundin P, Bates GP, Leavitt BR, Moller T, Tabrizi SJ (2008) A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med 205:1869–1877

    PubMed  Google Scholar 

  76. Boillee S, Vande VC, Cleveland DW (2006) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52:39–59

    CAS  PubMed  Google Scholar 

  77. Lowe J, Blanchard A, Morrell K, Lennox G, Reynolds L, Billett M, Landon M, Mayer RJ (1988) Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson’s disease, Pick’s disease, and Alzheimer’s disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and mallory bodies in alcoholic liver disease. J Pathol 155:9–15

    CAS  PubMed  Google Scholar 

  78. Lowe J, Lennox G, Jefferson D, Morrell K, McQuire D, Gray T, Landon M, Doherty FJ, Mayer RJ (1988) A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin. Neurosci Lett 94:203–210

    CAS  PubMed  Google Scholar 

  79. Keller JN, Hanni KB, Markesbery WR (2000) Impaired proteasome function in Alzheimer’s disease. J Neurochem 75:436–439

    CAS  PubMed  Google Scholar 

  80. McNaught KS, Jenner P (2001) Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci Lett 297:191–194

    CAS  PubMed  Google Scholar 

  81. Keller JN, Gee J, Ding Q (2002) The proteasome in brain aging. Ageing Res Rev 1:279–293

    CAS  PubMed  Google Scholar 

  82. Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53(Suppl 3):S26–S36

    CAS  PubMed  Google Scholar 

  83. van Leeuwen FW, de Kleijn DP, van den Hurk HH, Neubauer A, Sonnemans MA, Sluijs JA, Koycu S, Ramdjielal RDJ, Salehi A, Martens GJM, Grosveld FG, Peter J, Burbach H, Hol EM (1998) Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer’s and Down patients. Science 279:242–247

    PubMed  Google Scholar 

  84. Kitada T, Asakawa S, Minoshima S, Mizuno Y, Shimizu N (2000) Molecular cloning, gene expression, and identification of a splicing variant of the mouse parkin gene. Mamm Genome 11:417–421

    CAS  PubMed  Google Scholar 

  85. 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 392:605–608

    CAS  PubMed  Google Scholar 

  86. Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, Polymeropoulos MH (1998) The ubiquitin pathway in Parkinson’s disease. Nature 395:451–452

    CAS  PubMed  Google Scholar 

  87. Moore DJ, Dawson VL, Dawson TM (2003) Role for the ubiquitin-proteasome system in Parkinson’s disease and other neurodegenerative brain amyloidoses. Neuromolecular Med 4:95–108

    PubMed  Google Scholar 

  88. Przedborski S, Vila M, Jackson-Lewis V (2003) Neurodegeneration: what is it and where are we? J Clin Invest 111:3–10

    CAS  PubMed  Google Scholar 

  89. Gray DA, Tsirigotis M and Woulfe J (2003) Ubiquitin, proteasomes, and the aging brain. Sci Aging Knowl Environ 2003:RE6

  90. Carrard G, Bulteau A, Petropoulos I, Friguet B (2002) Impairment of proteasome structure and function in aging. Int J Biochem Cell Biol 34:1461

    CAS  PubMed  Google Scholar 

  91. Gaczynska M, Osmulski PA, Ward WF (2001) Caretaker or undertaker? The role of the proteasome in aging. Mech Ageing Dev 122:235–254

    CAS  PubMed  Google Scholar 

  92. Vernace VA, Schmidt-Glenewinkel T, Figueiredo-Pereira ME (2007) Aging and regulated protein degradation: who has the UPPer hand? Aging Cell 6:599–606

    CAS  PubMed  Google Scholar 

  93. Vernace VA, Arnaud L, Schmidt-Glenewinkel T, Figueiredo-Pereira ME (2007) Aging perturbs 26S proteasome assembly in Drosophila melanogaster. FASEB J 21:2672–2682

    CAS  PubMed  Google Scholar 

  94. Mayer RJ, Arnold J, Laszlo L, Landon M, Lowe J (1991) Ubiquitin in health and disease. Biochim Biophys Acta 1089:141–157

    CAS  PubMed  Google Scholar 

  95. van Leeuwen FW, Hol EM, Fischer DF (2006) Frameshift proteins in Alzheimer’s disease and in other conformational disorders: time for the ubiquitin-proteasome system. J Alzheimers Dis 9:319–325

    PubMed  Google Scholar 

  96. 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 97:9902–9906

    CAS  PubMed  Google Scholar 

  97. Lindsten K, de Vrij FM, Verhoef LG, Fischer DF, van Leeuwen FW, Hol EM, Masucci MG, Dantuma NP (2002) Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation. J Cell Biol 157:417–427

    CAS  PubMed  Google Scholar 

  98. Tank EM, True HL (2009) Disease-associated mutant ubiquitin causes proteasomal impairment and enhances the toxicity of protein aggregates. PLoS Genet 5:e1000382

    PubMed  Google Scholar 

  99. Tan Z, Sun X, Hou FS, Oh HW, Hilgenberg LG, Hol EM, van Leeuwen FW, Smith MA, O’Dowd DK, Schreiber SS (2007) Mutant ubiquitin found in Alzheimer’s disease causes neuritic beading of mitochondria in association with neuronal degeneration. Cell Death Differ 14:1721–1732

    CAS  PubMed  Google Scholar 

  100. Fischer DF, van DR, van TP, Hobo B, Verhage MC, van der Schors RC, Li KW, van MJ, Hol EM and van Leeuwen FW (2009) Long-term proteasome dysfunction in the mouse brain by expression of aberrant ubiquitin. Neurobiol Aging 30:847–863

  101. Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denefle P, Wood NW, Agid Y, Brice A (2000) Association between early-onset Parkinson’s disease and mutations in the parkin gene. French Parkinson’s Disease Genetics Study Group. N Engl J Med 342:1560–1567

    CAS  PubMed  Google Scholar 

  102. Sakata E, Yamaguchi Y, Kurimoto E, Kikuchi J, Yokoyama S, Yamada S, Kawahara H, Yokosawa H, Hattori N, Mizuno Y, Tanaka K, Kato K (2003) Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain. EMBO Rep 4:301–306

    CAS  PubMed  Google Scholar 

  103. Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyama S, Weissman AM (1999) RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci USA 96:11364–11369

    CAS  PubMed  Google Scholar 

  104. Ulrich HD, Jentsch S (2000) Two RING finger proteins mediate cooperation between ubiquitin-conjugating enzymes in DNA repair. EMBO J 19:3388–3397

    CAS  PubMed  Google Scholar 

  105. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25:302–305

    CAS  PubMed  Google Scholar 

  106. Beasley SA, Hristova VA, Shaw GS (2007) Structure of the Parkin in-between-ring domain provides insights for E3-ligase dysfunction in autosomal recessive Parkinson’s disease. Proc Natl Acad Sci USA 104:3095–3100

    CAS  PubMed  Google Scholar 

  107. 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 280:16619–16624

    CAS  PubMed  Google Scholar 

  108. Olzmann JA, Chin LS (2008) Parkin-mediated K63-linked polyubiquitination: a signal for targeting misfolded proteins to the aggresome-autophagy pathway. Autophagy 4:85–87

    CAS  PubMed  Google Scholar 

  109. Chung KK, Thomas B, Li X, Pletnikova O, Troncoso JC, Marsh L, Dawson VL, Dawson TM (2004) S-nitrosylation of parkin regulates ubiquitination and compromises Parkin’s protective function. Science 304:1328–1331

    CAS  PubMed  Google Scholar 

  110. Rubio la de TE, Luzon-Toro B, Forte-Lago I, Minguez-Castellanos A, Ferrer I, Hilfiker S (2009) Combined kinase inhibition modulates parkin inactivation. Hum Mol Genet 18:809–823

    Google Scholar 

  111. Shimura H, Hattori N, Kubo S, Yoshikawa M, Kitada T, Matsumine H, Asakawa S, Minoshima S, Yamamura Y, Shimizu N, Mizuno Y (1999) Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients. Ann Neurol 45:668–672

    CAS  PubMed  Google Scholar 

  112. Sha D, Chin LS, Li L (2010) Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. Hum Mol Genet 19:352–363

    CAS  PubMed  Google Scholar 

  113. Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA, Guo M (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166

    CAS  PubMed  Google Scholar 

  114. Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim JM, Chung J (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157–1161

    CAS  PubMed  Google Scholar 

  115. Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803

    CAS  PubMed  Google Scholar 

  116. Rothfuss O, Fischer H, Hasegawa T, Maisel M, Leitner P, Miesel F, Sharma M, Bornemann A, Berg D, Gasser T, Patenge N (2009) Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair. Hum Mol Genet 18:3832–3850

    CAS  PubMed  Google Scholar 

  117. Berger AK, Cortese GP, Amodeo KD, Weihofen A, Letai A, LaVoie MJ (2009) Parkin selectively alters the intrinsic threshold for mitochondrial cytochrome c release. Hum Mol Genet 18:4317–4328

    CAS  PubMed  Google Scholar 

  118. Burns MP, Zhang L, Rebeck GW, Querfurth HW, Moussa CE (2009) Parkin promotes intracellular Abeta1–42 clearance. Hum Mol Genet 18:3206–3216

    CAS  PubMed  Google Scholar 

  119. Helton TD, Otsuka T, Lee MC, Mu Y, Ehlers MD (2008) Pruning and loss of excitatory synapses by the parkin ubiquitin ligase. Proc Natl Acad Sci USA 105:19492–19497

    CAS  PubMed  Google Scholar 

  120. Morett E, Bork P (1999) A novel transactivation domain in parkin. Trends Biochem Sci 24:229–231

    CAS  PubMed  Google Scholar 

  121. da Costa CA, Sunyach C, Giaime E, West A, Corti O, Brice A, Safe S, bou-Sleiman PM, Wood NW, Takahashi H, Goldberg MS, Shen J, Checler F (2009) Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson’s disease. Nat Cell Biol 11:1370–1375

    PubMed  Google Scholar 

  122. Wilkinson KD (1997) Regulation of ubiquitin-dependent processes by deubiquitinating enzymes. FASEB J 11:1245–1256

    CAS  PubMed  Google Scholar 

  123. Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson’s disease susceptibility. Cell 111:209–218

    CAS  PubMed  Google Scholar 

  124. Setsuie R, Wada K (2007) The functions of UCH-L1 and its relation to neurodegenerative diseases. Neurochem Int 51:105–111

    CAS  PubMed  Google Scholar 

  125. Saigoh K, Wang YL, Suh JG, Yamanishi T, Sakai Y, Kiyosawa H, Harada T, Ichihara N, Wakana S, Kikuchi T, Wada K (1999) Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nat Genet 23:47–51

    CAS  PubMed  Google Scholar 

  126. MacDonald ME (1999) Gadzooks!. Nat Genet 23:10–11

    CAS  PubMed  Google Scholar 

  127. Ragland M, Hutter C, Zabetian C, Edwards K (2009) Association between the ubiquitin carboxyl-terminal esterase L1 gene (UCHL1) S18Y variant and Parkinson’s disease: a HuGE review and meta-analysis. Am J Epidemiol 170:1344–1357

    PubMed  Google Scholar 

  128. Kyratzi E, Pavlaki M, Stefanis L (2008) The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells. Hum Mol Genet 17:2160–2171

    CAS  PubMed  Google Scholar 

  129. Choi J, Levey AI, Weintraub ST, Rees HD, Gearing M, Chin LS, Li L (2004) Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson’s and Alzheimer’s diseases. J Biol Chem 279:13256–13264

    CAS  PubMed  Google Scholar 

  130. Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, Moolman D, Zhang H, Shelanski M, Arancio O (2006) Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory. Cell 126:775–788

    CAS  PubMed  Google Scholar 

  131. Kabuta T, Furuta A, Aoki S, Furuta K, Wada K (2008) Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy. J Biol Chem 283:23731–23738

    CAS  PubMed  Google Scholar 

  132. Kabuta T, Wada K (2008) Insights into links between familial and sporadic Parkinson’s disease: physical relationship between UCH-L1 variants and chaperone-mediated autophagy. Autophagy 4:827–829

    CAS  PubMed  Google Scholar 

  133. Liu Z, Meray RK, Grammatopoulos TN, Fredenburg RA, Cookson MR, Liu Y, Logan T, Lansbury PT Jr (2009) Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson’s disease. Proc Natl Acad Sci USA 106:4635–4640

    CAS  PubMed  Google Scholar 

  134. Lopez-Salon M, Alonso M, Vianna MR, Viola H, Mello e Souza T, Izquierdo I, Pasquini JM, Medina JH (2001) The ubiquitin-proteasome cascade is required for mammalian long-term memory formation. Eur J Neurosci 14:1820–1826

    CAS  PubMed  Google Scholar 

  135. Hegde AN, Inokuchi K, Pei W, Casadio A, Ghirardi M, Chain DG, Martin KC, Kandel ER, Schwartz JH (1997) Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia. Cell 89:115–126

    CAS  PubMed  Google Scholar 

  136. Lombardino AJ, Li XC, Hertel M, Nottebohm F (2005) Replaceable neurons and neurodegenerative disease share depressed UCHL1 levels. Proc Natl Acad Sci USA 102:8036–8041

    CAS  PubMed  Google Scholar 

  137. Masino L, Musi V, Menon RP, Fusi P, Kelly G, Frenkiel TA, Trottier Y, Pastore A (2003) Domain architecture of the polyglutamine protein ataxin-3: a globular domain followed by a flexible tail. FEBS Lett 549:21–25

    CAS  PubMed  Google Scholar 

  138. Maciel P, Costa MC, Ferro A, Rousseau M, Santos CS, Gaspar C, Barros J, Rouleau GA, Coutinho P, Sequeiros J (2001) Improvement in the molecular diagnosis of Machado-Joseph disease. Arch Neurol 58:1821–1827

    CAS  PubMed  Google Scholar 

  139. 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

    CAS  PubMed  Google Scholar 

  140. Macedo-Ribeiro S, Cortes L, Maciel P, Carvalho AL (2009) Nucleocytoplasmic shuttling activity of ataxin-3. PLoS One 4:e5834

    PubMed  Google Scholar 

  141. Reina CP, Zhong X, Pittman RN (2010) Proteotoxic stress increases nuclear localization of ataxin-3. Hum Mol Genet 19:235–249

    CAS  PubMed  Google Scholar 

  142. Wang G, Sawai N, Kotliarova S, Kanazawa I, Nukina N (2000) Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B. Hum Mol Genet 9:1795–1803

    CAS  PubMed  Google Scholar 

  143. Winborn BJ, Travis SM, Todi SV, Scaglione KM, Xu P, Williams AJ, Cohen RE, Peng J, Paulson HL (2008) The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem 283:26436–26443

    CAS  PubMed  Google Scholar 

  144. Todi SV, Winborn BJ, Scaglione KM, Blount JR, Travis SM, Paulson HL (2009) Ubiquitination directly enhances activity of the deubiquitinating enzyme ataxin-3. EMBO J 28:372–382

    CAS  PubMed  Google Scholar 

  145. Ying Z, Wang H, Fan H, Zhu X, Zhou J, Fei E, Wang G (2009) Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation. Hum Mol Genet 18:4268–4281

    CAS  PubMed  Google Scholar 

  146. Chou AH, Yeh TH, Kuo YL, Kao YC, Jou MJ, Hsu CY, Tsai SR, Kakizuka A, Wang HL (2006) Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL. Neurobiol Dis 21:333–345

    CAS  PubMed  Google Scholar 

  147. Jung J, Xu K, Lessing D, Bonini NM (2009) Preventing Ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3. Hum Mol Genet 18:4843–4852

    CAS  PubMed  Google Scholar 

  148. Babu JR, Geetha T, Wooten MW (2005) Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem 94:192–203

    CAS  PubMed  Google Scholar 

  149. Ramesh BJ, Lamar SM, Peng J, Strom AL, Kemppainen R, Cox N, Zhu H, Wooten MC, Diaz-Meco MT, Moscat J, Wooten MW (2008) Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration. J Neurochem 106:107–120

    Google Scholar 

  150. Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J (1999) The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation. EMBO J 18:3044–3053

    CAS  PubMed  Google Scholar 

  151. Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, Moscat J (2001) The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor. J Biol Chem 276:7709–7712

    CAS  PubMed  Google Scholar 

  152. Sanz L, Diaz-Meco MT, Nakano H, Moscat J (2000) The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway. EMBO J 19:1576–1586

    CAS  PubMed  Google Scholar 

  153. Geetha T, Wooten MW (2002) Structure and functional properties of the ubiquitin binding protein p62. FEBS Lett 512:19–24

    CAS  PubMed  Google Scholar 

  154. 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 282:24131–24145

    CAS  PubMed  Google Scholar 

  155. Puls A, Schmidt S, Grawe F, Stabel S (1997) Interaction of protein kinase C zeta with ZIP, a novel protein kinase C-binding protein. Proc Natl Acad Sci USA 94:6191–6196

    CAS  PubMed  Google Scholar 

  156. Wooten MW, Hu X, Babu JR, Seibenhener ML, Geetha T, Paine MG, Wooten MC (2006) Signaling, polyubiquitination, trafficking, and inclusions: sequestosome 1/p62’s role in neurodegenerative disease. J Biomed Biotechnol 2006:62079

    PubMed  Google Scholar 

  157. Gal J, Strom AL, Kwinter DM, Kilty R, Zhang J, Shi P, Fu W, Wooten MW, Zhu H (2009) Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism. J Neurochem 111:1062–1073

    CAS  PubMed  Google Scholar 

  158. Seibenhener ML, Geetha T, Wooten MW (2007) Sequestosome 1/p62–more than just a scaffold. FEBS Lett 581:175–179

    CAS  PubMed  Google Scholar 

  159. Kuusisto E, Salminen A, Alafuzoff I (2001) Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. Neuroreport 12:2085–2090

    CAS  PubMed  Google Scholar 

  160. Zatloukal K, Stumptner C, Fuchsbichler A, Heid H, Schnoelzer M, Kenner L, Kleinert R, Prinz M, Aguzzi A, Denk H (2002) p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases. Am J Pathol 160:255–263

    CAS  PubMed  Google Scholar 

  161. Furukawa Y, Iseki E, Hino H, Kanai A, Odawara T, Kosaka K (2004) Ubiquitin and ubiquitin-related proteins in neurons and dendrites of brains of atypical Pick’s disease without Pick bodies. Neuropathology 24:38–45

    PubMed  Google Scholar 

  162. Nakano T, Nakaso K, Nakashima K, Ohama E (2004) Expression of ubiquitin-binding protein p62 in ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis with dementia: analysis of five autopsy cases with broad clinicopathological spectrum. Acta Neuropathol (Berl) 107:359–364

    CAS  Google Scholar 

  163. 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 28:228–237

    CAS  PubMed  Google Scholar 

  164. Nakaso K, Yoshimoto Y, Nakano T, Takeshima T, Fukuhara Y, Yasui K, Araga S, Yanagawa T, Ishii T, Nakashima K (2004) Transcriptional activation of p62/A170/ZIP during the formation of the aggregates: possible mechanisms and the role in Lewy body formation in Parkinson’s disease. Brain Res 1012:42–51

    CAS  PubMed  Google Scholar 

  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 91:57–68

    CAS  PubMed  Google Scholar 

  166. Nan L, Wu Y, Bardag-Gorce F, Li J, French BA, Fu AN, Francis T, Vu J, French SW (2004) p62 is involved in the mechanism of Mallory body formation. Exp Mol Pathol 77:168–175

    CAS  PubMed  Google Scholar 

  167. Du Y, Wooten MC, Wooten MW (2009) Oxidative damage to the promoter region of SQSTM1/p62 is common to neurodegenerative disease. Neurobiol Dis 35:302–310

    CAS  PubMed  Google Scholar 

  168. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Blade J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487–2498

    CAS  PubMed  Google Scholar 

  169. Ustrell V, Hoffman L, Pratt G, Rechsteiner M (2002) PA200, a nuclear proteasome activator involved in DNA repair. EMBO J 21:3516–3525

    CAS  PubMed  Google Scholar 

  170. Ortega J, Heymann JB, Kajava AV, Ustrell V, Rechsteiner M, Steven AC (2005) The axial channel of the 20S proteasome opens upon binding of the PA200 activator. J Mol Biol 346:1221–1227

    CAS  PubMed  Google Scholar 

  171. Blickwedehl J, Agarwal M, Seong C, Pandita RK, Melendy T, Sung P, Pandita TK, Bangia N (2008) Role for proteasome activator PA200 and postglutamyl proteasome activity in genomic stability. Proc Natl Acad Sci USA 105:16165–16170

    CAS  PubMed  Google Scholar 

  172. Mao I, Liu J, Li X, Luo H (2008) REGgamma, a proteasome activator and beyond? Cell Mol Life Sci 65:3971–3980

    CAS  PubMed  Google Scholar 

  173. Schwarz K, Eggers M, Soza A, Koszinowski UH, Kloetzel PM, Groettrup M (2000) The proteasome regulator PA28alpha/beta can enhance antigen presentation without affecting 20S proteasome subunit composition. Eur J Immunol 30:3672–3679

    CAS  PubMed  Google Scholar 

  174. Ferrington DA, Hussong SA, Roehrich H, Kapphahn RJ, Kavanaugh SM, Heuss ND, Gregerson DS (2008) Immunoproteasome responds to injury in the retina and brain. J Neurochem 106:158–169

    CAS  PubMed  Google Scholar 

  175. Mishto M, Bellavista E, Santoro A, Stolzing A, Ligorio C, Nacmias B, Spazzafumo L, Chiappelli M, Licastro F, Sorbi S, Pession A, Ohm T, Grune T, Franceschi C (2006) Immunoproteasome and LMP2 polymorphism in aged and Alzheimer’s disease brains. Neurobiol Aging 27:54–66

    CAS  PubMed  Google Scholar 

  176. Diaz-Hernandez M, Hernandez F, Martin-Aparicio E, Gomez-Ramos P, Moran MA, Castano JG, Ferrer I, Avila J, Lucas JJ (2003) Neuronal induction of the immunoproteasome in Huntington’s disease. J Neurosci 23:11653–11661

    CAS  PubMed  Google Scholar 

  177. Seo H, Sonntag KC, Kim W, Cattaneo E, Isacson O (2007) Proteasome activator enhances survival of Huntington’s disease neuronal model cells. PLoS One 2:e238

    PubMed  Google Scholar 

  178. Verma R, Peters NR, D’Onofrio M, Tochtrop GP, Sakamoto KM, Varadan R, Zhang M, Coffino P, Fushman D, Deshaies RJ, King RW (2004) Ubistatins inhibit proteasome-dependent degradation by binding the ubiquitin chain. Science 306:117–120

    CAS  PubMed  Google Scholar 

  179. Hol EM, Fischer DF, Ovaa H, Scheper W (2006) Ubiquitin proteasome system as a pharmacological target in neurodegeneration. Expert Rev Neurother 6:1337–1347

    CAS  PubMed  Google Scholar 

  180. Hanna J, Finley D (2007) A proteasome for all occasions. FEBS Lett 581:2854–2861

    CAS  PubMed  Google Scholar 

  181. Chondrogianni N, Tzavelas C, Pemberton AJ, Nezis IP, Rivett AJ, Gonos ES (2005) Overexpression of proteasome beta5 assembled subunit increases the amount of proteasome and confers ameliorated response to oxidative stress and higher survival rates. J Biol Chem 280:11840–11850

    CAS  PubMed  Google Scholar 

  182. Chondrogianni N, Gonos ES (2007) Overexpression of hUMP1/POMP proteasome accessory protein enhances proteasome-mediated antioxidant defence. Exp Gerontol 42:899–903

    CAS  PubMed  Google Scholar 

  183. Stanhill A, Haynes CM, Zhang Y, Min G, Steele MC, Kalinina J, Martinez E, Pickart CM, Kong XP, Ron D (2006) An arsenite-inducible 19S regulatory particle-associated protein adapts proteasomes to proteotoxicity. Mol Cell 23:875–885

    CAS  PubMed  Google Scholar 

  184. Dahlmann B, Rutschmann M, Kuehn L, Reinauer H (1985) Activation of the multicatalytic proteinase from rat skeletal muscle by fatty acids or sodium dodecyl sulphate. Biochem J 228:171–177

    CAS  PubMed  Google Scholar 

  185. Watanabe N, Yamada S (1996) Activation of 20S proteasomes from spinach leaves by fatty acids. Plant Cell Physiol 37:147–151

    CAS  PubMed  Google Scholar 

  186. Wilk S, Chen WE (1997) Synthetic peptide-based activators of the proteasome. Mol Biol Rep 24:119–124

    CAS  PubMed  Google Scholar 

  187. Kisselev AF, Kaganovich D, Goldberg AL (2002) Binding of hydrophobic peptides to several non-catalytic sites promotes peptide hydrolysis by all active sites of 20 S proteasomes. Evidence for peptide-induced channel opening in the alpha-rings. J Biol Chem 277:22260–22270

    CAS  PubMed  Google Scholar 

  188. Katsiki M, Chondrogianni N, Chinou I, Rivett AJ, Gonos ES (2007) The olive constituent oleuropein exhibits proteasome stimulatory properties in vitro and confers life span extension of human embryonic fibroblasts. Rejuvenation Res 10:157–172

    CAS  PubMed  Google Scholar 

  189. Kwak MK, Wakabayashi N, Greenlaw JL, Yamamoto M, Kensler TW (2003) Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol 23:8786–8794

    CAS  PubMed  Google Scholar 

  190. Kwak MK, Cho JM, Huang B, Shin S, Kensler TW (2007) Role of increased expression of the proteasome in the protective effects of sulforaphane against hydrogen peroxide-mediated cytotoxicity in murine neuroblastoma cells. Free Radic Biol Med 43:809–817

    CAS  PubMed  Google Scholar 

  191. Thimmulappa RK, Fuchs RJ, Malhotra D, Scollick C, Traore K, Bream JH, Trush MA, Liby KT, Sporn MB, Kensler TW, Biswal S (2007) Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal 9:1963–1970

    CAS  PubMed  Google Scholar 

  192. Huang L, Ho P, Chen CH (2007) Activation and inhibition of the proteasome by betulinic acid and its derivatives. FEBS Lett 581:4955–4959

    CAS  PubMed  Google Scholar 

  193. Orlowski RZ, Kuhn DJ (2008) Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res 14:1649–1657

    CAS  PubMed  Google Scholar 

  194. Chondrogianni N, Petropoulos I, Franceschi C, Friguet B, Gonos ES (2000) Fibroblast cultures from healthy centenarians have an active proteasome. Exp Gerontol 35:721–728

    CAS  PubMed  Google Scholar 

  195. Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ (2001) Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA 98:8554–8559

    CAS  PubMed  Google Scholar 

  196. Schneekloth AR, Pucheault M, Tae HS, Crews CM (2008) Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics. Bioorg Med Chem Lett 18:5904–5908

    CAS  PubMed  Google Scholar 

  197. Yasuda T, Miyachi S, Kitagawa R, Wada K, Nihira T, Ren YR, Hirai Y, Ageyama N, Terao K, Shimada T, Takada M, Mizuno Y, Mochizuki H (2007) Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates. Neuroscience 144:743–753

    CAS  PubMed  Google Scholar 

  198. 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 20:525–538

    CAS  PubMed  Google Scholar 

  199. 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 280:23727–23734

    CAS  PubMed  Google Scholar 

  200. Ko HS, Bailey R, Smith WW, Liu Z, Shin JH, Lee YI, Zhang YJ, Jiang H, Ross CA, Moore DJ, Patterson C, Petrucelli L, Dawson TM, Dawson VL (2009) CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. Proc Natl Acad Sci USA 106:2897–2902

    CAS  PubMed  Google Scholar 

  201. Sahara N, Murayama M, Mizoroki T, Urushitani M, Imai Y, Takahashi R, Murata S, Tanaka K, Takashima A (2005) In vivo evidence of CHIP up-regulation attenuating tau aggregation. J Neurochem 94:1254–1263

    CAS  PubMed  Google Scholar 

  202. Oddo S, Caccamo A, Tseng B, Cheng D, Vasilevko V, Cribbs DH, LaFerla FM (2008) Blocking Abeta42 accumulation delays the onset and progression of tau pathology via the C terminus of heat shock protein70-interacting protein: a mechanistic link between Abeta and tau pathology. J Neurosci 28:12163–12175

    CAS  PubMed  Google Scholar 

  203. Dickey CA, Yue M, Lin WL, Dickson DW, Dunmore JH, Lee WC, Zehr C, West G, Cao S, Clark AM, Caldwell GA, Caldwell KA, Eckman C, Patterson C, Hutton M, Petrucelli L (2006) Deletion of the ubiquitin ligase CHIP leads to the accumulation, but not the aggregation, of both endogenous phospho- and caspase-3-cleaved tau species. J Neurosci 26:6985–6996

    CAS  PubMed  Google Scholar 

  204. Jana NR, Dikshit P, Goswami A, Kotliarova S, Murata S, Tanaka K, Nukina N (2005) Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes. J Biol Chem 280:11635–11640

    CAS  PubMed  Google Scholar 

  205. Sha Y, Pandit L, Zeng S, Eissa NT (2009) A critical role for CHIP in the aggresome pathway. Mol Cell Biol 29:116–128

    CAS  PubMed  Google Scholar 

  206. Matunis MJ, Pickart CM (2005) Beginning at the end with SUMO. Nat Struct Mol Biol 12:565–566

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  210. Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426:895–899

    CAS  PubMed  Google Scholar 

  211. Gorman AM (2008) Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling. J Cell Mol Med 12:2263–2280

    CAS  PubMed  Google Scholar 

  212. Waldmeier P, Bozyczko-Coyne D, Williams M, Vaught JL (2006) Recent clinical failures in Parkinson’s disease with apoptosis inhibitors underline the need for a paradigm shift in drug discovery for neurodegenerative diseases. Biochem Pharmacol 72:1197–1206

    CAS  PubMed  Google Scholar 

  213. Schmidt-Glenewinkel T, Figueiredo-Pereira ME (2006) Inflammation as a mediator of oxidative stress and UPS dysfunction. In: Stefanis L, Keller JN (eds) The proteasome in neurodegeneration. Springer, New York, pp 105–131

    Google Scholar 

  214. Streit WJ, Miller KR, Lopes KO, Njie E (2008) Microglial degeneration in the aging brain–bad news for neurons? Front Biosci 13:3423–3438

    CAS  PubMed  Google Scholar 

  215. Brundin P, Li JY, Holton JL, Lindvall O, Revesz T (2008) Research in motion: the enigma of Parkinson’s disease pathology spread. Nat Rev Neurosci 9:741–745

    CAS  PubMed  Google Scholar 

  216. Ullrich O, Diestel A, Bechmann I, Homberg M, Grune T, Hass R, Nitsch R (2001) Turnover of oxidatively damaged nuclear proteins in BV-2 microglial cells is linked to their activation state by poly-ADP-ribose polymerase. FASEB J 15:1460–1462

    CAS  PubMed  Google Scholar 

  217. Lucin KM, Wyss-Coray T (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64:110–122

    CAS  PubMed  Google Scholar 

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Acknowledgments

Please note that this review is not intended to be comprehensive and we apologize to the authors whose work is not mentioned. Supported by National Institutes of Health (NIH) [AG028847 to M.F.-P. from National Institute of Aging; NS41073 (Specialized Neuroscience Research Programs) to M.F.-P. (head of subproject) from National Institute of Neurological Disorders and Stroke; RR03037 to Hunter College (infrastructure) from National Institute of General Medical Sciences (NIGMS)/RCMI (Research Centers in Minority Institutions)].

Conflict of interest statement

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biological Sciences, Hunter College of City University of New York, 695 Park Avenue, New York, NY, 10065, USA

    Qian Huang & Maria E. Figueiredo-Pereira

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  1. Qian Huang
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  2. Maria E. Figueiredo-Pereira
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Correspondence to Maria E. Figueiredo-Pereira.

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Huang, Q., Figueiredo-Pereira, M.E. Ubiquitin/proteasome pathway impairment in neurodegeneration: therapeutic implications. Apoptosis 15, 1292–1311 (2010). https://doi.org/10.1007/s10495-010-0466-z

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  • DOI: https://doi.org/10.1007/s10495-010-0466-z

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