Journal Mobile Options
Table of Contents
Vol. 8, No. 6, 2011
Issue release date: August 2011
Neurodegenerative Dis 2011;8:397–412
(DOI:10.1159/000324514)

Molecular Chaperones and Associated Cellular Clearance Mechanisms against Toxic Protein Conformers in Parkinson’s Disease

Hinault M.-P. · Farina-Henriquez-Cuendet A. · Goloubinoff P.
DBMV, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder marked by the loss of dopaminergic neurons (in particular in the substantia nigra) causing severe impairment of movement coordination and locomotion, associated with the accumulation of aggregated α-synuclein (α-Syn) into proteinaceous inclusions named Lewy bodies. Various early forms of misfolded α-Syn oligomers are cytotoxic. Their formation is favored by mutations and external factors, such as heavy metals, pesticides, trauma-related oxidative stress and heat shock. Here, we discuss the role of several complementing cellular defense mechanisms that may counteract PD pathogenesis, especially in youth, and whose effectiveness decreases with age. Particular emphasis is given to the ‘holdase’ and ‘unfoldase’ molecular chaperones that provide cells with potent means to neutralize and scavenge toxic protein conformers. Because chaperones can specifically recognize misfolded proteins, they are key specificity factors for other cellular defenses, such as proteolysis by the proteasome and autophagy. The efficiency of the cellular defenses decreases in stressed or aging neurons, leading to neuroinflammation, apoptosis and tissue loss. Thus, drugs that can upregulate the molecular chaperones, the ubiquitin-proteasome system and autophagy in brain tissues are promising avenues for therapies against PD and other mutation-, stress- or age-dependent protein-misfolding diseases.



Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Fitzgerald JC, Plun-Favreau H: Emerging pathways in genetic Parkinson’s disease: autosomal-recessive genes in Parkinson’s disease – a common pathway? FEBS J 2008;275:5758–5766.
  2. Gasser T: Molecular pathogenesis of Parkinson disease: insights from genetic studies. Expert Rev Mol Med 2009;11:e22.

    External Resources

  3. Hindle JV: Ageing, neurodegeneration and Parkinson’s disease. Age Ageing 2010;39:156–161.

    External Resources

  4. Richardson JR, Shalat SL, Buckley B, Winnik B, O’Suilleabhain P, Diaz-Arrastia R, Reisch J, German DC: Elevated serum pesticide levels and risk of Parkinson disease. Arch Neurol 2009;66:870–875.

    External Resources

  5. Uryu K, Chen XH, Martinez D, Browne KD, Johnson VE, Graham DI, Lee VM, Trojanowski JQ, Smith DH: Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans. Exp Neurol 2007;208:185–192.
  6. Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM: Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci 2008;28:7687–7698.
  7. Henchcliffe C, Beal MF: Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 2008;4:600–609.
  8. Yazawa I, Giasson BI, Sasaki R, Zhang B, Joyce S, Uryu K, Trojanowski JQ, Lee VM: Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 2005;45:847–859.
  9. Dauer W, Przedborski S: Parkinson’s disease: mechanisms and models. Neuron 2003;39:889–909.
  10. Cookson MR: The biochemistry of Parkinson’s disease. Annu Rev Biochem 2005;74:29–52.
  11. Shibasaki Y, Baillie DA, St Clair D, Brookes AJ: High-resolution mapping of SNCA encoding alpha-synuclein, the non-A beta component of Alzheimer’s disease amyloid precursor, to human chromosome 4q21.3–>q22 by fluorescence in situ hybridization. Cytogenet Cell Genet 1995;71:54–55.
  12. Lavedan C: The synuclein family. Genome Res 1998;8:871–880.
  13. Kahle PJ, Neumann M, Ozmen L, Haass C: Physiology and pathophysiology of alphasynuclein: cell culture and transgenic animal models based on a Parkinson’s diseaseassociated protein. Ann NY Acad Sci 2000;920:33–41.
  14. Murphy DD, Rueter SM, Trojanowski JQ, Lee VM: Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 2000;20:3214–3220.
  15. Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H: NACP/alphasynuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol 2000;99:14–20.
  16. Tofaris GK, Spillantini MG: Physiological and pathological properties of alphasynuclein. Cell Mol Life Sci 2007;64:2194–2201.
  17. Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC: Alphasynuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 2005;123:383–396.
  18. Volles MJ, Lansbury PT Jr: Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson’s disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 2002;41:4595–4602.
  19. Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT Jr: Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 2002;418:291.
  20. Lashuel HA, Petre BM, Wall J, Simon M, Nowak RJ, Walz T, Lansbury PT Jr: Alpha-synuclein, especially the Parkinson’s disease-associated mutants, forms porelike annular and tubular protofibrils. J Mol Biol 2002;322:1089–1102.
  21. Lashuel HA, Lansbury PT Jr: Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins? Q Rev Biophys 2006;39:167–201.
  22. Hinault MP, Cuendet AF, Mattoo RU, Mensi M, Dietler G, Lashuel HA, Goloubinoff P: Stable alpha-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones. J Biol Chem 2010;285:38173–38182.
  23. Shin Y, Klucken J, Patterson C, Hyman BT, McLean PJ: The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways. J Biol Chem 2005;280:23727–23734.
  24. Koga H, Kaushik S, Cuervo AM: Protein homeostasis and aging: the importance of exquisite quality control. Ageing Res Rev 2010, E-pub ahead of print.
  25. Hartl FU, Hayer-Hartl M: Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 2002;295:1852–1858.
  26. Hinault MP, Ben-Zvi A, Goloubinoff P: Chaperones and proteases: cellular fold-controlling factors of proteins in neurodegenerative diseases and aging. J Mol Neurosci 2006;30:249–265.
  27. Meriin AB, Sherman MY: Role of molecular chaperones in neurodegenerative disorders. Int J Hyperthermia 2005;21:403–419.
  28. Brown IR: Heat shock proteins and protection of the nervous system. Ann NY Acad Sci 2007;1113:147–158.
  29. Luo GR, Chen S, Le WD: Are heat shock proteins therapeutic target for Parkinson’s disease? Int J Biol Sci 2007;3:20–26.
  30. Adachi H, Katsuno M, Waza M, Minamiyama M, Tanaka F, Sobue G: Heat shock proteins in neurodegenerative diseases: pathogenic roles and therapeutic implications. Int J Hyperthermia 2009;25:647–654.
  31. Goloubinoff P, Christeller JT, Gatenby AA, Lorimer GH: Reconstitution of active dimeric ribulose bisphosphate carboxylase from an unfolded state depends on two chaperonin proteins and Mg-ATP. Nature 1989;342:884–889.
  32. Buchner J, Schmidt M, Fuchs M, Jaenicke R, Rudolph R, Schmid FX, Kiefhaber T: GroE facilitates refolding of citrate synthase by suppressing aggregation. Biochemistry 1991;30:1586–1591.
  33. Veinger L, Diamant S, Buchner J, Goloubinoff P: The small heat-shock protein IbpB from Escherichia coli stabilizes stress-denatured proteins for subsequent refolding by a multichaperone network. J Biol Chem 1998;273:11032–11037.
  34. Van Montfort R, Slingsby C, Vierling E: Structure and function of the small heat shock protein/alpha-crystallin family of molecular chaperones. Adv Protein Chem 2001;59:105–156.
  35. Rudiger S, Germeroth L, Schneider-Mergener J, Bukau B: Substrate specificity of the DnaK chaperone determined by screening cellulose-bound peptide libraries. Embo J 1997;16:1501–1507.
  36. Sharma SK, Christen P, Goloubinoff P: Disaggregating chaperones: an unfolding story. Curr Protein Pept Sci 2009;10:432–446.
  37. Finka A, Mattoo RU, Goloubinoff P: Meta-analysis of heat-and chemically upregulated chaperone genes in plant and human cells. Cell Stress Chaperones 2011;16:15–31.
  38. Rekas A, Adda CG, Andrew Aquilina J, Barnham KJ, Sunde M, Galatis D, Williamson NA, Masters CL, Anders RF, Robinson CV, Cappai R, Carver JA: Interaction of the molecular chaperone alphaB-crystallin with alpha-synuclein: effects on amyloid fibril formation and chaperone activity. J Mol Biol 2004;340:1167–1183.
  39. Zourlidou A, Payne Smith MD, Latchman DS: HSP27 but not HSP70 has a potent protective effect against alpha-synuclein-induced cell death in mammalian neuronal cells. J Neurochem 2004;88:1439–1448.
  40. Kitao Y, Matsuyama T, Takano K, Tabata Y, Yoshimoto T, Momoi T, Yamatodani A, Ogawa S, Hori O: Does ORP150/HSP12A protect dopaminergic neurons against MPTP/MPP(+)-induced neurotoxicity? Antioxid Redox Signal 2007;9:589–595.
  41. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P: Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299:256–259.
  42. Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A: DJ-1 is a redoxdependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol 2004;2:e362.

    External Resources

  43. Inden M, Taira T, Kitamura Y, Yanagida T, Tsuchiya D, Takata K, Yanagisawa D, Nishimura K, Taniguchi T, Kiso Y, Yoshimoto K, Agatsuma T, Koide-Yoshida S, Iguchi-Ariga SM, Shimohama S, Ariga H: PARK7 DJ-1 protects against degeneration of nigral dopaminergic neurons in Parkinson’s disease rat model. Neurobiol Dis 2006;24:144–158.
  44. Liu F, Nguyen JL, Hulleman JD, Li L, Rochet JC: Mechanisms of DJ-1 neuroprotection in a cellular model of Parkinson’s disease. J Neurochem 2008;105:2435–2453.
  45. Johnston JA, Ward CL, Kopito RR: Aggresomes: a cellular response to misfolded proteins. J Cell Biol 1998;143:1883–1898.
  46. Garcia-Mata R, Bebok Z, Sorscher EJ, Sztul ES: Characterization and dynamics of aggresome formation by a cytosolic GFP-chimera. J Cell Biol 1999;146:1239–1254.
  47. Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM: Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 2002;295:865–868.
  48. Dong Z, Wolfer DP, Lipp HP, Bueler H: Hsp70 gene transfer by adeno-associated virus inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease. Mol Ther 2005;11:80–88.
  49. Klucken J, Shin Y, Masliah E, Hyman BT, McLean PJ: Hsp70 reduces alpha-synuclein aggregation and toxicity. J Biol Chem 2004;279:25497–25502.
  50. Huang C, Cheng H, Hao S, Zhou H, Zhang X, Gao J, Sun QH, Hu H, Wang CC: Heat shock protein 70 inhibits alpha-synuclein fibril formation via interactions with diverse intermediates. J Mol Biol 2006;364:323–336.
  51. Dedmon MM, Christodoulou J, Wilson MR, Dobson CM: Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. J Biol Chem 2005;280:14733–14740.
  52. Durrenberger PF, Filiou MD, Moran LB, Michael GJ, Novoselov S, Cheetham ME, Clark P, Pearce RK, Graeber MB: DnaJB6 is present in the core of Lewy bodies and is highly up-regulated in parkinsonian astrocytes. J Neurosci Res 2009;87:238–245.
  53. Hageman J, Rujano MA, van Waarde MA, Kakkar V, Dirks RP, Govorukhina N, Oosterveld-Hut HM, Lubsen NH, Kampinga HH: A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation. Mol Cell 2010;37:355–369.
  54. Falsone SF, Kungl AJ, Rek A, Cappai R, Zangger K: The molecular chaperone Hsp90 modulates intermediate steps of amyloid assembly of the Parkinson-related protein alpha-synuclein. J Biol Chem 2009;284:31190–31199.
  55. Kong B, Chae Y, Lee K: Degradation of wild-type alpha-synuclein by a molecular chaperone leads to reduced aggregate formation. Cell Biochem Funct 2005;23:125–132.
  56. Lo Bianco C, Shorter J, Regulier E, Lashuel H, Iwatsubo T, Lindquist S, Aebischer P: Hsp104 antagonizes alpha-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease. J Clin Invest 2008;118:3087–3097.
  57. Glover JR, Lindquist S: Hsp104, Hsp70, and Hsp40:a novel chaperone system that rescues previously aggregated proteins. Cell 1998;94:73–82.
  58. Goloubinoff P, Mogk A, Zvi AP, Tomoyasu T, Bukau B: Sequential mechanism of solubilization and refolding of stable protein aggregates by a bichaperone network. Proc Natl Acad Sci USA 1999;96:13732–13737.
  59. Schuermann JP, Jiang J, Cuellar J, Llorca O, Wang L, Gimenez LE, Jin S, Taylor AB, Demeler B, Morano KA, Hart PJ, Valpuesta JM, Lafer EM, Sousa R: Structure of the Hsp110:Hsc70 nucleotide exchange machine. Mol Cell 2008;31:232–243.
  60. Shorter J, Lindquist S: Destruction or potentiation of different prions catalyzed by similar Hsp104 remodeling activities. Mol Cell 2006;23:425–438.
  61. Diamant S, Ben-Zvi AP, Bukau B, Goloubinoff P: Size-dependent disaggregation of stable protein aggregates by the DnaK chaperone machinery. J Biol Chem 2000;275:21107–21113.
  62. Ben-Zvi A, De Los Rios P, Dietler G, Goloubinoff P: Active solubilization and refolding of stable protein aggregates by cooperative unfolding action of individual hsp70 chaperones. J Biol Chem 2004;279:37298–37303.
  63. Goloubinoff P, De Los Rios P: The mechanism of Hsp70 chaperones: (entropic) pulling the models together. Trends Biochem Sci 2007;32:372–380.
  64. Arias E, Cuervo AM: Chaperone-mediated autophagy in protein quality control. Curr Opin Cell Biol 2010, E-pub ahead of print.
  65. Nardai G, Csermely P, Soti C: Chaperone function and chaperone overload in the aged: a preliminary analysis. Exp Gerontol 2002;37:1257–1262.
  66. Mandel S, Grunblatt E, Riederer P, Amariglio N, Jacob-Hirsch J, Rechavi G, Youdim MB: Gene expression profiling of sporadic Parkinson’s disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKP1A, aldehyde dehydrogenase, and chaperone HSC-70. Ann NY Acad Sci 2005;1053:356–375.
  67. Chu Y, Dodiya H, Aebischer P, Olanow CW, Kordower JH: Alterations in lysosomal and proteasomal markers in Parkinson’s disease: relationship to alpha-synuclein inclusions. Neurobiol Dis 2009;35:385–398.
  68. Jin J, Hulette C, Wang Y, Zhang T, Pan C, Wadhwa R, Zhang J: Proteomic identification of a stress protein, mortalin/mthsp70/GRP75:relevance to Parkinson disease. Mol Cell Proteomics 2006;5:1193–1204.
  69. Moran LB, Duke DC, Deprez M, Dexter DT, Pearce RK, Graeber MB: Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson’s disease. Neurogenetics 2006;7:1–11.
  70. Bernasconi R, Molinari M: ERAD and ERAD tuning: disposal of cargo and of ERAD regulators from the mammalian ER. Curr Opin Cell Biol 2010, E-pub ahead of print.
  71. Jung T, Catalgol B, Grune T: The proteasomal system. Mol Aspects Med 2009;30:191–296.
  72. Dembla-Rajpal N, Seipelt R, Wang Q, Rymond BC: Proteasome inhibition alters the transcription of multiple yeast genes. Biochim Biophys Acta 2004;1680:34–45.
  73. Kahn NW, Rea SL, Moyle S, Kell A, Johnson TE: Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidative-stress response in Caenorhabditis elegans. Biochem J 2008;409:205–213.
  74. Borissenko L, Groll M: Diversity of proteasomal missions: fine tuning of the immune response. Biol Chem 2007;388:947–955.
  75. Rideout HJ, Larsen KE, Sulzer D, Stefanis L: Proteasomal inhibition leads to formation of ubiquitin/alpha-synuclein-immunoreactive inclusions in PC12 cells. J Neurochem 2001;78:899–908.
  76. Rideout HJ, Lang-Rollin IC, Savalle M, Stefanis L: Dopaminergic neurons in rat ventral midbrain cultures undergo selective apoptosis and form inclusions, but do not up-regulate iHSP70, following proteasomal inhibition. J Neurochem 2005;93:1304–1313.
  77. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC: Alpha-synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003;278:25009–25013.
  78. Ancolio K, Alves da Costa C, Ueda K, Checler F: Alpha-synuclein and the Parkinson’s disease-related mutant Ala53Thr-alpha-synuclein do not undergo proteasomal degradation in HEK293 and neuronal cells. Neurosci Lett 2000;285:79–82.
  79. Paxinou E, Chen Q, Weisse M, Giasson BI, Norris EH, Rueter SM, Trojanowski JQ, Lee VM, Ischiropoulos H: Induction of alpha-synuclein aggregation by intracellular nitrative insult. J Neurosci 2001;21:8053–8061.
  80. Machiya Y, Hara S, Arawaka S, Fukushima S, Sato H, Sakamoto M, Koyama S, Kato T: Phosphorylated alpha-synuclein at Ser-129 is targeted to the proteasome pathway in a ubiquitin-independent manner. J Biol Chem 2010;285:40732–40744.
  81. Verhoef LG, Lindsten K, Masucci MG, Dantuma NP: Aggregate formation inhibits proteasomal degradation of polyglutamine proteins. Hum Mol Genet 2002;11:2689–2700.
  82. Rubinsztein DC: The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 2006;443:780–786.
  83. Zhang NY, Tang Z, Liu CW: alpha-Synuclein protofibrils inhibit 26 S proteasome-mediated protein degradation: understanding the cytotoxicity of protein protofibrils in neurodegenerative disease pathogenesis. J Biol Chem 2008;283:20288–20298.
  84. Sneppen K, Lizana L, Jensen MH, Pigolotti S, Otzen D: Modeling proteasome dynamics in Parkinson’s disease. Phys Biol 2009;6:036005.

    External Resources

  85. McNaught KS, Belizaire R, Isacson O, Jenner P, Olanow CW: Altered proteasomal function in sporadic Parkinson’s disease. Exp Neurol 2003;179:38–46.
  86. Tofaris GK, Razzaq A, Ghetti B, Lilley KS, Spillantini MG: Ubiquitination of alphasynuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. J Biol Chem 2003;278:44405–44411.
  87. Duke DC, Moran LB, Kalaitzakis ME, Deprez M, Dexter DT, Pearce RK, Graeber MB: Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson’s disease. Neurogenetics 2006;7:139–148.
  88. Sharma N, Hewett J, Ozelius LJ, Ramesh V, McLean PJ, Breakefield XO, Hyman BT: A close association of torsinA and alpha-synuclein in Lewy bodies: a fluorescence resonance energy transfer study. Am J Pathol 2001;159:339–344.
  89. McLean PJ, Kawamata H, Shariff S, Hewett J, Sharma N, Ueda K, Breakefield XO, Hyman BT: Torsin A and heat shock proteins act as molecular chaperones: suppression of alpha-synuclein aggregation. J Neurochem 2002;83:846–854.
  90. Cao S, Gelwix CC, Caldwell KA, Caldwell GA: Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans. J Neurosci 2005;25:3801–3812.
  91. Kopito RR: Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 2000;10:524–530.
  92. Opazo F, Krenz A, Heermann S, Schulz JB, Falkenburger BH: Accumulation and clearance of alpha-synuclein aggregates demonstrated by time-lapse imaging. J Neurochem 2008;106:529–540.
  93. Wong ES, Tan JM, Soong WE, Hussein K, Nukina N, Dawson VL, Dawson TM, Cuervo AM, Lim KL: Autophagy-mediated clearance of aggresomes is not a universal phenomenon. Hum Mol Genet 2008;17:2570–2582.
  94. Zhao J, Ren Y, Jiang Q, Feng J: Parkin is recruited to the centrosome in response to inhibition of proteasomes. J Cell Sci 2003;116:4011–4019.
  95. Ardley HC, Scott GB, Rose SA, Tan NG, Robinson PA: UCH-L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson’s disease. J Neurochem 2004;90:379–391.
  96. Tanaka M, Kim YM, Lee G, Junn E, Iwatsubo T, Mouradian MM: Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem 2004;279:4625–4631.
  97. Zaarur N, Meriin AB, Gabai VL, Sherman MY: Triggering aggresome formation: dissecting aggresome-targeting and aggregation signals in synphilin 1. J Biol Chem 2008;283:27575–27584.
  98. Muqit MM, Davidson SM, Payne Smith MD, MacCormac LP, Kahns S, Jensen PH, Wood NW, Latchman DS: Parkin is recruited into aggresomes in a stress-specific manner: over-expression of parkin reduces aggresome formation but can be dissociated from parkin’s effect on neuronal survival. Hum Mol Genet 2004;13:117–135.
  99. Diaz-Corrales FJ, Asanuma M, Miyazaki I, Miyoshi K, Ogawa N: Rotenone induces aggregation of gamma-tubulin protein and subsequent disorganization of the centrosome: relevance to formation of inclusion bodies and neurodegeneration. Neuroscience 2005;133:117–135.
  100. Ding WX, Yin XM: Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy 2008;4:141–150.
  101. Ravikumar B, Duden R, Rubinsztein DC: Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 2002;11:1107–1117.
  102. Lamark T, Johansen T: Autophagy: links with the proteasome. Curr Opin Cell Biol 2010;22:192–198.
  103. Iwata A, Riley BE, Johnston JA, Kopito RR: HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem 2005;280:40282–40292.
  104. 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: HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 2007;447:859–863.
  105. Rideout HJ, Lang-Rollin I, Stefanis L: Involvement of macroautophagy in the dissolution of neuronal inclusions. Int J Biochem Cell Biol 2004;36:2551–2562.
  106. De Duve C, Wattiaux R: Functions of lysosomes. Annu Rev Physiol 1966;28:435–492.
  107. Cuervo AM: Autophagy: many paths to the same end. Mol Cell Biochem 2004;263:55–72.
  108. Levine B, Klionsky DJ: Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004;6:463–477.
  109. Klionsky DJ: The molecular machinery of autophagy: unanswered questions. J Cell Sci 2005;118:7–18.
  110. Massey AC, Zhang C, Cuervo AM: Chaperone-mediated autophagy in aging and disease. Curr Top Dev Biol 2006;73:205–235.
  111. Yang Q, She H, Gearing M, Colla E, Lee M, Shacka JJ, Mao Z: Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science 2009;323:124–127.
  112. Todde V, Veenhuis M, van der Klei IJ: Autophagy: principles and significance in health and disease. Biochim Biophys Acta 2009;1792:3–13.
  113. Koga H, Cuervo AM: Chaperone-mediated autophagy dysfunction in the pathogenesis of neurodegeneration. Neurobiol Dis 2010, E-pub ahead of print.
  114. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D: Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 2004;305:1292–1295.
  115. Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L: Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 2008;283:23542–23556.
  116. Yu WH, Dorado B, Figueroa HY, Wang L, Planel E, Cookson MR, Clark LN, Duff KE: Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric alpha-synuclein. Am J Pathol 2009;175:736–747.
  117. Mak SK, McCormack AL, Manning-Bog AB, Cuervo AM, Di Monte DA: Lysosomal degradation of alpha-synuclein in vivo. J Biol Chem 2010;285:13621–13629.
  118. Bejarano E, Cuervo AM: Chaperone-mediated autophagy. Proc Am Thorac Soc 2010;7:29–39.

    External Resources

  119. Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L: Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS One 2009;4:e5515.

    External Resources

  120. Massey AC, Kaushik S, Sovak G, Kiffin R, Cuervo AM: Consequences of the selective blockage of chaperone-mediated autophagy. Proc Natl Acad Sci USA 2006;103:5805–5810.
  121. Isidoro C, Biagioni F, Giorgi FS, Fulceri F, Paparelli A, Fornai F: The role of autophagy on the survival of dopamine neurons. Curr Top Med Chem 2009;9:869–879.
  122. Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D, Cuervo AM: Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest 2008;118:777–788.
  123. Kabuta T, Furuta A, Aoki S, Furuta K, Wada K: Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy. J Biol Chem 2008;283:23731–23738.
  124. Sevlever D, Jiang P, Yen SH: Cathepsin D is the main lysosomal enzyme involved in the degradation of alpha-synuclein and generation of its carboxy-terminally truncated species. Biochemistry 2008;47:9678–9687.
  125. Morimoto RI, Cuervo AM: Protein homeostasis and aging: taking care of proteins from the cradle to the grave. J Gerontol A Biol Sci Med Sci 2009;64:167–170.

    External Resources

  126. Hahn GM, Shiu EC, Auger EA: Mammalian stress proteins HSP70 and HSP28 coinduced by nicotine and either ethanol or heat. Mol Cell Biol 1991;11:6034–6040.
  127. 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: Bimoclomol: a nontoxic, hydroxylamine derivative with stress protein-inducing activity and cytoprotective effects. Nat Med 1997;3:1150–1154.
  128. Kato K, Ito H, Kamei K, Iwamoto I: Stimulation of the stress-induced expression of stress proteins by curcumin in cultured cells and in rat tissues in vivo. Cell Stress Chaperones 1998;3:152–160.
  129. Griffin TM, Valdez TV, Mestril R: Radicicol activates heat shock protein expression and cardioprotection in neonatal rat cardiomyocytes. Am J Physiol Heart Circ Physiol 2004;287:H1081–H1088.
  130. Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L: Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med 2004;10:402–405.
  131. Westerheide SD, Bosman JD, Mbadugha BN, Kawahara TL, Matsumoto G, Kim S, Gu W, Devlin JP, Silverman RB, Morimoto RI: Celastrols as inducers of the heat shock response and cytoprotection. J Biol Chem 2004;279:56053–56060.
  132. Shen HY, He JC, Wang Y, Huang QY, Chen JF: Geldanamycin induces heat shock protein 70 and protects against MPTP-induced dopaminergic neurotoxicity in mice. J Biol Chem 2005;280:39962–39969.
  133. Wang Q, Mosser DD, Bag J: Induction of HSP70 expression and recruitment of HSC70 and HSP70 in the nucleus reduce aggregation of a polyalanine expansion mutant of PABPN1 in HeLa cells. Hum Mol Genet 2005;14:3673–3684.
  134. Westerheide SD, Morimoto RI: Heat shock response modulators as therapeutic tools for diseases of protein conformation. J Biol Chem 2005;280:33097–33100.
  135. Waza M, Adachi H, Katsuno M, Minamiyama M, Tanaka F, Doyu M, Sobue G: Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein. J Mol Med 2006;84:635–646.
  136. Andringa G, Jongenelen CA, Halfhide L, Drukarch B: The thiol antioxidant 1,2dithiole-3-thione stimulates the expression of heat shock protein 70 in dopaminergic PC12 cells. Neurosci Lett 2007;416:76–81.
  137. Haap T, Triebskorn R, Kohler HR: Acute effects of diclofenac and DMSO to Daphnia magna: immobilisation and hsp70-induction. Chemosphere 2008;73:353–359.
  138. Sloan LA, Fillmore MC, Churcher I: Small-molecule modulation of cellular chaperones to treat protein misfolding disorders. Curr Opin Drug Discov Devel 2009;12:666–681.
  139. Wrona IE, Gozman A, Taldone T, Chiosis G, Panek JS: Synthesis of reblastatin, autolytimycin, and non-benzoquinone analogues: potent inhibitors of heat shock protein 90. J Org Chem 2010;75:2820–2835.
  140. Sarkar S, Ravikumar B, Floto RA, Rubinsztein DC: Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ 2009;16:46–56.
  141. Riedel M, Goldbaum O, Schwarz L, Schmitt S, Richter-Landsberg C: 17-AAG induces cytoplasmic alpha-synuclein aggregate clearance by induction of autophagy. PLoS One 2010;5:e8753.

    External Resources

  142. Diamant S, Eliahu N, Rosenthal D, Goloubinoff P: Chemical chaperones regulate molecular chaperones in vitro and in cells under combined salt and heat stresses. J Biol Chem 2001;276:39586–39591.
  143. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC: Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 2007;282:5641–5652.
  144. Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E: Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci 2009;29:13578–13588.
  145. Umeda-Kameyama Y, Tsuda M, Ohkura C, Matsuo T, Namba Y, Ohuchi Y, Aigaki T: Thioredoxin suppresses Parkin-associated endothelin receptor-like receptor-induced neurotoxicity and extends longevity in Drosophila. J Biol Chem 2007;282:11180–11187.
  146. Johnson JA, Johnson DA, Kraft AD, Calkins MJ, Jakel RJ, Vargas MR, Chen PC: The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Ann NY Acad Sci 2008;1147:61–69.
  147. Yates MS, Kensler TW: Chemopreventive promise of targeting the Nrf2 pathway. Drug News Perspect 2007;20:109–117.
  148. Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist S: Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 2006;313:324–328.
  149. Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA, Cooper AA, Rochet JC, Lindquist S: Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet 2009;41:308–315.
  150. Liu F, Hindupur J, Nguyen JL, Ruf KJ, Zhu J, Schieler JL, Bonham CC, Wood KV, Davisson VJ, Rochet JC: Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson’s disease-related insults. Free Radic Biol Med 2008;45:242–255.
  151. Smith WW, Liu Z, Liang Y, Masuda N, Swing DA, Jenkins NA, Copeland NG, Troncoso JC, Pletnikov M, Dawson TM, Martin LJ, Moran TH, Lee MK, Borchelt DR, Ross CA: Synphilin-1 attenuates neuronal degeneration in the A53T alpha-synuclein transgenic mouse model. Hum Mol Genet 2010;19:2087–2098.
  152. Rao JN, Dua V, Ulmer TS: Characterization of alpha-synuclein interactions with selected aggregation-inhibiting small molecules. Biochemistry 2008;47:4651–4656.
  153. Lendel C, Bertoncini CW, Cremades N, Waudby CA, Vendruscolo M, Dobson CM, Schenk D, Christodoulou J, Toth G: On the mechanism of nonspecific inhibitors of protein aggregation: dissecting the interactions of alpha-synuclein with Congo red and Lacmoid. Biochemistry 2009;48:8322–8334.
  154. Amer DA, Irvine GB, El-Agnaf OM: Inhibitors of alpha-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson’s disease and related disorders. Exp Brain Res 2006;173:223–233.
  155. Abe K, Kobayashi N, Sode K, Ikebukuro K: Peptide ligand screening of alpha-synuclein aggregation modulators by in silico panning. BMC Bioinformatics 2007;8:451.

    External Resources

  156. Ghosh JG, Houck SA, Clark JI: Interactive sequences in the molecular chaperone, human alphaB crystallin modulate the fibrillation of amyloidogenic proteins. Int J Biochem Cell Biol 2008;40:954–967.
  157. Zhu M, Rajamani S, Kaylor J, Han S, Zhou F, Fink AL: The flavonoid baicalein inhibits fibrillation of alpha-synuclein and disaggregates existing fibrils. J Biol Chem 2004;279:26846–26857.
  158. Jiang M, Porat-Shliom Y, Pei Z, Cheng Y, Xiang L, Sommers K, Li Q, Gillardon F, Hengerer B, Berlinicke C, Smith WW, Zack DJ, Poirier MA, Ross CA, Duan W: Baicalein reduces E46K alpha-synuclein aggregation in vitro and protects cells against E46K alpha-synuclein toxicity in cell models of familiar Parkinsonism. J Neurochem 2010;114:419–429.
  159. Kim J, Harada R, Kobayashi M, Kobayashi N, Sode K: The inhibitory effect of pyrroloquinoline quinone on the amyloid formation and cytotoxicity of truncated alpha-synuclein. Mol Neurodegener 2010;5:20.

    External Resources

  160. Kobayashi M, Kim J, Kobayashi N, Han S, Nakamura C, Ikebukuro K, Sode K: Pyrroloquinoline quinone (PQQ) prevents fibril formation of alpha-synuclein. Biochem Biophys Res Commun 2006;349:1139–1144.
  161. Teiten MH, Eifes S, Reuter S, Duvoix A, Dicato M, Diederich M: Gene expression profiling related to anti-inflammatory properties of curcumin in K562 leukemia cells. Ann NY Acad Sci 2009;1171:391–398.
  162. Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, Rock CL, Pruitt MA, Yang F, Hudspeth B, Hu S, Faull KF, Teter B, Cole GM, Frautschy SA: Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. J Pharmacol Exp Ther 2008;326:196–208.
  163. Cole GM, Morihara T, Lim GP, Yang F, Begum A, Frautschy SA: NSAID and antioxidant prevention of Alzheimer’s disease: lessons from in vitro and animal models. Ann NY Acad Sci 2004;1035:68–84.
  164. Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM: Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. Neurobiol Aging 2001;22:993–1005.
  165. Wang MS, Boddapati S, Emadi S, Sierks MR: Curcumin reduces alpha-synuclein induced cytotoxicity in Parkinson’s disease cell model. BMC Neurosci 2010;11:57.

    External Resources

  166. Ono K, Yamada M: Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. J Neurochem 2006;97:105–115.
  167. Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE: Curcumin inhibits aggregation of alpha-synuclein. Acta Neuropathol 2008;115:479–489.
  168. Di Giovanni S, Eleuteri S, Paleologou KE, Yin G, Zweckstetter M, Carrupt PA, Lashuel HA: Entacapone and tolcapone, two catechol O-methyltransferase inhibitors, block fibril formation of alpha-synuclein and beta-amyloid and protect against amyloid- induced toxicity. J Biol Chem 2010;285:14941–14954.
  169. Outeiro TF, Grammatopoulos TN, Altmann S, Amore A, Standaert DG, Hyman BT, Kazantsev AG: Pharmacological inhibition of PARP-1 reduces alpha-synuclein-and MPP+–induced cytotoxicity in Parkinson’s disease in vitro models. Biochem Biophys Res Commun 2007;357:596–602.
  170. Kritzer JA, Hamamichi S, McCaffery JM, Santagata S, Naumann TA, Caldwell KA, Caldwell GA, Lindquist S: Rapid selection of cyclic peptides that reduce alpha-synuclein toxicity in yeast and animal models. Nat Chem Biol 2009;5:655–663.
  171. Su LJ, Auluck PK, Outeiro TF, Yeger-Lotem E, Kritzer JA, Tardiff DF, Strathearn KE, Liu F, Cao S, Hamamichi S, Hill KJ, Caldwell KA, Bell GW, Fraenkel E, Cooper AA, Caldwell GA, McCaffery JM, Rochet JC, Lindquist S: Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson’s disease models. Dis Model Mech 2010;3:194–208.
  172. Liu Z, Meray RK, Grammatopoulos TN, Fredenburg RA, Cookson MR, Liu Y, Logan T, Lansbury PT Jr: Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson’s disease. Proc Natl Acad Sci USA 2009;106:4635–4640.
  173. Inden M, Kitamura Y, Takeuchi H, Yanagida T, Takata K, Kobayashi Y, Taniguchi T, Yoshimoto K, Kaneko M, Okuma Y, Taira T, Ariga H, Shimohama S: Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone. J Neurochem 2007;101:1491–1504.
  174. Ono K, Ikemoto M, Kawarabayashi T, Ikeda M, Nishinakagawa T, Hosokawa M, Shoji M, Takahashi M, Nakashima M: A chemical chaperone, sodium 4-phenylbutyric acid, attenuates the pathogenic potency in human alpha-synuclein A30P + A53T transgenic mice. Parkinsonism Relat Disord 2009;15:649–654.

    External Resources

  175. Vigh L, Horvath I, Maresca B, Harwood JL: Can the stress protein response be controlled by ‘membrane-lipid therapy’? Trends Biochem Sci 2007;32:357–363.
  176. Saidi Y, Finka A, Muriset M, Bromberg Z, Weiss YG, Maathuis FJ, Goloubinoff P: The heat shock response in moss plants is regulated by specific calcium-permeable channels in the plasma membrane. Plant Cell 2009;21:2829–2843.
  177. Saidi Y, Peter M, Finka A, Cicekli C, Vigh L, Goloubinoff P: Membrane lipid composition affects plant heat sensing and modulates Ca (2+)-dependent heat shock response. Plant Signal Behav 2010;1:5.
  178. Chung J, Nguyen AK, Henstridge DC, Holmes AG, Chan MH, Mesa JL, Lancaster GI, Southgate RJ, Bruce CR, Duffy SJ, Horvath I, Mestril R, Watt MJ, Hooper PL, Kingwell BA, Vigh L, Hevener A, Febbraio MA: HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci USA 2008;105:1739–1744.
  179. Kalmar B, Novoselov S, Gray A, Cheetham ME, Margulis B, Greensmith L: Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS. J Neurochem 2008;107:339–350.
  180. Weiss YG, Bromberg Z, Raj N, Raphael J, Goloubinoff P, Ben-Neriah Y, Deutschman CS: Enhanced heat shock protein 70 expression alters proteasomal degradation of IkappaB kinase in experimental acute respiratory distress syndrome. Crit Care Med 2007;35:2128–2138.
  181. Sharma SK, De los Rios P, Christen P, Lustig A, Goloubinoff P: The kinetic parameters and energy cost of the Hsp70 chaperone as a polypeptide unfoldase. Nat Chem Biol 2010;6:914–920.
  182. Balch WE, Morimoto RI, Dillin A, Kelly JW: Adapting proteostasis for disease intervention. Science 2008;319:916–919.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50