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Molecular Neurobiology

, Volume 48, Issue 1, pp 141–156 | Cite as

Protein Quality Control System in Neurodegeneration: A Healing Company Hard to Beat but Failure is Fatal

  • Deepak Chhangani
  • Amit Mishra
Article

Abstract

A common feature in most neurodegenerative diseases and aging is the progressive accumulation of damaged proteins. Proteins are essential for all crucial biological functions. Under some notorious conditions, proteins loss their three dimensional native conformations and are converted into disordered aggregated structures. Such changes rise into pathological conditions and eventually cause serious protein conformation disorders. Protein aggregation and inclusion bodies formation mediated multifactorial proteotoxic stress has been reported in the progression of Parkinson’s disease (PD), Huntington’s disease (HD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Prion disease. Ongoing studies have been remarkably informative in providing a systematic outlook for better understanding the concept and fundamentals of protein misfolding and aggregations. However, the precise role of protein quality control system and precursors of this mechanism remains elusive. In this review, we highlight recent insights and discuss emerging cytoprotective strategies of cellular protein quality control system implicated in protein deposition diseases. Our current review provides a clear, understandable framework of protein quality control system that may offer the more suitable therapeutic strategies for protein-associated diseases.

Keywords

Protein quality control system Misfolded proteins Chaperones Ubiquitin proteasome system Autophagy Neurodegenerative diseases 

Notes

Acknowledgments

This work was supported by Department of Biotechnology, Government of India. A.M. was supported by a Ramalinganswami fellowship from the Department of Biotechnology, Government of India. The authors thank Mr. Bharat Pareek and Mr. Rahul Sathya Babu for their support and management during manuscript preparation.

Conflicts of interest

The authors declare no conflicts of interest.

References

  1. 1.
    Brandman O, Stewart-Ornstein J, Wong D, Larson A, Williams CC, Li GW, Zhou S, King D, Shen PS, Weibezahn J, Dunn JG, Rouskin S, Inada T, Frost A, Weissman JS (2012) A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress. Cell 151(5):1042–1054. doi: 10.1016/j.cell.2012.10.044 PubMedCrossRefGoogle Scholar
  2. 2.
    Beckmann R, Bubeck D, Grassucci R, Penczek P, Verschoor A, Blobel G, Frank J (1997) Alignment of conduits for the nascent polypeptide chain in the ribosome-Sec61 complex. Science 278(5346):2123–2126PubMedCrossRefGoogle Scholar
  3. 3.
    Chen B, Retzlaff M, Roos T, Frydman J (2011) Cellular strategies of protein quality control. Cold Spring Harb Perspect Biol 3(8):a004374. doi: 10.1101/cshperspect.a004374 PubMedCrossRefGoogle Scholar
  4. 4.
    Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333–366. doi: 10.1146/annurev.biochem.75.101304.123901 PubMedCrossRefGoogle Scholar
  5. 5.
    Gregersen N, Bross P (2010) Protein misfolding and cellular stress: an overview. Methods Mol Biol 648:3–23. doi: 10.1007/978-1-60761-756-3_1 PubMedCrossRefGoogle Scholar
  6. 6.
    Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10(Suppl):S10–S17. doi: 10.1038/nm1066 PubMedCrossRefGoogle Scholar
  7. 7.
    Dobson CM (2003) Protein folding and misfolding. Nature 426(6968):884–890. doi: 10.1038/nature02261 PubMedCrossRefGoogle Scholar
  8. 8.
    Selkoe DJ (2003) Folding proteins in fatal ways. Nature 426(6968):900–904. doi: 10.1038/nature02264 PubMedCrossRefGoogle Scholar
  9. 9.
    Fulda S, Gorman AM, Hori O, Samali A (2010) Cellular stress responses: cell survival and cell death. Int J Cell Biol 2010:214074. doi: 10.1155/2010/214074 PubMedGoogle Scholar
  10. 10.
    Forman MS, Trojanowski JQ, Lee VM (2004) Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med 10(10):1055–1063. doi: 10.1038/nm1113 PubMedCrossRefGoogle Scholar
  11. 11.
    Layfield R, Lowe J, Bedford L (2005) The ubiquitin–proteasome system and neurodegenerative disorders. Essays Biochem 41:157–171. doi: 10.1042/EB0410157 PubMedCrossRefGoogle Scholar
  12. 12.
    Dennissen FJ, Kholod N, van Leeuwen FW (2012) The ubiquitin proteasome system in neurodegenerative diseases: culprit, accomplice or victim? Prog Neurobiol 96(2):190–207. doi: 10.1016/j.pneurobio.2012.01.003 PubMedCrossRefGoogle Scholar
  13. 13.
    Glickman MH, Ciechanover A (2002) The ubiquitin–proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82(2):373–428. doi: 10.1152/physrev.00027.2001 PubMedGoogle Scholar
  14. 14.
    Voges D, Zwickl P, Baumeister W (1999) The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem 68:1015–1068. doi: 10.1146/annurev.biochem.68.1.1015 PubMedCrossRefGoogle Scholar
  15. 15.
    Chhangani D, Joshi AP, Mishra A (2012) E3 ubiquitin ligases in protein quality control mechanism. Mol Neurobiol 45(3):571–585. doi: 10.1007/s12035-012-8273-x PubMedCrossRefGoogle Scholar
  16. 16.
    Ardley HC, Robinson PA (2004) The role of ubiquitin–protein ligases in neurodegenerative disease. Neurodegener Dis 1(2–3):71–87. doi: 10.1159/000080048 PubMedCrossRefGoogle Scholar
  17. 17.
    Yonashiro R, Sugiura A, Miyachi M, Fukuda T, Matsushita N, Inatome R, Ogata Y, Suzuki T, Dohmae N, Yanagi S (2009) Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and attenuates mutant SOD1-induced reactive oxygen species generation. Mol Biol Cell 20(21):4524–4530. doi: 10.1091/mbc.E09-02-0112 PubMedCrossRefGoogle Scholar
  18. 18.
    Mishra A, Maheshwari M, Chhangani D, Fujimori-Tonou N, Endo F, Joshi AP, Jana NR, Yamanaka K (2013) E6-AP association promotes SOD1 aggresomes degradation and suppresses toxicity. Neurobiol Aging. doi: 10.1016/j.neurobiolaging.2012.08.016
  19. 19.
    Niwa J, Ishigaki S, Hishikawa N, Yamamoto M, Doyu M, Murata S, Tanaka K, Taniguchi N, Sobue G (2002) Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity. J Biol Chem 277(39):36793–36798. doi: 10.1074/jbc.M206559200 PubMedCrossRefGoogle Scholar
  20. 20.
    Urushitani M, Kurisu J, Tateno M, Hatakeyama S, Nakayama K, Kato S, Takahashi R (2004) CHIP promotes proteasomal degradation of familial ALS-linked mutant SOD1 by ubiquitinating Hsp/Hsc70. J Neurochem 90(1):231–244. doi: 10.1111/j.1471-4159.2004.02486.x PubMedCrossRefGoogle Scholar
  21. 21.
    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(22):4268–4281. doi: 10.1093/hmg/ddp380 PubMedCrossRefGoogle Scholar
  22. 22.
    Miyazaki K, Fujita T, Ozaki T, Kato C, Kurose Y, Sakamoto M, Kato S, Goto T, Itoyama Y, Aoki M, Nakagawara A (2004) NEDL1, a novel ubiquitin–protein isopeptide ligase for dishevelled-1, targets mutant superoxide dismutase-1. J Biol Chem 279(12):11327–11335. doi: 10.1074/jbc.M312389200 PubMedCrossRefGoogle Scholar
  23. 23.
    Ren Y, Zhao J, Feng J (2003) Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. J Neurosci Off J Soc Neurosci 23(8):3316–3324Google Scholar
  24. 24.
    Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama K, Takahashi R (2002) CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. Mol Cell 10(1):55–67. doi: 10.1016/s1097-2765(02)00583-x PubMedCrossRefGoogle Scholar
  25. 25.
    Kalia L, Kalia S, Chau H, Lozano A, Hyman B, McLean P (2011) Ubiquitinylation of α-synuclein by carboxyl terminus Hsp70-interacting protein (CHIP) is regulated by Bcl-2-associated athanogene 5 (BAG5). PLoS One 6(2): doi: 10.1371/journal.pone.0014695 CrossRefGoogle Scholar
  26. 26.
    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
  27. 27.
    Skinner P, Koshy B, Cummings C, Klement I, Helin K, Servadio A, Zoghbi H, Orr H (1997) Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389(6654):971–974. doi: 10.1038/40153 PubMedCrossRefGoogle Scholar
  28. 28.
    Ross C (1997) Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases? Neuron 19(6):1147–1150. doi: 10.1016/s0896-6273(00)80405-5 PubMedCrossRefGoogle Scholar
  29. 29.
    Mishra A, Dikshit P, Purkayastha S, Sharma J, Nukina N, Jana NR (2008) E6-AP promotes misfolded polyglutamine proteins for proteasomal degradation and suppresses polyglutamine protein aggregation and toxicity. J Biol Chem 283(12):7648–7656. doi: 10.1074/jbc.M706620200 PubMedCrossRefGoogle Scholar
  30. 30.
    Garyali P, Siwach P, Singh PK, Puri R, Mittal S, Sengupta S, Parihar R, Ganesh S (2009) The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin–proteasome system. Hum Mol Genet 18(4):688–700. doi: 10.1093/hmg/ddn398 PubMedCrossRefGoogle Scholar
  31. 31.
    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(12):11635–11640. doi: 10.1074/jbc.M412042200 PubMedCrossRefGoogle Scholar
  32. 32.
    Tsai YC, Fishman PS, Thakor NV, Oyler GA (2003) Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function. J Biol Chem 278(24):22044–22055. doi: 10.1074/jbc.M212235200 PubMedCrossRefGoogle Scholar
  33. 33.
    Chhangani D, Jana NR, Mishra A (2013) Misfolded proteins recognition strategies of E3 ubiquitin ligases and neurodegenerative diseases. Mol Neurobiol. doi: 10.1007/s12035-012-8351-0
  34. 34.
    Stefani M, Dobson C (2003) Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med (Berlin, Germany) 81(11):678–699. doi: 10.1007/s00109-003-0464-5 CrossRefGoogle Scholar
  35. 35.
    Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson C, Stefani M (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416(6880):507–511. doi: 10.1038/416507a PubMedCrossRefGoogle Scholar
  36. 36.
    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
  37. 37.
    Mizushima N, Levine B, Cuervo A, Klionsky D (2008) Autophagy fights disease through cellular self-digestion. Nature 451(7182):1069–1075. doi: 10.1038/nature06639 PubMedCrossRefGoogle Scholar
  38. 38.
    Menzies FM, Moreau K, Rubinsztein DC (2011) Protein misfolding disorders and macroautophagy. Curr Opin Cell Biol 23(2):190–197. doi: 10.1016/j.ceb.2010.10.010 PubMedCrossRefGoogle Scholar
  39. 39.
    Kon M, Cuervo AM (2010) Autophagy: an alternative degradation mechanism for misfolded proteins. John Wiley & Sons, Inc., Hoboken, pp 113–129Google Scholar
  40. 40.
    Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10(7):458–467. doi: 10.1038/nrm2708 PubMedCrossRefGoogle Scholar
  41. 41.
    Mijaljica D, Prescott M, Devenish R (2011) Microautophagy in mammalian cells: revisiting a 40-year-old conundrum. Autophagy 7(7):673–682PubMedCrossRefGoogle Scholar
  42. 42.
    Dice J (2007) Chaperone-mediated autophagy. Autophagy 3(4):295–299PubMedGoogle Scholar
  43. 43.
    Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147(4):728–741. doi: 10.1016/j.cell.2011.10.026 PubMedCrossRefGoogle Scholar
  44. 44.
    Nixon RA (2006) Autophagy in neurodegenerative disease: friend, foe or turncoat? Trends Neurosci 29(9):528–535. doi: 10.1016/j.tins.2006.07.003 PubMedCrossRefGoogle Scholar
  45. 45.
    Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107–132. doi: 10.1146/annurev-cellbio-092910-154005 PubMedCrossRefGoogle Scholar
  46. 46.
    Ragusa MJ, Stanley RE, Hurley JH (2012) Architecture of the atg17 complex as a scaffold for autophagosome biogenesis. Cell 151(7):1501–1512. doi: 10.1016/j.cell.2012.11.028 PubMedCrossRefGoogle Scholar
  47. 47.
    Kraft C, Peter M, Hofmann K (2010) Selective autophagy: ubiquitin-mediated recognition and beyond. Nat Cell Biol 12(9):836–841. doi: 10.1038/ncb0910-836 PubMedCrossRefGoogle Scholar
  48. 48.
    Kirkin V, McEwan D, Novak I, Dikic I (2009) A role for ubiquitin in selective autophagy. Mol Cell 34(3):259–269. doi: 10.1016/j.molcel.2009.04.026 PubMedCrossRefGoogle Scholar
  49. 49.
    Bjørkøy 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(4):603–614. doi: 10.2307/3658468 PubMedCrossRefGoogle Scholar
  50. 50.
    Kirkin V, Lamark T, Sou Y-S, Bjørkøy G, Nunn J, Bruun J-A, Shvets E, McEwan D, Clausen T, Wild P, Bilusic I, Theurillat J-P, Øvervatn A, Ishii T, Elazar Z, Komatsu M, Dikic I, Johansen T (2009) A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell 33(4):505–516. doi: 10.1016/j.molcel.2009.01.020 PubMedCrossRefGoogle Scholar
  51. 51.
    Pankiv S, Clausen T, Lamark T, Brech A, Bruun J-A, Outzen H, Øvervatn A, Bjørkøy G, Johansen T (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282(33):24131–24145. doi: 10.1074/jbc.M702824200 PubMedCrossRefGoogle Scholar
  52. 52.
    Chiang HL, Dice JF (1988) Peptide sequences that target proteins for enhanced degradation during serum withdrawal. J Biol Chem 263(14):6797–6805PubMedGoogle Scholar
  53. 53.
    Cuervo A, Dice J (1996) A receptor for the selective uptake and degradation of proteins by lysosomes. Science (New York, NY) 273(5274):501–503CrossRefGoogle Scholar
  54. 54.
    Schatz G, Dobberstein B (1996) Common principles of protein translocation across membranes. Science (New York, NY) 271(5255):1519–1526CrossRefGoogle Scholar
  55. 55.
    Chirico W, Waters M, Blobel G (1988) 70K heat shock related proteins stimulate protein translocation into microsomes. Nature 332(6167):805–810. doi: 10.1038/332805a0 PubMedCrossRefGoogle Scholar
  56. 56.
    Chiang H, Terlecky S, Plant C, Dice J (1989) A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science (New York, NY) 246(4928):382–385CrossRefGoogle Scholar
  57. 57.
    Nylandsted J, Gyrd-Hansen M, Danielewicz A, Fehrenbacher N, Lademann U, Høyer-Hansen M, Weber E, Multhoff G, Rohde M, Jäättelä M (2004) Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J Exp Med 200(4):425–435. doi: 10.1084/jem.20040531 PubMedCrossRefGoogle Scholar
  58. 58.
    Kirkegaard T, Roth A, Petersen N, Mahalka A, Olsen O, Moilanen I, Zylicz A, Knudsen J, Sandhoff K, Arenz C, Kinnunen P, Nylandsted J, Jäättelä M (2010) Hsp70 stabilizes lysosomes and reverts Niemann–Pick disease-associated lysosomal pathology. Nature 463(7280):549–553. doi: 10.1038/nature08710 PubMedCrossRefGoogle Scholar
  59. 59.
    Qi L, Zhang X-D, Wu J-C, Lin F, Wang J, Difiglia M, Qin Z-H (2012) The role of chaperone-mediated autophagy in huntingtin degradation. PLoS One 7(10): doi: 10.1371/journal.pone.0046834 Google Scholar
  60. 60.
    Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441(7095):885–889. doi: 10.1038/nature04724 PubMedCrossRefGoogle Scholar
  61. 61.
    Komatsu M, Waguri S, Chiba T, Murata S, Iwata J-i, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441(7095):880–884. doi: 10.1038/nature04723 PubMedCrossRefGoogle Scholar
  62. 62.
    Malkus K, Ischiropoulos H (2012) Regional deficiencies in chaperone-mediated autophagy underlie α-synuclein aggregation and neurodegeneration. Neurobiol Dis 46(3):732–744. doi: 10.1016/j.nbd.2012.03.017 PubMedCrossRefGoogle Scholar
  63. 63.
    d’Azzo A, Bongiovanni A, Nastasi T (2005) E3 ubiquitin ligases as regulators of membrane protein trafficking and degradation. Traffic 6(6):429–441. doi: 10.1111/j.1600-0854.2005.00294.x Google Scholar
  64. 64.
    Chakrabarti O, Hegde R (2009) Functional depletion of mahogunin by cytosolically exposed prion protein contributes to neurodegeneration. Cell 137(6):1136–1147. doi: 10.1016/j.cell.2009.03.042 PubMedCrossRefGoogle Scholar
  65. 65.
    Lévy F, Muehlethaler K, Salvi S, Peitrequin A-L, Lindholm C, Cerottini J-C, Rimoldi D (2005) Ubiquitylation of a melanosomal protein by HECT-E3 ligases serves as sorting signal for lysosomal degradation. Mol Biol Cell 16(4):1777–1787. doi: 10.1091/mbc.E04-09-0803 PubMedCrossRefGoogle Scholar
  66. 66.
    Squier TC (2001) Oxidative stress and protein aggregation during biological aging. Exp Gerontol 36(9):1539–1550PubMedCrossRefGoogle Scholar
  67. 67.
    Rao RV, Bredesen DE (2004) Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr Opin Cell Biol 16(6):653–662. doi: 10.1016/j.ceb.2004.09.012 PubMedCrossRefGoogle Scholar
  68. 68.
    Malhotra JD, Kaufman RJ (2007) Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 9(12):2277–2293. doi: 10.1089/ars.2007.1782 PubMedCrossRefGoogle Scholar
  69. 69.
    Sato B, Schulz D, Do P, Hampton R (2009) Misfolded membrane proteins are specifically recognized by the transmembrane domain of the Hrd1p ubiquitin ligase. Mol Cell 34(2):212–222. doi: 10.1016/j.molcel.2009.03.010 PubMedCrossRefGoogle Scholar
  70. 70.
    Mannini B, Cascella R, Zampagni M, van Waarde-Verhagen M, Meehan S, Roodveldt C, Campioni S, Boninsegna M, Penco A, Relini A, Kampinga HH, Dobson CM, Wilson MR, Cecchi C, Chiti F (2012) Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers. Proc Natl Acad Sci U S A 109(31):12479–12484. doi: 10.1073/pnas.1117799109 PubMedCrossRefGoogle Scholar
  71. 71.
    Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295(5561):1852–1858. doi: 10.1126/science.1068408 PubMedCrossRefGoogle Scholar
  72. 72.
    Morimoto RI (1998) Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 12(24):3788–3796PubMedCrossRefGoogle Scholar
  73. 73.
    Finka A, Mattoo RU, Goloubinoff P (2011) Meta-analysis of heat- and chemically upregulated chaperone genes in plant and human cells. Cell Stress Chaperones 16(1):15–31. doi: 10.1007/s12192-010-0216-8 PubMedCrossRefGoogle Scholar
  74. 74.
    Banerjee Mustafi S, Chakraborty PK, Dey RS, Raha S (2009) Heat stress upregulates chaperone heat shock protein 70 and antioxidant manganese superoxide dismutase through reactive oxygen species (ROS), p38MAPK, and Akt. Cell Stress Chaperones 14(6):579–589. doi: 10.1007/s12192-009-0109-x PubMedCrossRefGoogle Scholar
  75. 75.
    Bruening W, Roy J, Giasson B, Figlewicz DA, Mushynski WE, Durham HD (1999) Up-regulation of protein chaperones preserves viability of cells expressing toxic Cu/Zn-superoxide dismutase mutants associated with amyotrophic lateral sclerosis. J Neurochem 72(2):693–699PubMedCrossRefGoogle Scholar
  76. 76.
    Morimoto RI (2008) Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev 22(11):1427–1438. doi: 10.1101/gad.1657108 PubMedCrossRefGoogle Scholar
  77. 77.
    Goldbaum O, Oppermann M, Handschuh M, Dabir D, Zhang B, Forman MS, Trojanowski JQ, Lee VM, Richter-Landsberg C (2003) Proteasome inhibition stabilizes tau inclusions in oligodendroglial cells that occur after treatment with okadaic acid. J Neurosci 23(26):8872–8880PubMedGoogle Scholar
  78. 78.
    Ito H, Kamei K, Iwamoto I, Inaguma Y, Garcia-Mata R, Sztul E, Kato K (2002) Inhibition of proteasomes induces accumulation, phosphorylation, and recruitment of HSP27 and alphaB-crystallin to aggresomes. J Biochem 131(4):593–603PubMedCrossRefGoogle Scholar
  79. 79.
    Voellmy R, Boellmann F (2007) Chaperone regulation of the heat shock protein response. Adv Exp Med Biol 594:89–99. doi: 10.1007/978-0-387-39975-1_9 PubMedCrossRefGoogle Scholar
  80. 80.
    Henderson B (2010) Integrating the cell stress response: a new view of molecular chaperones as immunological and physiological homeostatic regulators. Cell Biochem Funct 28(1):1–14. doi: 10.1002/cbf.1609 PubMedCrossRefGoogle Scholar
  81. 81.
    Papp E, Nardai G, Soti C, Csermely P (2003) Molecular chaperones, stress proteins and redox homeostasis. Biofactors 17(1–4):249–257PubMedCrossRefGoogle Scholar
  82. 82.
    Qian SB, McDonough H, Boellmann F, Cyr DM, Patterson C (2006) CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70. Nature 440(7083):551–555. doi: 10.1038/nature04600 PubMedCrossRefGoogle Scholar
  83. 83.
    Tsuiji H, Iguchi Y, Furuya A, Kataoka A, Hatsuta H, Atsuta N, Tanaka F, Hashizume Y, Akatsu H, Murayama S, Sobue G, Yamanaka K (2012) Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Mol Med. doi: 10.1002/emmm.201202303
  84. 84.
    Fernandes R, Ramalho J, Pereira P (2006) Oxidative stress upregulates ubiquitin proteasome pathway in retinal endothelial cells. Mol Vis 12:1526–1535PubMedGoogle Scholar
  85. 85.
    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(46):35661–35664. doi: 10.1074/jbc.C000447200 PubMedCrossRefGoogle Scholar
  86. 86.
    Braten O, Shabek N, Kravtsova-Ivantsiv Y, Ciechanover A (2012) Generation of free ubiquitin chains is up-regulated in stress and facilitated by the HECT domain ubiquitin ligases UFD4 and HUL5. Biochem J 444(3):611–617. doi: 10.1042/BJ20111840 PubMedCrossRefGoogle Scholar
  87. 87.
    Ding WX, Ni HM, Gao W, Yoshimori T, Stolz DB, Ron D, Yin XM (2007) Linking of autophagy to ubiquitin–proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 171(2):513–524. doi: 10.2353/ajpath.2007.070188 PubMedCrossRefGoogle Scholar
  88. 88.
    Bennett EJ, Bence NF, Jayakumar R, Kopito RR (2005) Global impairment of the ubiquitin–proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Mol Cell 17(3):351–365. doi: 10.1016/j.molcel.2004.12.021 PubMedCrossRefGoogle Scholar
  89. 89.
    Cecarini V, Bonfili L, Cuccioloni M, Mozzicafreddo M, Rossi G, Buizza L, Uberti D, Angeletti M, Eleuteri AM (2012) Crosstalk between the ubiquitin–proteasome system and autophagy in a human cellular model of Alzheimer's disease. Biochim Biophys Acta 1822(11):1741–1751. doi: 10.1016/j.bbadis.2012.07.015 PubMedCrossRefGoogle Scholar
  90. 90.
    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 PubMedCrossRefGoogle Scholar
  91. 91.
    Gamerdinger M, Kaya AM, Wolfrum U, Clement AM, Behl C (2011) BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins. EMBO Rep 12(2):149–156. doi: 10.1038/embor.2010.203 PubMedCrossRefGoogle Scholar
  92. 92.
    Behl C (2011) BAG3 and friends: co-chaperones in selective autophagy during aging and disease. Autophagy 7(7):795–798. doi: 10.4161/auto.7.7.15844 PubMedCrossRefGoogle Scholar
  93. 93.
    Metcalf DJ, Garcia-Arencibia M, Hochfeld WE, Rubinsztein DC (2010) Autophagy and misfolded proteins in neurodegeneration. Exp Neurol 238(1):22–28. doi: 10.1016/j.expneurol.2010.11.003 PubMedCrossRefGoogle Scholar
  94. 94.
    Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26(24):9220–9231. doi: 10.1128/MCB.01453-06 PubMedCrossRefGoogle Scholar
  95. 95.
    Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB (2008) Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ 15(1):171–182. doi: 10.1038/sj.cdd.4402233 PubMedCrossRefGoogle Scholar
  96. 96.
    Ge PF, Zhang JZ, Wang XF, Meng FK, Li WC, Luan YX, Ling F, Luo YN (2009) Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells. Acta Pharmacol Sin 30(7):1046–1052. doi: 10.1038/aps.2009.71 PubMedCrossRefGoogle Scholar
  97. 97.
    Liu TT, Hu CH, Tsai CD, Li CW, Lin YF, Wang JY (2010) Heat stroke induces autophagy as a protection mechanism against neurodegeneration in the brain. Shock 34(6):643–648. doi: 10.1097/SHK.0b013e3181e761c1 PubMedCrossRefGoogle Scholar
  98. 98.
    Yorimitsu T, Nair U, Yang Z, Klionsky DJ (2006) Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281(40):30299–30304. doi: 10.1074/jbc.M607007200 PubMedCrossRefGoogle Scholar
  99. 99.
    Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281(5381):1322–1326PubMedCrossRefGoogle Scholar
  100. 100.
    Tibbles LA, Woodgett JR (1999) The stress-activated protein kinase pathways. Cell Mol Life Sci 55(10):1230–1254PubMedCrossRefGoogle Scholar
  101. 101.
    Konishi H, Matsuzaki H, Tanaka M, Takemura Y, Kuroda S, Ono Y, Kikkawa U (1997) Activation of protein kinase B (Akt/RAC-protein kinase) by cellular stress and its association with heat shock protein Hsp27. FEBS Lett 410(2–3):493–498PubMedCrossRefGoogle Scholar
  102. 102.
    Nishiyama Y, Shimada Y, Yokoi T, Kobayashi H, Higuchi T, Eto Y, Ida H, Ohashi T (2012) Akt inactivation induces endoplasmic reticulum stress-independent autophagy in fibroblasts from patients with Pompe disease. Mol Genet Metab 107(3):490–495PubMedCrossRefGoogle Scholar
  103. 103.
    Goswami A, Dikshit P, Mishra A, Nukina N, Jana NR (2006) Expression of expanded polyglutamine proteins suppresses the activation of transcription factor NFkappaB. J Biol Chem 281(48):37017–37024. doi: 10.1074/jbc.M608095200 PubMedCrossRefGoogle Scholar
  104. 104.
    Shono T, Ono M, Izumi H, Jimi SI, Matsushima K, Okamoto T, Kohno K, Kuwano M (1996) Involvement of the transcription factor NF-kappaB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress. Mol Cell Biol 16(8):4231–4239PubMedGoogle Scholar
  105. 105.
    Nivon M, Abou-Samra M, Richet E, Guyot B, Arrigo AP, Kretz-Remy C (2012) NF-kappaB regulates protein quality control after heat stress through modulation of the BAG3-HspB8 complex. J Cell Sci 125(Pt 5):1141–1151. doi: 10.1242/jcs.091041 PubMedCrossRefGoogle Scholar
  106. 106.
    Kretz-Remy C, Munsch B, Arrigo AP (2001) NFkappa B-dependent transcriptional activation during heat shock recovery. Thermolability of the NF-kappaB.Ikappa B complex. J Biol Chem 276(47):43723–43733. doi: 10.1074/jbc.M010821200 PubMedCrossRefGoogle Scholar
  107. 107.
    Pahl HL, Baeuerle PA (1996) Activation of NF-kappa B by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers. FEBS Lett 392(2):129–136PubMedCrossRefGoogle Scholar
  108. 108.
    Mercurio F, Manning AM (1999) NF-kappaB as a primary regulator of the stress response. Oncogene 18(45):6163–6171. doi: 10.1038/sj.onc.1203174 PubMedCrossRefGoogle Scholar
  109. 109.
    Meusser B, Hirsch C, Jarosch E, Sommer T (2005) ERAD: the long road to destruction. Nat Cell Biol 7(8):766–772. doi: 10.1038/ncb0805-766 PubMedCrossRefGoogle Scholar
  110. 110.
    Lindholm D, Wootz H, Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13(3):385–392. doi: 10.1038/sj.cdd.4401778 PubMedCrossRefGoogle Scholar
  111. 111.
    Sekine Y, Takeda K, Ichijo H (2006) The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases. Curr Mol Med 6(1):87–97PubMedCrossRefGoogle Scholar
  112. 112.
    Watanabe S, Kaneko K, Yamanaka K (2012) Accelerated disease onset with stabilized familial Amyotrophic Lateral Sclerosis (ALS)-linked TDP-43 mutations. J Biol Chem. doi: 10.1074/jbc.M112.433615
  113. 113.
    Nishitoh H, Kadowaki H, Nagai A, Maruyama T, Yokota T, Fukutomi H, Noguchi T, Matsuzawa A, Takeda K, Ichijo H (2008) ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev 22(11):1451–1464. doi: 10.1101/gad.1640108 PubMedCrossRefGoogle Scholar
  114. 114.
    Atkin JD, Farg MA, Turner BJ, Tomas D, Lysaght JA, Nunan J, Rembach A, Nagley P, Beart PM, Cheema SS, Horne MK (2006) Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J Biol Chem 281(40):30152–30165. doi: 10.1074/jbc.M603393200 PubMedCrossRefGoogle Scholar
  115. 115.
    Kikuchi H, Almer G, Yamashita S, Guegan C, Nagai M, Xu Z, Sosunov AA, McKhann GM 2nd, Przedborski S (2006) Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc Natl Acad Sci U S A 103(15):6025–6030. doi: 10.1073/pnas.0509227103 PubMedCrossRefGoogle Scholar
  116. 116.
    Patel J, McLeod LE, Vries RG, Flynn A, Wang X, Proud CG (2002) Cellular stresses profoundly inhibit protein synthesis and modulate the states of phosphorylation of multiple translation factors. Eur J Biochem 269(12):3076–3085PubMedCrossRefGoogle Scholar
  117. 117.
    Stefani M, Dobson CM (2003) Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med (Berl) 81(11):678–699. doi: 10.1007/s00109-003-0464-5 CrossRefGoogle Scholar
  118. 118.
    Spriggs KA, Bushell M, Willis AE (2010) Translational regulation of gene expression during conditions of cell stress. Mol Cell 40(2):228–237. doi: 10.1016/j.molcel.2010.09.028 PubMedCrossRefGoogle Scholar
  119. 119.
    Fox S (2012) Lost in translation: misfolded proteins may cause neurodegeneration by inhibiting normal protein production. Mov Disord 27(10):1218PubMedCrossRefGoogle Scholar
  120. 120.
    Bahmanyar S, Higgins GA, Goldgaber D, Lewis DA, Morrison JH, Wilson MC, Shankar SK, Gajdusek DC (1987) Localization of amyloid beta protein messenger RNA in brains from patients with Alzheimer's disease. Science 237(4810):77–80PubMedCrossRefGoogle Scholar
  121. 121.
    Scheper GC, van der Knaap MS, Proud CG (2007) Translation matters: protein synthesis defects in inherited disease. Nat Rev Genet 8(9):711–723. doi: 10.1038/nrg2142 PubMedCrossRefGoogle Scholar
  122. 122.
    Mishra A, Jana NR (2008) Regulation of turnover of tumor suppressor p53 and cell growth by E6-AP, a ubiquitin protein ligase mutated in Angelman mental retardation syndrome. Cell Mol Life Sci 65(4):656–666. doi: 10.1007/s00018-007-7476-1 PubMedCrossRefGoogle Scholar
  123. 123.
    Mishra A, Godavarthi SK, Jana NR (2009) UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27. Neurobiol Dis 36(1):26–34. doi: 10.1016/j.nbd.2009.06.010 PubMedCrossRefGoogle Scholar
  124. 124.
    Novoa I, Zhang Y, Zeng H, Jungreis R, Harding HP, Ron D (2003) Stress-induced gene expression requires programmed recovery from translational repression. EMBO J 22(5):1180–1187. doi: 10.1093/emboj/cdg112 PubMedCrossRefGoogle Scholar
  125. 125.
    Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6(5):1099–1108PubMedCrossRefGoogle Scholar
  126. 126.
    Morimoto RI (1993) Cells in stress: transcriptional activation of heat shock genes. Science 259(5100):1409–1410PubMedCrossRefGoogle Scholar
  127. 127.
    Lesley SA, Graziano J, Cho CY, Knuth MW, Klock HE (2002) Gene expression response to misfolded protein as a screen for soluble recombinant protein. Protein Eng 15(2):153–160PubMedCrossRefGoogle Scholar
  128. 128.
    Kubota H (2009) Quality control against misfolded proteins in the cytosol: a network for cell survival. J Biochem 146(5):609–616. doi: 10.1093/jb/mvp139 PubMedCrossRefGoogle Scholar
  129. 129.
    Bukau B, Weissman J, Horwich A (2006) Molecular chaperones and protein quality control. Cell 125(3):443–451. doi: 10.1016/j.cell.2006.04.014 PubMedCrossRefGoogle Scholar
  130. 130.
    Schlecht R, Erbse AH, Bukau B, Mayer MP (2011) Mechanics of Hsp70 chaperones enables differential interaction with client proteins. Nat Struct Mol Biol 18(3):345–351. doi: 10.1038/nsmb.2006 PubMedCrossRefGoogle Scholar
  131. 131.
    Albanese V, Frydman J (2002) Where chaperones and nascent polypeptides meet. Nat Struct Biol 9(10):716–718. doi: 10.1038/nsb1002-716 PubMedCrossRefGoogle Scholar
  132. 132.
    Frydman J, Nimmesgern E, Ohtsuka K, Hartl FU (1994) Folding of nascent polypeptide chains in a high molecular mass assembly with molecular chaperones. Nature 370(6485):111–117. doi: 10.1038/370111a0 PubMedCrossRefGoogle Scholar
  133. 133.
    Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL, Bonini NM (1999) Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 23(4):425–428. doi: 10.1038/70532 PubMedCrossRefGoogle Scholar
  134. 134.
    Muchowski PJ (2002) Protein misfolding, amyloid formation, and neurodegeneration: a critical role for molecular chaperones? Neuron 35(1):9–12PubMedCrossRefGoogle Scholar
  135. 135.
    Forman MS, Lee VM, Trojanowski JQ (2003) 'Unfolding' pathways in neurodegenerative disease. Trends Neurosci 26(8):407–410. doi: 10.1016/S0166-2236(03)00197-8 PubMedCrossRefGoogle Scholar
  136. 136.
    Frydman J (2001) Folding of newly translated proteins in vivo: the role of molecular chaperones. Annu Rev Biochem 70:603–647. doi: 10.1146/annurev.biochem.70.1.603 PubMedCrossRefGoogle Scholar
  137. 137.
    Koplin A, Preissler S, Ilina Y, Koch M, Scior A, Erhardt M, Deuerling E (2010) A dual function for chaperones SSB-RAC and the NAC nascent polypeptide-associated complex on ribosomes. J Cell Biol 189(1):57–68. doi: 10.1083/jcb.200910074 PubMedCrossRefGoogle Scholar
  138. 138.
    Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, Padmanabhan R, Hild M, Berry DL, Garza D, Hubbert CC, Yao TP, Baehrecke EH, Taylor JP (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
  139. 139.
    Nedelsky NB, Todd PK, Taylor JP (2008) Autophagy and the ubiquitin–proteasome system: collaborators in neuroprotection. Biochim Biophys Acta 1782(12):691–699. doi: 10.1016/j.bbadis.2008.10.002 PubMedCrossRefGoogle Scholar
  140. 140.
    Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426(6968):895–899. doi: 10.1038/nature02263 PubMedCrossRefGoogle Scholar
  141. 141.
    Kaganovich D, Kopito R, Frydman J (2008) Misfolded proteins partition between two distinct quality control compartments. Nature 454(7208):1088–1095. doi: 10.1038/nature07195 PubMedCrossRefGoogle Scholar
  142. 142.
    Bagola K, Sommer T (2008) Protein quality control: on IPODs and other JUNQ. Curr Biol 18(21):R1019–R1021. doi: 10.1016/j.cub.2008.09.036 PubMedCrossRefGoogle Scholar
  143. 143.
    Seckler R, Jaenicke R (1992) Protein folding and protein refolding. FASEB J 6(8):2545–2552PubMedGoogle Scholar
  144. 144.
    Wong E, Cuervo AM (2010) Integration of clearance mechanisms: the proteasome and autophagy. Cold Spring Harb Perspect Biol 2(12):a006734. doi: 10.1101/cshperspect.a006734 PubMedCrossRefGoogle Scholar
  145. 145.
    Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, Stefani M (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416(6880):507–511. doi: 10.1038/416507a PubMedCrossRefGoogle Scholar
  146. 146.
    Perisic O, Xiao H, Lis JT (1989) Stable binding of Drosophila heat shock factor to head-to-head and tail-to-tail repeats of a conserved 5 bp recognition unit. Cell 59(5):797–806PubMedCrossRefGoogle Scholar
  147. 147.
    Clos J, Rabindran S, Wisniewski J, Wu C (1993) Induction temperature of human heat shock factor is reprogrammed in a Drosophila cell environment. Nature 364(6434):252–255. doi: 10.1038/364252a0 PubMedCrossRefGoogle Scholar
  148. 148.
    Dai Q, Zhang C, Wu Y, McDonough H, Whaley RA, Godfrey V, Li HH, Madamanchi N, Xu W, Neckers L, Cyr D, Patterson C (2003) CHIP activates HSF1 and confers protection against apoptosis and cellular stress. EMBO J 22(20):5446–5458. doi: 10.1093/emboj/cdg529 PubMedCrossRefGoogle Scholar
  149. 149.
    Boellmann F, Guettouche T, Guo Y, Fenna M, Mnayer L, Voellmy R (2004) DAXX interacts with heat shock factor 1 during stress activation and enhances its transcriptional activity. Proc Natl Acad Sci U S A 101(12):4100–4105. doi: 10.1073/pnas.0304768101 PubMedCrossRefGoogle Scholar
  150. 150.
    Biro K, Palhalmi J, Toth AJ, Kukorelli T, Juhasz G (1998) Bimoclomol improves early electrophysiological signs of retinopathy in diabetic rats. Neuroreport 9(9):2029–2033PubMedCrossRefGoogle Scholar
  151. 151.
    Polakowski JS, Wegner CD, Cox BF (2002) Bimoclomol elevates heat shock protein 70 and cytoprotects rat neonatal cardiomyocytes. Eur J Pharmacol 435(1):73–77PubMedCrossRefGoogle Scholar
  152. 152.
    Lubbers NL, Polakowski JS, Wegner CD, Burke SE, Diaz GJ, Daniell KM, Cox BF (2002) Oral bimoclomol elevates heat shock protein 70 and reduces myocardial infarct size in rats. Eur J Pharmacol 435(1):79–83PubMedCrossRefGoogle Scholar
  153. 153.
    Erdo F, Erdo SL (1998) Bimoclomol protects against vascular consequences of experimental subarachnoid hemorrhage in rats. Brain Res Bull 45(2):163–166PubMedCrossRefGoogle Scholar
  154. 154.
    Vigh L, Literati PN, Horvath I, Torok Z, Balogh G, Glatz A, Kovacs E, Boros I, Ferdinandy P, Farkas B, Jaszlits L, Jednakovits A, Koranyi L, Maresca B (1997) Bimoclomol: a nontoxic, hydroxylamine derivative with stress protein-inducing activity and cytoprotective effects. Nat Med 3(10):1150–1154PubMedCrossRefGoogle Scholar
  155. 155.
    Hargitai J, Lewis H, Boros I, Racz T, Fiser A, Kurucz I, Benjamin I, Vigh L, Penzes Z, Csermely P, Latchman DS (2003) Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1. Biochem Biophys Res Commun 307(3):689–695PubMedCrossRefGoogle Scholar
  156. 156.
    Liu AY, Mathur R, Mei N, Langhammer CG, Babiarz B, Firestein BL (2011) Neuroprotective drug riluzole amplifies the heat shock factor 1 (HSF1)- and glutamate transporter 1 (GLT1)-dependent cytoprotective mechanisms for neuronal survival. J Biol Chem 286(4):2785–2794. doi: 10.1074/jbc.M110.158220 PubMedCrossRefGoogle Scholar
  157. 157.
    Miller RG, Mitchell JD, Moore DH (2007) Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 3:CD001447. doi: 10.1002/14651858.CD001447.pub3 Google Scholar
  158. 158.
    Yang J, Bridges K, Chen KY, Liu AY (2008) Riluzole increases the amount of latent HSF1 for an amplified heat shock response and cytoprotection. PLoS One 3(8):e2864. doi: 10.1371/journal.pone.0002864 PubMedCrossRefGoogle Scholar
  159. 159.
    Lillie SH, Pringle JR (1980) Reserve carbohydrate metabolism in Saccharomyces cerevisiae: responses to nutrient limitation. J Bacteriol 143(3):1384–1394PubMedGoogle Scholar
  160. 160.
    Singer MA, Lindquist S (1998) Multiple effects of trehalose on protein folding in vitro and in vivo. Mol Cell 1(5):639–648PubMedCrossRefGoogle Scholar
  161. 161.
    Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa M, Nekooki M, Nukina N (2004) Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10(2):148–154. doi: 10.1038/nm985 PubMedCrossRefGoogle Scholar
  162. 162.
    Uversky VN, Li J, Fink AL (2001) Trimethylamine-N-oxide-induced folding of alpha-synuclein. FEBS Lett 509(1):31–35PubMedCrossRefGoogle Scholar
  163. 163.
    Wei H, Kim SJ, Zhang Z, Tsai PC, Wisniewski KE, Mukherjee AB (2008) ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones. Hum Mol Genet 17(4):469–477. doi: 10.1093/hmg/ddm324 PubMedCrossRefGoogle Scholar
  164. 164.
    Sato S, Ward CL, Krouse ME, Wine JJ, Kopito RR (1996) Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. J Biol Chem 271(2):635–638PubMedCrossRefGoogle Scholar
  165. 165.
    Mishra R, Bhat R, Seckler R (2007) Chemical chaperone-mediated protein folding: stabilization of P22 tailspike folding intermediates by glycerol. Biol Chem 388(8):797–804. doi: 10.1515/BC.2007.096 PubMedCrossRefGoogle Scholar
  166. 166.
    Yoshida H, Yoshizawa T, Shibasaki F, Shoji S, Kanazawa I (2002) Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado–Joseph disease gene product with an expanded polyglutamine stretch. Neurobiol Dis 10(2):88–99PubMedCrossRefGoogle Scholar
  167. 167.
    Wong E, Cuervo AM (2010) Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 13(7):805–811. doi: 10.1038/nn.2575 PubMedCrossRefGoogle Scholar
  168. 168.
    Bedford L, Hay D, Devoy A, Paine S, Powe DG, Seth R, Gray T, Topham I, Fone K, Rezvani N, Mee M, Soane T, Layfield R, Sheppard PW, Ebendal T, Usoskin D, Lowe J, Mayer RJ (2008) Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci 28(33):8189–8198. doi: 10.1523/JNEUROSCI.2218-08.2008 PubMedCrossRefGoogle Scholar
  169. 169.
    Egeler EL, Urner LM, Rakhit R, Liu CW, Wandless TJ (2011) Ligand-switchable substrates for a ubiquitin–proteasome system. J Biol Chem 286(36):31328–31336. doi: 10.1074/jbc.M111.264101 PubMedCrossRefGoogle Scholar
  170. 170.
    Banaszynski LA, Chen LC, Maynard-Smith LA, Ooi AG, Wandless TJ (2006) A rapid, reversible, and tunable method to regulate protein function in living cells using synthetic small molecules. Cell 126(5):995–1004. doi: 10.1016/j.cell.2006.07.025 PubMedCrossRefGoogle Scholar
  171. 171.
    Ochocka AM, Kampanis P, Nicol S, Allende-Vega N, Cox M, Marcar L, Milne D, Fuller-Pace F, Meek D (2009) FKBP25, a novel regulator of the p53 pathway, induces the degradation of MDM2 and activation of p53. FEBS Lett 583(4):621–626. doi: 10.1016/j.febslet.2009.01.009 PubMedCrossRefGoogle Scholar
  172. 172.
    Gestwicki JE, Crabtree GR, Graef IA (2004) Harnessing chaperones to generate small-molecule inhibitors of amyloid beta aggregation. Science 306(5697):865–869. doi: 10.1126/science.1101262 PubMedCrossRefGoogle Scholar
  173. 173.
    Zhou P, Bogacki R, McReynolds L, Howley PM (2000) Harnessing the ubiquitination machinery to target the degradation of specific cellular proteins. Mol Cell 6(3):751–756PubMedCrossRefGoogle Scholar
  174. 174.
    Zhang D, Baek SH, Ho A, Lee H, Jeong YS, Kim K (2004) Targeted degradation of proteins by small molecules: a novel tool for functional proteomics. Comb Chem High Throughput Screen 7(7):689–697PubMedCrossRefGoogle Scholar
  175. 175.
    Sakamoto KM (2005) Chimeric molecules to target proteins for ubiquitination and degradation. Methods Enzymol 399:833–847. doi: 10.1016/S0076-6879(05)99054-X PubMedCrossRefGoogle Scholar
  176. 176.
    Tang YQ, Han BM, Yao XQ, Hong Y, Wang Y, Zhao FJ, Yu SQ, Sun XW, Xia SJ (2009) Chimeric molecules facilitate the degradation of androgen receptors and repress the growth of LNCaP cells. Asian J Androl 11(1):119–126. doi: 10.1038/aja.2008.26 PubMedCrossRefGoogle Scholar
  177. 177.
    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 U S A 98(15):8554–8559. doi: 10.1073/pnas.141230798 PubMedCrossRefGoogle Scholar
  178. 178.
    Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B, Wyss-Coray T (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 118(6):2190–2199. doi: 10.1172/JCI33585 PubMedGoogle Scholar
  179. 179.
    Mizushima N, Ohsumi Y, Yoshimori T (2002) Autophagosome formation in mammalian cells. Cell Struct Funct 27(6):421–429PubMedCrossRefGoogle Scholar
  180. 180.
    Harris CD, Ermak G, Davies KJ (2007) RCAN1-1L is overexpressed in neurons of Alzheimer's disease patients. FEBS J 274(7):1715–1724. doi: 10.1111/j.1742-4658.2007.05717.x PubMedCrossRefGoogle Scholar
  181. 181.
    Liu H, Wang P, Song W, Sun X (2009) Degradation of regulator of calcineurin 1 (RCAN1) is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways. FASEB J 23(10):3383–3392. doi: 10.1096/fj.09-134296 PubMedCrossRefGoogle Scholar
  182. 182.
    Nalepa G, Rolfe M, Harper JW (2006) Drug discovery in the ubiquitin–proteasome system. Nat Rev Drug Discov 5(7):596–613. doi: 10.1038/nrd2056 PubMedCrossRefGoogle Scholar
  183. 183.
    Ringseis R, Keller J, Lukas I, Spielmann J, Most E, Couturier A, Konig B, Hirche F, Stangl GI, Wen G, Eder K (2013) Treatment with pharmacological PPARalpha agonists stimulates the ubiquitin proteasome pathway and myofibrillar protein breakdown in skeletal muscle of rodents. Biochim Biophys Acta 1830(1):2105–2117. doi: 10.1016/j.bbagen.2012.09.024 PubMedCrossRefGoogle Scholar
  184. 184.
    Liu J, Zheng H, Tang M, Ryu YC, Wang X (2008) A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome. Am J Physiol Heart Circ Physiol 295(6):H2541–H2550. doi: 10.1152/ajpheart.01052.2008 PubMedCrossRefGoogle Scholar
  185. 185.
    Jin S, White E (2008) Tumor suppression by autophagy through the management of metabolic stress. Autophagy 4(5):563–566PubMedGoogle Scholar
  186. 186.
    Beljanski V, Knaak C, Smith CD (2010) A novel sphingosine kinase inhibitor induces autophagy in tumor cells. J Pharmacol Exp Ther 333(2):454–464. doi: 10.1124/jpet.109.163337 PubMedCrossRefGoogle Scholar
  187. 187.
    Menzies FM, Huebener J, Renna M, Bonin M, Riess O, Rubinsztein DC (2010) Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133(Pt 1):93–104. doi: 10.1093/brain/awp292 PubMedCrossRefGoogle Scholar
  188. 188.
    McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, Skipper L, Murphy MP, Beard J, Das P, Jansen K, Delucia M, Lin WL, Dolios G, Wang R, Eckman CB, Dickson DW, Hutton M, Hardy J, Golde T (2005) Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47(2):191–199. doi: 10.1016/j.neuron.2005.06.030 PubMedCrossRefGoogle Scholar
  189. 189.
    Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS One 5(4):e9979. doi: 10.1371/journal.pone.0009979 PubMedCrossRefGoogle Scholar
  190. 190.
    Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460(7253):392–395. doi: 10.1038/nature08221 PubMedGoogle Scholar
  191. 191.
    Kettern N, Dreiseidler M, Tawo R, Hohfeld J (2010) Chaperone-assisted degradation: multiple paths to destruction. Biol Chem 391(5):481–489. doi: 10.1515/BC.2010.058 PubMedCrossRefGoogle Scholar
  192. 192.
    Mishra A, Godavarthi SK, Maheshwari M, Goswami A, Jana NR (2009) The ubiquitin ligase E6-AP is induced and recruited to aggresomes in response to proteasome inhibition and may be involved in the ubiquitination of Hsp70-bound misfolded proteins. J Biol Chem 284(16):10537–10545. doi: 10.1074/jbc.M806804200 PubMedCrossRefGoogle Scholar
  193. 193.
    Murata S, Minami Y, Minami M, Chiba T, Tanaka K (2001) CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep 2(12):1133–1138. doi: 10.1093/embo-reports/kve246 PubMedCrossRefGoogle Scholar
  194. 194.
    Murata S, Chiba T, Tanaka K (2003) CHIP: a quality-control E3 ligase collaborating with molecular chaperones. Int J Biochem Cell Biol 35(5):572–578PubMedCrossRefGoogle Scholar
  195. 195.
    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 U S A 102(37):13135–13140. doi: 10.1073/pnas.0505801102 PubMedCrossRefGoogle Scholar
  196. 196.
    Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Furst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Hohfeld J (2010) Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol 20(2):143–148. doi: 10.1016/j.cub.2009.11.022 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Cellular and Molecular Neurobiology LaboratoryIndian Institute of TechnologyJodhpurIndia

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