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Biochemistry Research International
Volume 2011 (2011), Article ID 618127, 18 pages
http://dx.doi.org/10.1155/2011/618127
Review Article

Hsp70 and Its Molecular Role in Nervous System Diseases

Department of Cellular and Developmental Biology, University of Palermo, Viale delle Scienze, 90128 Palermo, Italy

Received 1 July 2010; Revised 19 October 2010; Accepted 5 January 2011

Academic Editor: Jan A. Miernyk

Copyright © 2011 Giuseppina Turturici et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. B. Anfinsen, “Principles that govern the folding of protein chains,” Science, vol. 181, no. 4096, pp. 223–230, 1973. View at Google Scholar · View at Scopus
  2. R. J. Ellis, “The molecular chaperone concept,” Seminars in Cell Biology, vol. 1, no. 1, pp. 1–9, 1990. View at Google Scholar · View at Scopus
  3. E. A. Craig, B. D. Gambill, and R. J. Nelson, “Heat shock proteins: molecular chaperones of protein biogenesis,” Microbiological Reviews, vol. 57, no. 2, pp. 402–414, 1993. View at Google Scholar · View at Scopus
  4. C. Georgopoulos and W. J. Welch, “Role of the major heat shock proteins as molecular chaperones,” Annual Review of Cell Biology, vol. 9, pp. 601–634, 1993. View at Google Scholar · View at Scopus
  5. F. U. Hartl, “Molecular chaperones in cellular protein folding,” Nature, vol. 381, no. 6583, pp. 571–580, 1996. View at Publisher · View at Google Scholar · View at Scopus
  6. F. R. Sharp, S. M. Massa, and R. A. Swanson, “Heat-shock protein protection,” Trends in Neurosciences, vol. 22, no. 3, pp. 97–99, 1999. View at Publisher · View at Google Scholar · View at Scopus
  7. R. G. Giffard, L. Xu, H. Zhao et al., “Chaperones, protein aggregation, and brain protection from hypoxic/ischemic injury,” Journal of Experimental Biology, vol. 207, no. 18, pp. 3213–3220, 2004. View at Publisher · View at Google Scholar · View at Scopus
  8. H. M. Beere, “'the stress of dying': the role of heat shock proteins in the regulation of apoptosis,” Journal of Cell Science, vol. 117, no. 13, pp. 2641–2651, 2004. View at Publisher · View at Google Scholar · View at Scopus
  9. M. A. Yenari, “Heat shock proteins and neuroprotection,” Advances in Experimental Medicine and Biology, vol. 513, pp. 281–299, 2002. View at Google Scholar · View at Scopus
  10. J. A. Foster and I. R. Brown, “Differential induction of heat shock mRNA in oligodendrocytes, microglia, and astrocytes following hyperthermia,” Molecular Brain Research, vol. 45, no. 2, pp. 207–218, 1997. View at Publisher · View at Google Scholar · View at Scopus
  11. S. K. Calderwood, S. S. Mambula, P. J. Gray Jr., and J. R. Theriault, “Extracellular heat shock proteins in cell signaling,” FEBS Letters, vol. 581, no. 19, pp. 3689–3694, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. P. J. Muchowski and J. L. Wacker, “Modulation of neurodegeneration by molecular chaperones,” Nature Reviews Neuroscience, vol. 6, no. 1, pp. 11–22, 2005. View at Publisher · View at Google Scholar · View at Scopus
  13. F. U. Hartl and M. Hayer-Hartl, “Protein folding. Molecular chaperones in the cytosol: from nascent chain to folded protein,” Science, vol. 295, no. 5561, pp. 1852–1858, 2002. View at Publisher · View at Google Scholar · View at Scopus
  14. S. V. Slepenkov and S. N. Witt, “The unfolding story of the Escherichia coli Hsp70 DnaK: is DnaK a holdase or an unfoldase?” Molecular Microbiology, vol. 45, no. 5, pp. 1197–1206, 2002. View at Publisher · View at Google Scholar · View at Scopus
  15. B. Bukau, J. Weissman, and A. Horwich, “Molecular chaperones and protein quality control,” Cell, vol. 125, no. 3, pp. 443–451, 2006. View at Publisher · View at Google Scholar · View at Scopus
  16. C. Wu, “Heat shock transcription factors: structure and regulation,” Annual Review of Cell and Developmental Biology, vol. 11, pp. 441–469, 1995. View at Google Scholar · View at Scopus
  17. R. I. Morimoto and M. Gabriella Santoro, “Stress-inducible responses and heat shock proteins: new pharmacologic targets for cytoprotection,” Nature Biotechnology, vol. 16, no. 9, pp. 833–838, 1998. View at Google Scholar · View at Scopus
  18. L. Pirkkala, P. Nykänen, and L. Sistonen, “Roles of the heat shock transcription factors in regulation of the heat shock response and beyond,” FASEB Journal, vol. 15, no. 7, pp. 1118–1131, 2001. View at Publisher · View at Google Scholar · View at Scopus
  19. R. Voellmy, “On mechanisms that control heat shock transcription factor activity in metazoan cells,” Cell Stress and Chaperones, vol. 9, no. 2, pp. 122–133, 2004. View at Publisher · View at Google Scholar · View at Scopus
  20. B. Wu, C. Hunt, and R. Morimoto, “Structure and expression of the human gene encoding major heat shock protein HSP70,” Molecular and Cellular Biology, vol. 5, no. 2, pp. 330–341, 1985. View at Google Scholar · View at Scopus
  21. K. L. Milarski and R. I. Morimoto, “Mutational analysis of the human HSP70 protein: distinct domains for nucleolar localization and adenosine triphosphate binding,” Journal of Cell Biology, vol. 109, no. 5, pp. 1947–1962, 1989. View at Google Scholar · View at Scopus
  22. M. T. Ryan and N. Pfanner, “Hsp70 proteins in protein translocation,” Advances in Protein Chemistry, vol. 59, pp. 223–242, 2001. View at Publisher · View at Google Scholar · View at Scopus
  23. J. C. Young, J. M. Barral, and F. U. Hartl, “More than folding: localized functions of cytosolic chaperones,” Trends in Biochemical Sciences, vol. 28, no. 10, pp. 541–547, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. W. B. Pratt and D. O. Toft, “Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery,” Experimental Biology and Medicine, vol. 228, no. 2, pp. 111–133, 2003. View at Google Scholar · View at Scopus
  25. T. G. Chappell, W. J. Welch, D. M. Schlossman, K. B. Palter, M. J. Schlesinger, and J. E. Rothman, “Uncoating ATPase is a member of the 70 kilodalton family of stress proteins,” Cell, vol. 45, no. 1, pp. 3–13, 1986. View at Google Scholar
  26. D. Straus, W. Walter, and C. A. Gross, “DnaK, DnaJ, and GrpE heat shock proteins negatively regulate heat shock gene expression by controlling the synthesis and stability of σ32,” Genes and Development, vol. 4, no. 12, pp. 2202–2209, 1990. View at Google Scholar · View at Scopus
  27. M. P. Mayer and B. Bukau, “Hsp70 chaperones: cellular functions and molecular mechanism,” Cellular and Molecular Life Sciences, vol. 62, no. 6, pp. 670–684, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. J. E. Rothman, “Polypeptide chain binding proteins: catalysts of protein folding and related processes in cells,” Cell, vol. 59, no. 4, pp. 591–601, 1989. View at Google Scholar · View at Scopus
  29. S. M. Wilbanks and D. B. McKay, “How potassium affects the activity of the molecular chaperone Hsc70. II. Potassium binds specifically in the ATPase active site,” Journal of Biological Chemistry, vol. 270, no. 5, pp. 2251–2257, 1995. View at Publisher · View at Google Scholar · View at Scopus
  30. P. Bork, C. Sander, and A. Valencia, “An ATPase domain common to prokaryotic cell cycle proteins, sugar kinases, actin, and hsp70 heat shock proteins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 16, pp. 7290–7294, 1992. View at Google Scholar · View at Scopus
  31. E. B. Bertelsena, L. Chang, J. E. Gestwicki, and E. R. P. Zuiderweg, “Solution conformation of wild-type E. coli Hsp70 (DnaK) chaperone complexed with ADP and substrate,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 21, pp. 8471–8476, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. X. Zhu, X. Zhao, W. F. Burkholder et al., “Structural analysis of substrate binding by the molecular chaperone DnaK,” Science, vol. 272, no. 5268, pp. 1606–1614, 1996. View at Google Scholar · View at Scopus
  33. M. P. Mayer, H. Schröder, S. Rüdiger, K. Paal, T. Laufen, and B. Bukau, “Multistep mechanism of substrate binding determines chaperone activity of Hsp70,” Nature Structural Biology, vol. 7, no. 7, pp. 586–593, 2000. View at Publisher · View at Google Scholar · View at Scopus
  34. D. M. Cyr, T. Langer, and M. G. Douglas, “DnaJ-like proteins: molecular chaperones and specific regulators of Hsp70,” Trends in Biochemical Sciences, vol. 19, no. 4, pp. 176–181, 1994. View at Publisher · View at Google Scholar · View at Scopus
  35. J. Rassow, O. von Ahsen, and N. Pfanner, “Molecular chaperones: towards a characterization of the heat-shock protein 70 family,” Trends in Cell Biology, vol. 7, no. 3, pp. 129–133, 1997. View at Publisher · View at Google Scholar · View at Scopus
  36. M. E. Cheetham and A. J. Caplan, “Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function,” Cell Stress and Chaperones, vol. 3, no. 1, pp. 28–36, 1998. View at Publisher · View at Google Scholar · View at Scopus
  37. K. Liberek, J. Marszalek, D. Ang, C. Georgopoulos, and M. Zylicz, “Escherichia coli DnaJ and GrpE heat shock proteins jointly stimulate ATPase activity of DnaK,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 7, pp. 2874–2878, 1991. View at Google Scholar · View at Scopus
  38. T. Langer, C. Lu, H. Echols, J. Flanagan, M. K. Hayer, and F. U. Hartl, “Successive action of DnaK, DnaJ and GroEL along the pathway of chaperone-mediated protein folding,” Nature, vol. 356, no. 6371, pp. 683–689, 1992. View at Publisher · View at Google Scholar · View at Scopus
  39. D. M. Cyr, X. Lu, and M. G. Douglas, “Regulation of Hsp70 function by a eukaryotic dnaJ homolog,” Journal of Biological Chemistry, vol. 267, no. 29, pp. 20927–20931, 1992. View at Google Scholar · View at Scopus
  40. B. Misselwitz, O. Staeck, and T. A. Rapoport, “J proteins catalytically activate Hsp70 molecules to trap a wide range of peptide sequences,” Molecular Cell, vol. 2, no. 5, pp. 593–603, 1998. View at Google Scholar · View at Scopus
  41. J. L. Brodsky and R. Schekman, “A Sec63p-BiP complex from yeast is required for protein translocation in a reconstituted proteoliposome,” Journal of Cell Biology, vol. 123, no. 6, pp. 1355–1363, 1993. View at Publisher · View at Google Scholar · View at Scopus
  42. D. M. Cyr and W. Neupert, “Roles for hsp70 in protein translocation across membranes of organelles,” EXS, vol. 77, pp. 25–40, 1996. View at Google Scholar · View at Scopus
  43. Y. Shen, L. Meunier, and L. M. Hendershot, “Identification and characterization of a novel endoplasmic reticulum (ER) DnaJ homologue, which stimulates ATPase activity of BiP in vitro and is induced by ER stress,” Journal of Biological Chemistry, vol. 277, no. 18, pp. 15947–15956, 2002. View at Publisher · View at Google Scholar
  44. J. Hohfeld, Y. Minami, and F. U. Hartl, “Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hsp40 reaction cycle,” Cell, vol. 83, no. 4, pp. 589–598, 1995. View at Google Scholar · View at Scopus
  45. M. Kabani, C. McLellan, D. A. Raynes, V. Guerriero, and J. L. Brodsky, “HspBP1, a homologue of the yeast Fes1 and Sls1 proteins, is an Hsc70 nucleotide exchange factor,” FEBS Letters, vol. 531, no. 2, pp. 339–342, 2002. View at Publisher · View at Google Scholar · View at Scopus
  46. M. Kabbage and M. B. Dickman, “The BAG proteins: a ubiquitous family of chaperone regulators,” Cellular and Molecular Life Sciences, vol. 65, no. 9, pp. 1390–1402, 2008. View at Publisher · View at Google Scholar · View at Scopus
  47. C. Harrison, “GrpE, a nucleotide exchange factor for DnaK,” Cell Stress and Chaperones, vol. 8, no. 3, pp. 218–224, 2003. View at Publisher · View at Google Scholar · View at Scopus
  48. F. A. Agarraberes and J. F. Dice, “A molecular chaperone complex at the lysosomal membrane is required for protein translocation,” Journal of Cell Science, vol. 114, no. 13, pp. 2491–2499, 2001. View at Google Scholar · View at Scopus
  49. R. Nikolay, T. Wiederkehr, W. Rist, G. Kramer, M. P. Mayer, and B. Bukau, “Dimerization of the human E3 ligase CHIP via a coiled-coil domain is essential for its activity,” Journal of Biological Chemistry, vol. 279, no. 4, pp. 2673–2678, 2004. View at Publisher · View at Google Scholar · View at Scopus
  50. G. C. Meacham, C. Patterson, W. Zhang, J. M. Younger, and D. M. Cyr, “The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation,” Nature Cell Biology, vol. 3, no. 1, pp. 100–105, 2001. View at Publisher · View at Google Scholar · View at Scopus
  51. J. Höhfeld, D. M. Cyr, and C. Patterson, “From the cradle to the grave: molecular chaperones that may choose between folding and degradation,” EMBO Reports, vol. 2, no. 10, pp. 885–890, 2001. View at Publisher · View at Google Scholar · View at Scopus
  52. P. Connell, C. A. Ballinger, J. Jiang et al., “The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins,” Nature Cell Biology, vol. 3, no. 1, pp. 93–96, 2001. View at Publisher · View at Google Scholar · View at Scopus
  53. J. Jiang, D. Cyr, R. W. Babbitt, W. C. Sessa, and C. Patterson, “Chaperone-dependent regulation of endothelial nitric-oxide synthase intracellular trafficking by the co-chaperone/ubiquitin ligase CHIP,” Journal of biological chemistry, vol. 278, no. 49, pp. 49332–49341, 2003. View at Google Scholar · View at Scopus
  54. A. Kakizuka, “Protein precipitation: a common etiology in neurodegenerative disorders?” Trends in Genetics, vol. 14, no. 10, pp. 396–402, 1998. View at Publisher · View at Google Scholar · View at Scopus
  55. S. W. Davies, M. Turmaine, B. A. Cozens et al., “Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation,” Cell, vol. 90, no. 3, pp. 537–548, 1997. View at Publisher · View at Google Scholar · View at Scopus
  56. M. DiFiglia, E. Sapp, K. O. Chase et al., “Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain,” Science, vol. 277, no. 5334, pp. 1990–1993, 1997. View at Publisher · View at Google Scholar · View at Scopus
  57. H. L. Paulson, M. K. Perez, Y. Trottier et al., “Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3,” Neuron, vol. 19, no. 2, pp. 333–344, 1997. View at Publisher · View at Google Scholar · View at Scopus
  58. F. Elefant and K. B. Palter, “Tissue-specific expression of dominant negative mutant Drosophila HSC70 causes developmental defects and lethality,” Molecular Biology of the Cell, vol. 10, no. 7, pp. 2101–2117, 1999. View at Google Scholar · View at Scopus
  59. M. D. Kaytor and S. T. Warren, “Aberrant protein deposition and neurological disease,” Journal of Biological Chemistry, vol. 274, no. 53, pp. 37507–37510, 1999. View at Publisher · View at Google Scholar · View at Scopus
  60. P. Kazemi-Esfarjani and S. Benzer, “Genetic suppression of polyglutamine toxicity in Drosophila,” Science, vol. 287, no. 5459, pp. 1837–1840, 2000. View at Publisher · View at Google Scholar · View at Scopus
  61. J. M. Warrick, H. Y. E. Chan, G. L. Gray-Board, Y. Chai, H. L. Paulson, and N. M. Bonini, “Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70,” Nature Genetics, vol. 23, no. 4, pp. 425–428, 1999. View at Publisher · View at Google Scholar · View at Scopus
  62. D. L. Stenoien, C. J. Cummings, H. P. Adams et al., “Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone,” Human Molecular Genetics, vol. 8, no. 5, pp. 731–741, 1999. View at Google Scholar · View at Scopus
  63. N. R. Jana, M. Tanaka, G. H. Wang, and N. Nukina, “Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity,” Human Molecular Genetics, vol. 9, no. 13, pp. 2009–2018, 2000. View at Google Scholar · View at Scopus
  64. S. T. Suhr, M. C. Senut, J. P. Whitelegge, K. F. Faull, D. B. Cuizon, and F. H. Gage, “Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression,” Journal of Cell Biology, vol. 153, no. 2, pp. 283–294, 2001. View at Publisher · View at Google Scholar · View at Scopus
  65. K. Mitsui, H. Nakayama, T. Akagi et al., “Purification of polyglutamine aggregates and identification of elongation factor-1α and heat shock protein 84 as aggregate-interacting proteins,” Journal of Neuroscience, vol. 22, no. 21, pp. 9267–9277, 2002. View at Google Scholar · View at Scopus
  66. D. G. Hay, K. Sathasivam, S. Tobaben et al., “Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach,” Human Molecular Genetics, vol. 13, no. 13, pp. 1389–1405, 2004. View at Publisher · View at Google Scholar · View at Scopus
  67. M. Watanabe, M. Dykes-Hoberg, V. Cizewski Culotta, D. L. Price, P. C. Wong, and J. D. Rothstein, “Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues,” Neurobiology of Disease, vol. 8, no. 6, pp. 933–941, 2001. View at Publisher · View at Google Scholar · View at Scopus
  68. M. Tanaka, Y. M. Kim, G. Lee, E. Junn, T. Iwatsubo, and M. M. Mouradian, “Aggresomes formed by α-synuclein and synphilin-1 are cytoprotective,” Journal of Biological Chemistry, vol. 279, no. 6, pp. 4625–4631, 2004. View at Publisher · View at Google Scholar · View at Scopus
  69. F. Dou, W. J. Netzer, K. Tanemura et al., “Chaperones increase association of tau protein with microtubules,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 2, pp. 721–726, 2003. View at Publisher · View at Google Scholar · View at Scopus
  70. J. B. Martin, “Molecular basis of the neurodegenerative disorders,” New England Journal of Medicine, vol. 340, no. 25, pp. 1970–1980, 1999. View at Publisher · View at Google Scholar · View at Scopus
  71. A. H. V. Schapira and C. W. Olanow, “Neuroprotection in parkinson disease: mysteries, myths, and misconceptions,” Journal of the American Medical Association, vol. 291, no. 3, pp. 358–364, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. L. I. Bruijn, T. M. Miller, and D. W. Cleveland, “Unraveling the mechanisms involved in motor neuron degeneration in ALS,” Annual Review of Neuroscience, vol. 27, pp. 723–749, 2004. View at Publisher · View at Google Scholar · View at Scopus
  73. Y. Nagai, N. Fujikake, H. A. Popiel, and K. Wada, “Induction of molecular chaperones as a therapeutic strategy for the polyglutamine diseases,” Current Pharmaceutical Biotechnology, vol. 11, no. 2, pp. 188–197, 2010. View at Publisher · View at Google Scholar · View at Scopus
  74. S. Chen and I. R. Brown, “Neuronal expression of constitutive heat shock proteins: implications for neurodegenerative diseases,” Cell Stress and Chaperones, vol. 12, no. 1, pp. 51–58, 2007. View at Publisher · View at Google Scholar · View at Scopus
  75. A. M. Chow and I. R. Brown, “Induction of heat shock proteins in differentiated human and rodent neurons by celastrol,” Cell Stress and Chaperones, vol. 12, no. 3, pp. 237–244, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. C. M. Dobson, “Protein folding and misfolding,” Nature, vol. 426, no. 6968, pp. 884–890, 2003. View at Publisher · View at Google Scholar · View at Scopus
  77. T. F. Outeiro, P. Putcha, J. E. Tetzlaff et al., “Formation of toxic oligomeric α-synuclein species in living cells,” PLoS ONE, vol. 3, no. 4, article e1867, 2008. View at Publisher · View at Google Scholar · View at Scopus
  78. R. Kayed, E. Head, J. L. Thompson et al., “Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis,” Science, vol. 300, no. 5618, pp. 486–489, 2003. View at Publisher · View at Google Scholar · View at Scopus
  79. N. Fujikake, Y. Nagai, H. A. Popiel, Y. Okamoto, M. Yamaguchi, and T. Toda, “Heat shock transcription factor 1-activating compounds suppress polyglutamine-induced neurodegeneration through induction of multiple molecular chaperones,” Journal of Biological Chemistry, vol. 283, no. 38, pp. 26188–26197, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. J. L. Wacker, S. Y. Huang, A. D. Steele et al., “Loss of Hsp70 exacerbates pathogenesis but not levels of fibrillar aggregates in a mouse model of Huntington's disease,” Journal of Neuroscience, vol. 29, no. 28, pp. 9104–9114, 2009. View at Publisher · View at Google Scholar · View at Scopus
  81. C. J. Cummings, M. A. Mancini, B. Antalffy, D. B. DeFranco, H. T. Orr, and H. Y. Zoghbi, “Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1,” Nature Genetics, vol. 19, no. 2, pp. 148–154, 1998. View at Publisher · View at Google Scholar · View at Scopus
  82. Y. Chai, S. L. Koppenhafer, N. M. Bonini, and H. L. Paulson, “Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease,” Journal of Neuroscience, vol. 19, no. 23, pp. 10338–10347, 1999. View at Google Scholar · View at Scopus
  83. G. Yvert, K. S. Lindenberg, S. Picaud, G. B. Landwehrmeyer, J. A. Sahel, and J. L. Mandel, “Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice,” Human Molecular Genetics, vol. 9, no. 17, pp. 2491–2506, 2000. View at Google Scholar · View at Scopus
  84. T. Schmidt, K. S. Lindenberg, A. Krebs et al., “Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions,” Annals of Neurology, vol. 51, no. 3, pp. 302–310, 2002. View at Publisher · View at Google Scholar · View at Scopus
  85. T. Yamanaka, H. Miyazaki, F. Oyama et al., “Mutant Huntingtin reduces HSP70 expression through the sequestration of NF-Y transcription factor,” EMBO Journal, vol. 27, no. 6, pp. 827–839, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. N. Y. M. Huen and H. Y. E. Chan, “Dynamic regulation of molecular chaperone gene expression in polyglutamine disease,” Biochemical and Biophysical Research Communications, vol. 334, no. 4, pp. 1074–1084, 2005. View at Publisher · View at Google Scholar · View at Scopus
  87. K. Tagawa, S. Marubuchi, M. L. Qi et al., “The induction levels of heat shock protein 70 differentiate the vulnerabilities to mutant huntingtin among neuronal subtypes,” Journal of Neuroscience, vol. 27, no. 4, pp. 868–880, 2007. View at Publisher · View at Google Scholar · View at Scopus
  88. J. M. Warrick, H. L. Paulson, G. L. Gray-Board et al., “Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila,” Cell, vol. 93, no. 6, pp. 939–949, 1998. View at Publisher · View at Google Scholar · View at Scopus
  89. S. Krobitsch and S. Lindquist, “Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 4, pp. 1589–1594, 2000. View at Publisher · View at Google Scholar · View at Scopus
  90. P. J. Muchowski, G. Schaffar, A. Sittler, E. E. Wanker, M. K. Hayer-Hartl, and F. U. Hartl, “Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 14, pp. 7841–7846, 2000. View at Publisher · View at Google Scholar · View at Scopus
  91. Y. Kobayashi and G. Sobue, “Protective effect of chaperones on polyglutamine diseases,” Brain Research Bulletin, vol. 56, no. 3-4, pp. 165–168, 2001. View at Publisher · View at Google Scholar · View at Scopus
  92. H. Zhou, S. H. Li, and X. J. Li, “Chaperone suppression of cellular toxicity of huntingtin is independent of polyglutamine aggregation,” Journal of Biological Chemistry, vol. 276, no. 51, pp. 48417–48424, 2001. View at Google Scholar · View at Scopus
  93. S. Gunawardena, L. S. Her, R. G. Brusch et al., “Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila,” Neuron, vol. 40, no. 1, pp. 25–40, 2003. View at Publisher · View at Google Scholar · View at Scopus
  94. E. A. A. Nollen, S. M. Garcia, G. van Haaften et al., “Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 17, pp. 6403–6408, 2004. View at Publisher · View at Google Scholar · View at Scopus
  95. C. J. Cummings, Y. Sun, P. Opal et al., “Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice,” Human Molecular Genetics, vol. 10, no. 14, pp. 1511–1518, 2001. View at Google Scholar · View at Scopus
  96. H. Adachi, M. Katsuno, M. Minamiyama et al., “Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein,” Journal of Neuroscience, vol. 23, no. 6, pp. 2203–2211, 2003. View at Google Scholar · View at Scopus
  97. O. Hansson, J. Nylandsted, R. F. Castilho, M. Leist, M. Jäättelä, and P. Brundin, “Overexpression of heat shock protein 70 in R6/2 Huntington's disease mice has only modest effects on disease progression,” Brain Research, vol. 970, no. 1-2, pp. 47–57, 2003. View at Publisher · View at Google Scholar · View at Scopus
  98. Y. Kobayashi, A. Kume, M. Li et al., “Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract,” Journal of Biological Chemistry, vol. 275, no. 12, pp. 8772–8778, 2000. View at Publisher · View at Google Scholar · View at Scopus
  99. J. L. Wacker, M. H. Zareie, H. Fong, M. Sarikaya, and P. J. Muchowski, “Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer,” Nature Structural & Molecular Biology, vol. 11, no. 12, pp. 1215–1222, 2004. View at Google Scholar · View at Scopus
  100. M. Rimoldi, A. Servadio, and V. Zimarino, “Analysis of heat shock transcription factor for suppression of polyglutamine toxicity,” Brain Research Bulletin, vol. 56, no. 3-4, pp. 353–362, 2001. View at Publisher · View at Google Scholar · View at Scopus
  101. M. Fujimoto, E. Takaki, T. Hayashi et al., “Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models,” Journal of Biological Chemistry, vol. 280, no. 41, pp. 34908–34916, 2005. View at Publisher · View at Google Scholar · View at Scopus
  102. T. Lebouvier, T. Chaumette, S. Paillusson et al., “The second brain and Parkinson's disease,” European Journal of Neuroscience, vol. 30, no. 5, pp. 735–741, 2009. View at Publisher · View at Google Scholar · View at Scopus
  103. L. C. Serpell, J. Berriman, R. Jakes, M. Goedert, and R. A. Crowther, “Fiber diffraction of synthetic α-synuclein filaments shows amyloid-like cross-β conformation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 9, pp. 4897–4902, 2000. View at Publisher · View at Google Scholar
  104. B. Caughey and P. T. Lansbury, “Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders,” Annual Review of Neuroscience, vol. 26, pp. 267–298, 2003. View at Publisher · View at Google Scholar · View at Scopus
  105. A. L. Fink, “The aggregation and fibrillation of α-synuclein,” Accounts of Chemical Research, vol. 39, no. 9, pp. 628–634, 2006. View at Publisher · View at Google Scholar · View at Scopus
  106. P. K. Auluck, H. Y. E. Chan, J. Q. Trojanowski, V. M.-Y. Lee, and N. M. Bonini, “Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease,” Science, vol. 295, no. 5556, pp. 865–868, 2002. View at Publisher · View at Google Scholar
  107. J. Klucken, Y. Shin, E. Masliah, B. T. Hyman, and P. J. McLean, “Hsp70 reduces α-synuclein aggregation and toxicity,” Journal of Biological Chemistry, vol. 279, no. 24, pp. 25497–25502, 2004. View at Publisher · View at Google Scholar · View at Scopus
  108. C. Huang, H. Cheng, S. Hao et al., “Heat shock protein 70 inhibits α-synuclein Fibril formation via interactions with diverse intermediates,” Journal of Molecular Biology, vol. 364, no. 3, pp. 323–336, 2006. View at Publisher · View at Google Scholar
  109. M. M. Dedmon, J. Christodoulou, M. R. Wilson, and C. M. Dobson, “Heat shock protein 70 inhibits α-synuclein fibril formation via preferential binding to prefibrillar species,” Journal of Biological Chemistry, vol. 280, no. 15, pp. 14733–14740, 2005. View at Publisher · View at Google Scholar
  110. C. Roodveldt, C. W. Bertoncini, A. Andersson et al., “Chaperone proteostasis in Parkinson's disease: stabilization of the Hsp70/α-synuclein complex by Hip,” EMBO Journal, vol. 28, no. 23, pp. 3758–3770, 2009. View at Publisher · View at Google Scholar · View at Scopus
  111. C. R. Scherzer, A. C. Eklund, L. J. Morse et al., “Molecular markers of early Parkinson's disease based on gene expression in blood,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 3, pp. 955–960, 2007. View at Publisher · View at Google Scholar · View at Scopus
  112. A. Ahmad, “DnaK/DnaJ/GrpE of Hsp70 system have differing effects on α-synuclein fibrillation involved in Parkinson's disease,” International Journal of Biological Macromolecules, vol. 46, no. 2, pp. 275–279, 2010. View at Publisher · View at Google Scholar
  113. K. C. Luk, I. P. Mills, J. Q. Trojanowski, and V. M.-Y. Lee, “Interactions between Hsp70 and the hydrophobic core of α-synuclein inhibit fibril assembly,” Biochemistry, vol. 47, no. 47, pp. 12614–12625, 2008. View at Publisher · View at Google Scholar
  114. S. N. Witt, “Hsp70 molecular chaperons and Parkinson's disease,” Biopolymers, vol. 93, no. 3, pp. 218–228, 2010. View at Publisher · View at Google Scholar
  115. D. M. Walsh and D. J. Selkoe, “Oligomers in the brain: the emerging role of soluble protein aggregates in neurodegeneration,” Protein and Peptide Letters, vol. 11, no. 3, pp. 213–228, 2004. View at Publisher · View at Google Scholar · View at Scopus
  116. C. G. Evans, S. Wisén, and J. E. Gestwicki, “Heat shock proteins 70 and 90 inhibit early stages of amyloid β-(1–42) aggregation in vitro,” Journal of Biological Chemistry, vol. 281, no. 44, pp. 33182–33191, 2006. View at Publisher · View at Google Scholar
  117. J. I. Kakimura, Y. Kitamura, K. Takata et al., “Microglial activation and amyloid-β clearance induced by exogenous heat-shock proteins,” FASEB Journal, vol. 16, no. 6, pp. 601–603, 2002. View at Publisher · View at Google Scholar · View at Scopus
  118. J. P. Julien, “Amyotrophic lateral sclerosis: unfolding the toxicity of the misfolded,” Cell, vol. 104, no. 4, pp. 581–591, 2001. View at Publisher · View at Google Scholar · View at Scopus
  119. G. A. Shinder, M. C. Lacourse, S. Minotti, and H. D. Durham, “Mutant Cu/Zn-superoxide dismutase proteins have altered solubility and interact with heat shock/stress proteins in models of amyotrophic lateral sclerosis,” Journal of Biological Chemistry, vol. 276, no. 16, pp. 12791–12796, 2001. View at Publisher · View at Google Scholar · View at Scopus
  120. S. Zhu, I. G. Stavrovskaya, M. Drozda et al., “Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice,” Nature, vol. 417, no. 6884, pp. 74–78, 2002. View at Publisher · View at Google Scholar
  121. W. Bruening, R. Josée, B. Giasson, D. A. Figlewicz, W. E. Mushynski, and H. D. Durham, “Up-regulation of protein chaperones preserves viability of cells expressing toxic Cu/Zn-superoxide dismutase mutants associated with amyotrophic lateral sclerosis,” Journal of Neurochemistry, vol. 72, no. 2, pp. 693–699, 1999. View at Publisher · View at Google Scholar · View at Scopus
  122. Z. Batulan, D. M. Taylor, R. J. Aarons et al., “Induction of multiple heat shock proteins and neuroprotection in a primary culture model of familial amyotrophic lateral sclerosis,” Neurobiology of Disease, vol. 24, no. 2, pp. 213–225, 2006. View at Publisher · View at Google Scholar · View at Scopus
  123. Z. Dong, D. P. Wolfer, H. P. Lipp, and H. Büeler, “Hsp70 gene transfer by adeno-associated virusi inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease,” Molecular Therapy, vol. 11, no. 1, pp. 80–88, 2005. View at Publisher · View at Google Scholar · View at Scopus
  124. F. Nagel, B. H. Falkenburger, L. Tönges et al., “Tat-Hsp70 protects dopaminergic neurons in midbrain cultures and in the substantia nigra in models of Parkinson's disease,” Journal of Neurochemistry, vol. 105, no. 3, pp. 853–864, 2008. View at Publisher · View at Google Scholar · View at Scopus
  125. A. R. Stankiewicz, G. Lachapelle, C. P. Z. Foo, S. M. Radicioni, and D. D. Mosser, “Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation,” Journal of Biological Chemistry, vol. 280, no. 46, pp. 38729–38739, 2005. View at Publisher · View at Google Scholar · View at Scopus
  126. Y. Matsumori, S. M. Hong, K. Aoyama et al., “Hsp70 overexpression sequesters AIF and reduces neonatal hypoxic/ischemic brain injury,” Journal of Cerebral Blood Flow and Metabolism, vol. 25, no. 7, pp. 899–910, 2005. View at Publisher · View at Google Scholar · View at Scopus
  127. C. G. Evans, L. Chang, and J. E. Gestwicki, “Heat shock protein 70 (Hsp70) as an emerging drug target,” Journal of Medicinal Chemistry, vol. 53, no. 12, pp. 4585–4602, 2010. View at Publisher · View at Google Scholar · View at Scopus
  128. A. Sittler, R. Lurz, G. Lueder et al., “Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease,” Human Molecular Genetics, vol. 10, no. 12, pp. 1307–1315, 2001. View at Google Scholar · View at Scopus
  129. A. Abbott, “Neurologists strike gold in drug screen effort,” Nature, vol. 417, no. 6885, p. 109, 2002. View at Google Scholar · View at Scopus
  130. J. Heemskerk, A. J. Tobin, and L. J. Bain, “Teaching old drugs new tricks. Meeting of the Neurodegeneration Drug Screening Consortium, 7-8 April 2002, Washington, DC, USA.,” Trends in Neurosciences, vol. 25, no. 10, pp. 494–496, 2002. View at Google Scholar
  131. L. Whitesell, E. G. Mimnaugh, B. de Costa, C. E. Myers, and L. M. Neckers, “Inhibition of heat shock protein HSP90-pp60(v-src) heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 18, pp. 8324–8328, 1994. View at Google Scholar · View at Scopus
  132. C. Prodromou, S. M. Roe, R. O'Brien, J. E. Ladbury, P. W. Piper, and L. H. Pearl, “Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone,” Cell, vol. 90, no. 1, pp. 65–75, 1997. View at Publisher · View at Google Scholar · View at Scopus
  133. C. E. Stebbins, A. A. Russo, C. Schneider, N. Rosen, F. U. Hartl, and N. P. Pavletich, “Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent,” Cell, vol. 89, no. 2, pp. 239–250, 1997. View at Google Scholar · View at Scopus
  134. J. Zou, Y. Guo, T. Guettouche, D. F. Smith, and R. Voellmy, “Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1,” Cell, vol. 94, no. 4, pp. 471–480, 1998. View at Google Scholar · View at Scopus
  135. X. Xiao, X. Zuo, A. A. Davis et al., “HSF1 is required for extra-embryonic development, postnatal growth and protection during inflammatory responses in mice,” EMBO Journal, vol. 18, no. 21, pp. 5943–5952, 1999. View at Publisher · View at Google Scholar · View at Scopus
  136. R. Bagatell, O. Khan, G. Paine-Murrieta, C. W. Taylor, S. Akinaga, and L. Whitesell, “Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer,” Clinical Cancer Research, vol. 7, no. 7, pp. 2076–2084, 2001. View at Google Scholar · View at Scopus
  137. A. A. Knowlton and L. Sun, “Heat-shock factor-1, steroid hormones, and regulation of heat-shock protein expression in the heart,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 280, no. 1, pp. H455–H464, 2001. View at Google Scholar · View at Scopus
  138. P. J. McLean, J. Klucken, Y. Shin, and B. T. Hyman, “Geldanamycin induces Hsp70 and prevents α-synuclein aggregation and toxicity in vitro,” Biochemical and Biophysical Research Communications, vol. 321, no. 3, pp. 665–669, 2004. View at Publisher · View at Google Scholar
  139. P. K. Auluck, M. C. Meulener, and N. M. Bonini, “Mechanisms of suppression of α-synuclein neurotoxicity by geldanamycin in Drosophila,” Journal of Biological Chemistry, vol. 280, no. 4, pp. 2873–2878, 2005. View at Publisher · View at Google Scholar · View at Scopus
  140. H. Y. Shen, J. C. He, Y. Wang, Q. Y. Huang, and J. F. Chen, “Geldanamycin induces heat shock protein 70 and protects against MPTP-induced dopaminergic neurotoxicity in mice,” Journal of Biological Chemistry, vol. 280, no. 48, pp. 39962–39969, 2005. View at Publisher · View at Google Scholar · View at Scopus
  141. J. G. Supko, R. L. Hickman, M. R. Grever, and L. Malspeis, “Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent,” Cancer Chemotherapy and Pharmacology, vol. 36, no. 4, pp. 305–315, 1995. View at Publisher · View at Google Scholar · View at Scopus
  142. E. R. Glaze, A. L. Lambert, A. C. Smith et al., “Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino) -17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance,” Cancer Chemotherapy and Pharmacology, vol. 56, no. 6, pp. 637–647, 2005. View at Publisher · View at Google Scholar · View at Scopus
  143. T. W. Schulte and L. M. Neckers, “The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin,” Cancer Chemotherapy and Pharmacology, vol. 42, no. 4, pp. 273–279, 1998. View at Publisher · View at Google Scholar · View at Scopus
  144. M. Waza, H. Adachi, M. Katsuno et al., “17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration,” Nature Medicine, vol. 11, no. 10, pp. 1088–1095, 2005. View at Publisher · View at Google Scholar · View at Scopus
  145. M. Waza, H. Adachi, M. Katsuno, M. Minamiyama, F. Tanaka, and G. Sobue, “Alleviating neurodegeneration by an anticancer agent: an Hsp90 inhibitor (17-AAG),” Annals of the New York Academy of Sciences, vol. 1086, pp. 21–34, 2006. View at Publisher · View at Google Scholar · View at Scopus
  146. K. Tokui, H. Adachi, M. Waza et al., “17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse,” Human Molecular Genetics, vol. 18, no. 5, pp. 898–910, 2009. View at Publisher · View at Google Scholar
  147. P. Rusmini, F. Simonini, V. Crippa et al., “17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy,” Neurobiology of Disease, vol. 41, no. 1, pp. 83–95, 2011. View at Publisher · View at Google Scholar
  148. M. Riedel, O. Goldbaum, L. Schwarz, S. Schmitt, and C. Richter-Landsberg, “17-AAG induces cytoplasmic α-synuclein aggregate clearance by induction of autophagy,” PLoS ONE, vol. 5, no. 1, article e8753, 2010. View at Publisher · View at Google Scholar
  149. V. Smith, E. A. Sausville, R. F. Camalier, H. H. Fiebig, and A. M. Burger, “Comparison of 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17DMAG) and 17-allylamino-17-demethoxygeldanamycin (17AAG) in vitro: effects on Hsp90 and client proteins in melanoma models,” Cancer Chemotherapy and Pharmacology, vol. 56, no. 2, pp. 126–137, 2005. View at Publisher · View at Google Scholar · View at Scopus
  150. M. Herbst and E. E. Wanker, “Small molecule inducers of heat-shock response reduce polyQ-mediated huntingtin aggregation: a possible therapeutic strategy,” Neurodegenerative Diseases, vol. 4, no. 2-3, pp. 254–260, 2007. View at Publisher · View at Google Scholar · View at Scopus
  151. M. J. Egorin, T. F. Lagattuta, D. R. Hamburger et al., “Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)- 17-demethoxygeldanamycin (NSC 707545) in CDf mice and fischer 344 rats,” Cancer Chemotherapy and Pharmacology, vol. 49, no. 1, pp. 7–19, 2002. View at Publisher · View at Google Scholar · View at Scopus
  152. M. Wetzler, J. C. Earp, M. T. Brady, M. K. Keng, and W. J. Jusko, “Synergism between arsenic trioxide and heat shock protein 90 inhibitors on signal transducer and activator of transcription protein 3 activity—pharmacodynamic drug-drug interaction modeling,” Clinical Cancer Research, vol. 13, no. 7, pp. 2261–2270, 2007. View at Publisher · View at Google Scholar
  153. L. Whitesell and P. Cook, “Stable and specific binding of heat shock protein 90 by geldanamycin disrupts glucocorticoid receptor function in intact cells,” Molecular Endocrinology, vol. 10, no. 6, pp. 705–712, 1996. View at Publisher · View at Google Scholar · View at Scopus
  154. A. Salminen, M. Lehtonen, T. Paimela, and K. Kaarniranta, “Celastrol: molecular targets of Thunder God Vine,” Biochemical and Biophysical Research Communications, vol. 394, no. 3, pp. 439–442, 2010. View at Publisher · View at Google Scholar · View at Scopus
  155. T. Zhang, A. Hamza, X. Cao et al., “A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells,” Molecular Cancer Therapeutics, vol. 7, no. 1, pp. 162–170, 2008. View at Publisher · View at Google Scholar
  156. S. D. Westerheide, J. D. Bosman, B. N. A. Mbadugha et al., “Celastrols as inducers of the heat shock response and cytoprotection,” Journal of Biological Chemistry, vol. 279, no. 53, pp. 56053–56060, 2004. View at Publisher · View at Google Scholar · View at Scopus
  157. Y. Q. Zhang and K. D. Sarge, “Celastrol inhibits polyglutamine aggregation and toxicity though induction of the heat shock response,” Journal of Molecular Medicine, vol. 85, no. 12, pp. 1421–1428, 2007. View at Publisher · View at Google Scholar · View at Scopus
  158. C. Cleren, N. Y. Calingasan, J. Chen, and M. F. Beal, “Celastrol protects against MPTP- and 3-nitropropionic acid-induced neurotoxicity,” Journal of Neurochemistry, vol. 94, no. 4, pp. 995–1004, 2005. View at Publisher · View at Google Scholar · View at Scopus
  159. M. Kiaei, K. Kipiani, S. Petri, J. Chen, N. Y. Calingasan, and M. F. Beal, “Celastrol blocks neuronal cell death and extends life in transgenic mouse model of amyotrophic lateral sclerosis,” Neurodegenerative Diseases, vol. 2, no. 5, pp. 246–254, 2005. View at Publisher · View at Google Scholar
  160. D. Paris, N. J. Ganey, V. Laporte et al., “Reduction of β-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer's disease,” Journal of Neuroinflammation, vol. 7, article 17, 2010. View at Publisher · View at Google Scholar
  161. L. Vígh, P. N. Literáti, I. Horváth et al., “Bimoclomol: a nontoxic, hydroxylamine derivative with stress protein- inducing activity and cytoprotective effects,” Nature Medicine, vol. 3, no. 10, pp. 1150–1154, 1997. View at Publisher · View at Google Scholar · View at Scopus
  162. J. Hargitai, H. Lewis, I. Boros et al., “Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1,” Biochemical and Biophysical Research Communications, vol. 307, no. 3, pp. 689–695, 2003. View at Publisher · View at Google Scholar · View at Scopus
  163. D. Kieran, B. Kalmar, J. R. T. Dick, J. Riddoch-Contreras, G. Burnstock, and L. Greensmith, “Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice,” Nature Medicine, vol. 10, no. 4, pp. 402–405, 2004. View at Publisher · View at Google Scholar · View at Scopus
  164. B. Kalmar and L. Greensmith, “Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration—evidence for neuroprotective and neurotoxic effects,” Cellular and Molecular Biology Letters, vol. 14, no. 2, pp. 319–335, 2009. View at Publisher · View at Google Scholar · View at Scopus
  165. W. Löscher, “Animal models of intractable epilepsy,” Progress in Neurobiology, vol. 53, no. 2, pp. 239–258, 1997. View at Publisher · View at Google Scholar · View at Scopus
  166. J. V. Nadler, B. W. Perry, C. Gentry, and C. W. Cotman, “Degeneration of hippocampal CA3 pyramidal cells induced by intraventricular kainic acid,” Journal of Comparative Neurology, vol. 192, no. 2, pp. 333–359, 1980. View at Google Scholar · View at Scopus
  167. J. V. Nadler, “Kainic acid as a tool for the study of temporal lobe epilepsy,” Life Sciences, vol. 29, no. 20, pp. 2031–2042, 1981. View at Google Scholar · View at Scopus
  168. W. Lothman and R. C. Collins, “Kainic acid induced limbic seizures: metabolic, behavioral, electroencephalographic and neuropathological correlates,” Brain Research, vol. 218, no. 1-2, pp. 299–318, 1981. View at Google Scholar · View at Scopus
  169. K. Vass, M. L. Berger, T. S. Nowak, W. J. Welch Jr., and H. Lassmann, “Induction of stress protein HSP70 in nerve cells after status epilepticus in the rat,” Neuroscience Letters, vol. 100, no. 1–3, pp. 259–264, 1989. View at Google Scholar · View at Scopus
  170. P. Gass, P. Prior, and M. Kiessling, “Correlation between seizure intensity and stress protein expressions after limbic epilepsy in the rat brain,” Neuroscience, vol. 65, no. 1, pp. 27–36, 1995. View at Publisher · View at Google Scholar
  171. T. Yang, C. Hsu, W. Liao, and J. S. Chuang, “Heat shock protein 70 expression in epilepsy suggests stress rather than protection,” Acta Neuropathologica, vol. 115, no. 2, pp. 219–230, 2008. View at Publisher · View at Google Scholar · View at Scopus
  172. B. T. Jeon, D. H. Lee, K. H. Kim et al., “Ketogenic diet attenuates kainic acid-induced hippocampal cell death by decreasing AMPK/ACC pathway activity and HSP70,” Neuroscience Letters, vol. 453, no. 1, pp. 49–53, 2009. View at Publisher · View at Google Scholar · View at Scopus
  173. M. A. Yenari, S. L. Fink, G. H. Sun et al., “Gene therapy with HSP72 is neuroprotective in rat models of stroke and epilepsy,” Annals of Neurology, vol. 44, no. 4, pp. 584–591, 1998. View at Publisher · View at Google Scholar · View at Scopus
  174. A. H. Broquet, G. Thomas, J. Masliah, G. Trugnan, and M. Bachelet, “Expression of the molecular chaperone Hsp70 in detergent-resistant microdomains correlates with its membrane delivery and release,” Journal of Biological Chemistry, vol. 278, no. 24, pp. 21601–21606, 2003. View at Publisher · View at Google Scholar · View at Scopus
  175. A. L. Evdonin, I. V. Guzhova, B. A. Margulis, and N. D. Medvedeva, “Phospholipse c inhibitor, u73122, stimulates release of hsp-70 stress protein from A431 human carcinoma cells,” Cancer Cell International, vol. 4, article 2, 2004. View at Publisher · View at Google Scholar
  176. L. J. Houenou, L. Li, M. Lei, C. R. Kent, and M. Tytell, “Exogenous heat shock cognate protein Hsc70 prevents axotomy-induced death of spinal sensory neurons,” Cell Stress and Chaperones, vol. 1, no. 4, pp. 161–166, 1996. View at Google Scholar · View at Scopus
  177. A. Asea, S.-K. Kraeft, E. A. Kurt-Jones et al., “HSP70 stimulates cytokine production through a CD 14-dependant pathway, demonstrating its dual role as a chaperone and cytokine,” Nature Medicine, vol. 6, no. 4, pp. 435–442, 2000. View at Publisher · View at Google Scholar
  178. I. Guzhova, K. Kislyakova, O. Moskaliova et al., “In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stress tolerance,” Brain Research, vol. 914, no. 1-2, pp. 66–73, 2001. View at Publisher · View at Google Scholar · View at Scopus
  179. G. K. Sprang and I. R. Brown, “Selective induction of a heat shock gene in fibre tracts and cerebellar neurons of the rabbit brain detected by in situ hybridization,” Brain Research, vol. 427, no. 1, pp. 89–93, 1987. View at Google Scholar · View at Scopus
  180. M. Tytell, S. G. Greenberg, and R. J. Lasek, “Heat shock-like protein is transferred from glia to axon,” Brain Research, vol. 363, no. 1, pp. 161–164, 1986. View at Google Scholar · View at Scopus
  181. L. E. Hightower and P. T. Guidon Jr., “Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins,” Journal of Cellular Physiology, vol. 138, no. 2, pp. 257–266, 1989. View at Google Scholar · View at Scopus
  182. A. D. Johnson, P. A. Berberian, and M. G. Bond, “Effect of heat shock proteins on survival of isolated aortic cells from normal and atherosclerotic cynomolgus macaques,” Atherosclerosis, vol. 84, no. 2-3, pp. 111–119, 1990. View at Google Scholar · View at Scopus
  183. A. D. Johnson, P. A. Berberian, M. Tytell, and M. G. Bond, “Differential distribution of 70-kD heat shock proteins in atherosclerosis. Its potential role in arterial SMC survival,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 15, no. 1, pp. 27–36, 1995. View at Google Scholar · View at Scopus
  184. I. V. Guzhova, A. C. V. Arnholdt, Z. A. Darieva et al., “Effects of exogenous stress protein 70 on the functional properties of human promonocytes through binding to cell surface and internalization,” Cell Stress and Chaperones, vol. 3, no. 1, pp. 67–77, 1998. View at Publisher · View at Google Scholar
  185. S. M. Fujihara and S. G. Nadler, “Intranuclear targeted delivery of functional NF-κB by 70 kDa heat shock protein,” EMBO Journal, vol. 18, no. 2, pp. 411–419, 1999. View at Publisher · View at Google Scholar · View at Scopus
  186. Q. Yu, C. R. Kent, and M. Tytell, “Retinal uptake of intravitreally injected Hsc/Hsp70 and its effect on susceptibility to light damage,” Molecular Vision, vol. 7, pp. 48–56, 2001. View at Google Scholar · View at Scopus
  187. J. L. Tidwell, L. J. Houenou, and M. Tytell, “Administration of Hsp70 in vivo inhibits motor and sensory neuron degeneration,” Cell Stress and Chaperones, vol. 9, no. 1, pp. 88–98, 2004. View at Publisher · View at Google Scholar · View at Scopus
  188. I. R. Brown, “Expression of heat shock genes (hsp70) in the mammalian nervous system,” Results and Problems in Cell Differentiation, vol. 17, pp. 217–229, 1991. View at Google Scholar · View at Scopus
  189. T. V. Novoselova, B. A. Margulis, S. S. Novoselov et al., “Treatment with extracellular HSP70/HSC70 protein can reduce polyglutamine toxicity and aggregation,” Journal of Neurochemistry, vol. 94, no. 3, pp. 597–606, 2005. View at Publisher · View at Google Scholar · View at Scopus
  190. M. B. Robinson, J. L. Tidwell, T. Gould et al., “Extracellular heat shock protein 70: a critical component for motoneuron survival,” Journal of Neuroscience, vol. 25, no. 42, pp. 9735–9745, 2005. View at Publisher · View at Google Scholar · View at Scopus
  191. M. Edbladh, P. A. R. Ekstrom, and A. Edstrom, “Retrograde axonal transport of locally synthesized proteins, e.g., actin and heat shock protein 70, in regenerating adult frog sciatic sensory axons,” Journal of Neuroscience Research, vol. 38, no. 4, pp. 424–432, 1994. View at Publisher · View at Google Scholar · View at Scopus
  192. M. Tytell, “Release of heat shock proteins (Hsps) and the effects of extracellular Hsps on neural cells and tissues,” International Journal of Hyperthermia, vol. 21, no. 5, pp. 445–455, 2005. View at Publisher · View at Google Scholar · View at Scopus
  193. D. J. Gifondorwa, M. B. Robinson, C. D. Hayes et al., “Exogenous delivery of heat shock protein 70 increases lifespan in a mouse model of amyotrophic lateral sclerosis,” Journal of Neuroscience, vol. 27, no. 48, pp. 13173–13180, 2007. View at Publisher · View at Google Scholar · View at Scopus
  194. I. V. Ekimova, L. E. Nitsinskaya, I. V. Romanova, Y. F. Pastukhov, B. A. Margulis, and I. V. Guzhova, “Exogenous protein Hsp70/Hsc70 can penetrate into brain structures and attenuate the severity of chemically-induced seizures,” Journal of Neurochemistry, vol. 115, no. 4, pp. 1035–1044, 2010. View at Publisher · View at Google Scholar
  195. R. A. Browning, “Role of the brain-stem reticular formation in tonic-clonic seizures: lesion and pharmacological studies,” Federation Proceedings, vol. 44, no. 8, pp. 2425–2431, 1985. View at Google Scholar · View at Scopus
  196. M. E. Brevard, P. Kulkarni, J. A. King, and C. F. Ferris, “Imaging the neural substrates involved in the genesis of pentylenetetrazol-induced seizures,” Epilepsia, vol. 47, no. 4, pp. 745–754, 2006. View at Publisher · View at Google Scholar · View at Scopus
  197. H. Blumenfeld, “Functional MRI studies of animal models in epilepsy,” Epilepsia, vol. 48, no. 4, pp. 18–26, 2007. View at Publisher · View at Google Scholar · View at Scopus
  198. W. Chen, U. Syldath, K. Bellmann, V. Burkart, and H. Kolb, “Human 60-kDa heat-shock protein: a danger signal to the innate immune system,” Journal of Immunology, vol. 162, no. 6, pp. 3212–3219, 1999. View at Google Scholar
  199. T. Lehner, L. A. Bergmeier, Y. Wang et al., “Heat shock proteins generate β-chemokines which function as innate adjuvants enhancing adaptive immunity,” European Journal of Immunology, vol. 30, no. 2, pp. 594–603, 2000. View at Publisher · View at Google Scholar
  200. Y. Wang, C. G. Kelly, J. T. Karttunen et al., “Cd40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines,” Immunity, vol. 15, no. 6, pp. 971–983, 2001. View at Publisher · View at Google Scholar · View at Scopus
  201. H. Singh-Jasuja, N. Hilf, H. U. Scherer et al., “The heat shock protein gp96: a receptor-targeted cross-priming carrier and activator of dendritic cells,” Cell Stress and Chaperones, vol. 5, no. 5, pp. 462–470, 2000. View at Publisher · View at Google Scholar · View at Scopus
  202. R. A. Floto, P. A. MacAry, J. M. Boname et al., “Dendritic cell stimulation by mycobacterial Hsp70 is mediated through CCR5,” Science, vol. 314, no. 5798, pp. 454–458, 2006. View at Publisher · View at Google Scholar
  203. M. P. Mycko, H. Cwiklinska, A. Walczak, C. Libert, C. S. Raine, and K. W. Selmaj, “A heat shock protein gene (Hsp70.1) is critically involved in the generation of the immune response to myelin antigen,” European Journal of Immunology, vol. 38, no. 7, pp. 1999–2013, 2008. View at Publisher · View at Google Scholar · View at Scopus
  204. P. K. Srivastava, “Immunotherapy of human cancer: lessons from mice,” Nature Immunology, vol. 1, no. 5, pp. 363–366, 2000. View at Google Scholar · View at Scopus
  205. A. D. Wells and M. Malkovsky, “Heat shock proteins, tumor immunogenicity and antigen presentation: an integrated view,” Immunology Today, vol. 21, no. 3, pp. 129–132, 2000. View at Publisher · View at Google Scholar · View at Scopus
  206. H. Singh-Jasuja, N. Hilf, D. Arnold-Schild, and H. Schild, “The role of heat shock proteins and their receptors in the activation of the immune system,” Biological Chemistry, vol. 382, no. 4, pp. 629–636, 2001. View at Publisher · View at Google Scholar · View at Scopus
  207. Z. Li, A. Menoret, and P. Srivastava, “Roles of heat-shock proteins in antigen presentation and cross-presentation,” Current Opinion in Immunology, vol. 14, no. 1, pp. 45–51, 2002. View at Publisher · View at Google Scholar · View at Scopus
  208. P. Srivastava, “Roles of heat-shock proteins in innate and adaptive immunity,” Nature Reviews Immunology, vol. 2, no. 3, pp. 185–194, 2002. View at Google Scholar · View at Scopus
  209. M. P. Mycko, H. Cwiklinska, J. Szymanski et al., “Inducible heat shock protein 70 promotes myelin autoantigen presentation by the HLA class II,” Journal of Immunology, vol. 172, no. 1, pp. 202–213, 2004. View at Google Scholar · View at Scopus
  210. H. Udono and P. K. Srivastava, “Heat shock protein 70-associated peptides elicit specific cancer immunity,” Journal of Experimental Medicine, vol. 178, no. 4, pp. 1391–1396, 1993. View at Google Scholar · View at Scopus
  211. F. Castellino, P. E. Boucher, K. Eichelberg et al., “Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways,” Journal of Experimental Medicine, vol. 191, no. 11, pp. 1957–1964, 2000. View at Publisher · View at Google Scholar · View at Scopus
  212. D. Chen and M. J. Androlewicz, “Heat shock protein 70 moderately enhances peptide binding and transport by the transporter associated with antigen processing,” Immunology Letters, vol. 75, no. 2, pp. 143–148, 2001. View at Publisher · View at Google Scholar · View at Scopus
  213. H. F. McFarland and R. Martin, “Multiple sclerosis: a complicated picture of autoimmunity,” Nature Immunology, vol. 8, no. 9, pp. 913–919, 2007. View at Publisher · View at Google Scholar · View at Scopus
  214. S. I. Yokota, S. Chiba, H. Furuyama, and N. Fujii, “Cerebrospinal fluids containing anti-HSP70 autoantibodies from multiple sclerosis patients augment HSP70-induced proinflammatory cytokine production in monocytic cells,” Journal of Neuroimmunology, vol. 218, no. 1-2, pp. 129–133, 2010. View at Publisher · View at Google Scholar · View at Scopus
  215. D. Johnson, D. A. Hafler, R. J. Fallis et al., “Cell-mediated immunity to myelin-associated glycoprotein, proteolipid protein, and myelin basic protein in multiple sclerosis,” Journal of Neuroimmunology, vol. 13, no. 1, pp. 99–108, 1986. View at Google Scholar
  216. J. Sun, H. Link, T. Olsson et al., “T and B cell responses to myelin-oligodendrocyte glycoprotein in multiple sclerosis,” Journal of Immunology, vol. 146, no. 5, pp. 1490–1495, 1991. View at Google Scholar · View at Scopus
  217. J. L. Trotter, W. F. Hickey, R. C. van der Veen, and L. Sulze, “Peripheral blood mononuclear cells from multiple sclerosis patients recognize myelin proteolipid protein and selected peptides,” Journal of Neuroimmunology, vol. 33, no. 1, pp. 55–62, 1991. View at Publisher · View at Google Scholar · View at Scopus
  218. J. Correale, W. Gilmore, M. McMillan et al., “Patterns of cytokine secretion by autoreactive proteolipid protein- specific T cell clones during the course of multiple sclerosis,” Journal of Immunology, vol. 154, no. 6, pp. 2959–2968, 1995. View at Google Scholar · View at Scopus
  219. G. Birnbaum, L. Kotilinek, P. Schlievert et al., “Heat shock proteins and experimental autoimmune encephalomyelitis (EAE): I. Immunization with a peptide of the myelin protein 2′,3′ cyclic nucleotide 3′ phosphodiesterase that is cross-reactive with a heat shock protein alters the course of EAE,” Journal of Neuroscience Research, vol. 44, no. 4, pp. 381–396, 1996. View at Google Scholar · View at Scopus
  220. J. J. Bajramović, A. C. Plomp, A. van der Goes et al., “Presentation of αB-crystallin to T cells in active multiple sclerosis lesions: an early event following inflammatory demyelination,” Journal of Immunology, vol. 164, no. 8, pp. 4359–4366, 2000. View at Google Scholar
  221. M. Sospedra and R. Martin, “Immunology of multiple sclerosis,” Annual Review of Immunology, vol. 23, pp. 683–747, 2005. View at Publisher · View at Google Scholar · View at Scopus
  222. K. Selmaj, C. F. Brosnan, and C. S. Raine, “Colocalization of lymphocytes bearing γδ T-cell receptor and heat shock protein hsp65+ oligodendrocytes in multiple sclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 15, pp. 6452–6456, 1991. View at Publisher · View at Google Scholar
  223. K. Selmaj, C. F. Brosnan, and C. S. Raine, “Expression of heat shock protein-65 by oligodendrocytes in vivo and in vitro: implications for multiple sclerosis,” Neurology, vol. 42, no. 4, pp. 795–800, 1992. View at Google Scholar · View at Scopus
  224. D. A. Aquino, E. Capello, J. Weisstein et al., “Multiple sclerosis: altered expression of 70- and 27-kDa heat shock proteins in lesions and myelin,” Journal of Neuropathology and Experimental Neurology, vol. 56, no. 6, pp. 664–672, 1997. View at Google Scholar · View at Scopus
  225. J. J. Bajramović, H. Lassmann, and J. M. van Noort, “Expression of αB-crystallin in glia cells during lesional development in multiple sclerosis,” Journal of Neuroimmunology, vol. 78, no. 1-2, pp. 143–151, 1997. View at Publisher · View at Google Scholar · View at Scopus
  226. H. Cwiklinska, M. P. Mycko, O. Luvsannorov et al., “Heat shock protein 70 associations with myelin basic protein and proteolipid protein in multiple sclerosis brains,” International Immunology, vol. 15, no. 2, pp. 241–249, 2003. View at Publisher · View at Google Scholar · View at Scopus
  227. V. K. Kuchroo, A. C. Anderson, H. Waldner, M. Munder, E. Bettelli, and L. B. Nicholson, “T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire,” Annual Review of Immunology, vol. 20, pp. 101–123, 2002. View at Publisher · View at Google Scholar · View at Scopus
  228. R. Pedotti, J. J. de Voss, L. Steinman, and S. J. Galli, “Involvement of both 'allergic' and 'autoimmune' mechanisms in EAE, MS and other autoimmune diseases,” Trends in Immunology, vol. 24, no. 9, pp. 479–484, 2003. View at Publisher · View at Google Scholar · View at Scopus
  229. R. Martin, H. F. McFarland, and D. E. McFarlin, “Immunological aspects of demyelinating diseases,” Annual Review of Immunology, vol. 10, pp. 153–187, 1992. View at Google Scholar · View at Scopus
  230. C. F. Brosnan, L. Battistini, Y. L. Gao, C. S. Raine, and D. A. Aquino, “Heat shock proteins and multiple sclerosis: a review,” Journal of Neuropathology and Experimental Neurology, vol. 55, no. 4, pp. 389–402, 1996. View at Google Scholar · View at Scopus
  231. D. A. Aquino, A. A. Klipfel, C. F. Brosnan, and W. T. Norton, “The 70-kDa heat shock cognate protein (HSC70) is a major constituent of the central nervous system and is up-regulated only at the mRNA level in acute experimental autoimmune encephalomyelitis,” Journal of Neurochemistry, vol. 61, no. 4, pp. 1340–1348, 1993. View at Google Scholar · View at Scopus
  232. C. Stadelmann, S. Ludwin, T. Tabira et al., “Tissue preconditioning may explain concentric lesions in Baló's type of multiple sclerosis,” Brain, vol. 128, no. 5, pp. 979–987, 2005. View at Publisher · View at Google Scholar · View at Scopus
  233. H. Cwiklinska, M. P. Mycko, B. Szymanska, M. Matysiak, and K. W. Selmaj, “Aberrant stress-induced Hsp70 expression in immune cells in multiple sclerosis,” Journal of Neuroscience Research, vol. 88, no. 14, pp. 3102–3110, 2010. View at Publisher · View at Google Scholar
  234. W. Chen, U. Syldath, K. Bellmann, V. Burkart, and H. Kolb, “Human 60-kDa heat-shock protein: a danger signal to the innate immune system,” Journal of Immunology, vol. 162, no. 6, pp. 3212–3219, 1999. View at Google Scholar · View at Scopus
  235. N. Panjwani, O. Akbari, S. Garcia, M. Brazil, and B. Stockinger, “The HSC73 molecular chaperone: involvement in MHC class II antigen presentation,” Journal of Immunology, vol. 163, no. 4, pp. 1936–1942, 1999. View at Google Scholar · View at Scopus
  236. A. A. R. Tobian, D. H. Canaday, and C. V. Harding, “Bacterial heat shock proteins enhance class II MHC antigen processing and presentation of chaperoned peptides to CD4+ T cells,” Journal of Immunology, vol. 173, no. 8, pp. 5130–5137, 2004. View at Google Scholar · View at Scopus
  237. R. Wang, J. T. Kovalchin, P. Muhlenkamp, and R. Y. Chandawarkar, “Exogenous heat shock protein 70 binds macrophage lipid raft microdomain and stimulates phagocytosis, processing, and MHC-II presentation of antigens,” Blood, vol. 107, no. 4, pp. 1636–1642, 2006. View at Publisher · View at Google Scholar · View at Scopus
  238. M. Haug, C. P. Schepp, H. Kalbacher, G. E. Dannecker, and U. Holzer, “70-kDa heat shock proteins: specific interactions with HLA-DR molecules and their peptide fragments,” European Journal of Immunology, vol. 37, no. 4, pp. 1053–1063, 2007. View at Publisher · View at Google Scholar · View at Scopus
  239. N. Zietara, M. Łyszkiewicz, N. Gekara et al., “Absence of IFN-β impairs antigen presentation capacity of splenic dendritic cells via down-regulation of heat shock protein 70,” Journal of Immunology, vol. 183, no. 2, pp. 1099–1109, 2009. View at Publisher · View at Google Scholar
  240. C. Lagaudrière-Gesbert, S. L. Newmyer, T. F. Gregers, O. Bakke, and H. L. Ploegh, “Uncoating ATPase Hsc70 is recruited by invariant chain and controls the size of endocytic compartments,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 3, pp. 1515–1520, 2002. View at Publisher · View at Google Scholar
  241. B. T. Lund, Y. Chakryan, N. Ashikian et al., “Association of MBP peptides with Hsp70 in normal appearing human white matter,” Journal of the Neurological Sciences, vol. 249, no. 2, pp. 122–134, 2006. View at Publisher · View at Google Scholar · View at Scopus
  242. G. Galazka, M. Stasiolek, A. Walczak et al., “Brain-derived heat shock protein 70-peptide complexes induce NK cell-dependent tolerance to experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 176, no. 3, pp. 1588–1599, 2006. View at Google Scholar · View at Scopus
  243. P. Kizelsztein, S. Komarnytsky, and I. Raskin, “Oral administration of triptolide ameliorates the clinical signs of experimental autoimmune encephalomyelitis (EAE) by induction of HSP70 and stabilization of NF-κB/IκBα transcriptional complex,” Journal of Neuroimmunology, vol. 217, no. 1-2, pp. 28–37, 2009. View at Publisher · View at Google Scholar · View at Scopus