Currently available therapies for adult onset neurodegenerative diseases provide symptomatic relief but do not modify disease progression. Here we explore a new neuroprotective approach based on drugs targeting chaperone-directed protein quality control. Critical target proteins that unfold and aggregate in these diseases, such as the polyglutamine androgen receptor in spinal and bulbar muscular atrophy, huntingtin in Huntington's disease, α-synuclein in Parkinson's disease, and tau in Alzheimer's disease, are client proteins of heat shock protein 90 (Hsp90), and their turnover is regulated by the protein quality control function of the Hsp90/Hsp70-based chaperone machinery. Hsp90 and Hsp70 have opposing effects on client protein stability in protein quality control; Hsp90 stabilizes the clients and inhibits their ubiquitination, whereas Hsp70 promotes ubiquitination dependent on CHIP (C terminus of Hsc70-interacting protein) and proteasomal degradation. We discuss how drugs that modulate proteostasis by inhibiting Hsp90 function or promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models.


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Literature Cited

  1. Pratt WB, Toft DO. 1.  2003. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp. Biol. Med. (Maywood) 228:111–33 [Google Scholar]
  2. Sherman MY, Goldberg AL. 2.  2001. Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 29:15–32 [Google Scholar]
  3. Isaacs JS, Xu W, Neckers L. 3.  2003. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 3:213–17 [Google Scholar]
  4. Pratt WB, Morishima Y, Peng HM, Osawa Y. 4.  2010. Proposal for a role of the Hsp90/Hsp70-based chaperone machinery in making triage decisions when proteins undergo oxidative and toxic damage. Exp. Biol. Med. (Maywood) 235:278–89 [Google Scholar]
  5. Pratt WB, Morishima Y, Osawa Y. 5.  2008. The Hsp90 chaperone machinery regulates signaling by modulating ligand binding clefts. J. Biol. Chem. 283:22885–89 [Google Scholar]
  6. Peng HM, Morishima Y, Pratt WB, Osawa Y. 6.  2012. Modulation of heme/substrate binding cleft of neuronal nitric-oxide synthase (nNOS) regulates binding of Hsp90 and Hsp70 proteins and nNOS ubiquitination. J. Biol. Chem. 287:1556–65 [Google Scholar]
  7. Hershko A, Ciechanover A. 7.  1998. The ubiquitin system. Annu. Rev. Biochem. 67:425–79 [Google Scholar]
  8. Cyr DM, Höhfeld J, Patterson C. 8.  2002. Protein quality control: U-box-containing E3 ubiquitin ligases join the fold. Trends Biochem. Sci. 27:368–75 [Google Scholar]
  9. Connell P, Ballinger CA, Jiang J, Wu Y, Thomson LJ. 9.  et al. 2001. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat. Cell Biol. 3:93–96 [Google Scholar]
  10. Zhou P, Fernandes N, Dodge IL, Redd AL, Rao N. 10.  et al. 2003. ErbB2 degradation mediated by the co-chaperone protein CHIP. J. Biol. Chem. 278:13829–37 [Google Scholar]
  11. Jana NR, Dikshit P, Goswami A, Kotliarova S, Murata S. 11.  et al. 2005. Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes. J. Biol. Chem. 280:11635–40 [Google Scholar]
  12. Morishima Y, Wang AM, Yu Z, Pratt WB, Osawa Y, Lieberman AP. 12.  2008. CHIP deletion reveals functional redundancy of E3 ligases in promoting degradation of both signaling proteins and expanded glutamine proteins. Hum. Mol. Genet. 17:3942–52 [Google Scholar]
  13. Tateishi Y, Kawabe Y, Chiba T, Murata S, Ishikawa K. 13.  et al. 2004. Ligand-dependent switching of ubiquitin-proteasome pathways for estrogen receptor. EMBO J. 23:4813–23 [Google Scholar]
  14. Höhfeld J, Cyr DM, Patterson C. 14.  2001. From the cradle to the grave: molecular chaperones that may choose between folding and degradation. EMBO Rep. 2:885–90 [Google Scholar]
  15. Peng HM, Morishima Y, Clapp KM, Lau M, Pratt WB, Osawa Y. 15.  2009. Dynamic cycling with Hsp90 stabilizes neuronal nitric oxide synthase through calmodulin-dependent inhibition of ubiquitination. Biochemistry 48:8483–90 [Google Scholar]
  16. Pratt WB, Toft DO. 16.  1997. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr. Rev. 18:306–60 [Google Scholar]
  17. Stancato LF, Chow YH, Hutchinson KA, Perdew GH, Jove R, Pratt WB. 17.  1993. Raf exists in a native heterocomplex with hsp90 and p50 that can be reconstituted in a cell-free system. J. Biol. Chem. 268:21711–16 [Google Scholar]
  18. Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M. 18.  et al. 2001. Sensitivity of mature ErbB2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J. Biol. Chem. 276:3702–8 [Google Scholar]
  19. Citri A, Alroy I, Lavi S, Rubin C, Xu W. 19.  et al. 2002. Drug-induced ubiquitylation and degradation of ErbB2 receptor tyrosine kinases: implications for cancer therapy. EMBO J. 21:2407–17 [Google Scholar]
  20. Wijayaratne AL, McDonnell DP. 20.  2001. The human estrogen receptor-α is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators. J. Biol. Chem. 276:35684–92 [Google Scholar]
  21. Peng HM, Morishima Y, Jenkins GJ, Dunbar AY, Lau M. 21.  et al. 2004. Ubiquitylation of neuronal nitric-oxide synthase by CHIP, a chaperone-dependent E3 ligase. J. Biol. Chem. 279:52970–77 [Google Scholar]
  22. Fan M, Park A, Nephew KP. 22.  2005. CHIP (carboxyl terminus of Hsc70-interacting protein) promotes basal and geldanamycin-induced degradation of estrogen receptor-α. Mol. Endocrinol. 19:2901–14 [Google Scholar]
  23. Whitesell L, Lindquist SL. 23.  2005. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5:761–72 [Google Scholar]
  24. Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM. 24.  1994. Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc. Natl. Acad. Sci. USA 91:8324–28 [Google Scholar]
  25. Sepp-Lorenzino L, Ma Z, Lebwohl DE, Vinitsky A, Rosen N. 25.  1995. Herbimycin A induces the 20 S proteasome- and ubiquitin-dependent degradation of receptor tyrosine kinases. J. Biol. Chem. 270:16580–87 [Google Scholar]
  26. Mimnaugh EG, Chavany C, Neckers L. 26.  1996. Polyubiquitination and proteasomal degradation of the p185c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. J. Biol. Chem. 271:22796–801 [Google Scholar]
  27. Dutta R, Inouye M. 27.  2000. GHKL, an emergent ATPase/kinase superfamily. Trends Biochem. Sci. 25:24–28 [Google Scholar]
  28. Roe SM, Prodromou C, O'Brien R, Ladbury JE, Piper PW, Pearl LH. 28.  1999. Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J. Med. Chem. 42:260–66 [Google Scholar]
  29. Neckers L, Workman P. 29.  2012. Hsp90 molecular chaperone inhibitors: are we there yet?. Clin. Cancer Res. 18:64–76 [Google Scholar]
  30. Klucken J, Shin Y, Masliah E, Hyman BT, McLean PJ. 30.  2004. Hsp70 reduces α-synuclein aggregation and toxicity. J. Biol. Chem. 279:25497–502 [Google Scholar]
  31. Jana NR, Tanaka M, Wang G, Nukina N. 31.  2000. Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity. Hum. Mol. Genet. 9:2009–18 [Google Scholar]
  32. Bailey CK, Andriola IF, Kampinga HH, Merry DE. 32.  2002. Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy. Hum. Mol. Genet. 11:515–23 [Google Scholar]
  33. Zou J, Guo Y, Guettouche T, Smith DF, Voellmy R. 33.  1998. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94:471–80 [Google Scholar]
  34. Muchowski PJ, Wacker JL. 34.  2005. Modulation of neurodegeneration by molecular chaperones. Nat. Rev. Neurosci. 6:11–22 [Google Scholar]
  35. Auluck PK, Bonini NM. 35.  2002. Pharmacological prevention of Parkinson disease in Drosophila. Nat. Med. 8:1185–86 [Google Scholar]
  36. Hay DG, Sathasivam K, Tobaben S, Stahl B, Marber M. 36.  et al. 2004. Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach. Hum. Mol. Genet. 13:1389–405 [Google Scholar]
  37. Sittler A, Lurz R, Lueder G, Priller J, Hayer-Hartl MK. 37.  et al. 2001. Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease. Hum. Mol. Genet. 10:1307–15 [Google Scholar]
  38. Thomas M, Harrell JM, Morishima Y, Peng HM, Pratt WB, Lieberman AP. 38.  2006. Pharmacologic and genetic inhibition of hsp90-dependent trafficking reduces aggregation and promotes degradation of the expanded glutamine androgen receptor without stress protein induction. Hum. Mol. Genet. 15:1876–83 [Google Scholar]
  39. McLean PJ, Klucken J, Shin Y, Hyman BT. 39.  2004. Geldanamycin induces Hsp70 and prevents α-synuclein aggregation and toxicity in vitro. Biochem. Biophys. Res. Commun. 321:665–69 [Google Scholar]
  40. Zietkiewicz S, Lewandowska A, Stocki P, Liberek K. 40.  2006. Hsp70 chaperone machine remodels protein aggregates at the initial step of Hsp70-Hsp100-dependent disaggregation. J. Biol. Chem. 281:7022–29 [Google Scholar]
  41. Powers MV, Jones K, Barillari C, Westwood I, van Monfort RLM, Workman P. 41.  2010. Targeting HSP70: the second potentially druggable heat shock protein and molecular chaperone?. Cell Cycle 9:1542–50 [Google Scholar]
  42. Wang AM, Morishima Y, Clapp KM, Peng HM, Pratt WB. 42.  et al. 2010. Inhibition of hsp70 by methylene blue affects signaling protein function and ubiquitination and modulates polyglutamine protein degradation. J. Biol. Chem. 285:15714–23 [Google Scholar]
  43. Howarth JL, Glover CPJ, Uney JB. 43.  2009. HSP70 interacting protein prevents the accumulation of inclusions in polyglutamine disease. J. Neurochem. 108:945–51 [Google Scholar]
  44. Mayer MP, Brehmer D, Gassler CS, Bukau B. 44.  2001. Hsp70 chaperone machines. Adv. Protein Chem. 59:1–44 [Google Scholar]
  45. Wang AM, Miyata Y, Klinedinst S, Peng HM, Chua JP. 45.  et al. 2013. Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat. Chem. Biol. 9:112–18 [Google Scholar]
  46. Roodveldt C, Bertoncini CW, Andersson A, van der Goot AT, Hsu ST. 46.  et al. 2009. Chaperone proteostasis in Parkinson's disease: stabilization of the Hsp70/α-synuclein complex by Hip. EMBO J. 28:3758–70 [Google Scholar]
  47. Rousaki A, Miyata Y, Jinwal UK, Dicky CA, Gestwicki JE, Zuiderweg ER. 47.  2011. Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones. J. Mol. Biol. 411:614–32 [Google Scholar]
  48. Morishima Y, Lau M, Peng HM, Miyata Y, Gestwicki JE. 48.  et al. 2011. Heme-dependent activation of neuronal nitric oxide synthase by cytosol is due to an Hsp70-dependent, thioredoxin-mediated thiol-disulfide interchange in the heme/substrate binding cleft. Biochemistry 50:7146–56 [Google Scholar]
  49. Zoghbi HY, Orr HT. 49.  2000. Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23:217–47 [Google Scholar]
  50. Orr HT, Zoghbi HY. 50.  2007. Trinucleotide repeat disorders. Annu. Rev. Neurosci. 30:575–621 [Google Scholar]
  51. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. 51.  1991. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77–79 [Google Scholar]
  52. Merry DE, Kobayashi Y, Bailey CK, Taye AA, Fischbeck KH. 52.  1998. Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy. Hum. Mol. Genet. 7:693–701 [Google Scholar]
  53. Li M, Chevalier-Larsen ES, Merry DE, Diamond MI. 53.  2007. Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy. J. Biol. Chem. 282:3157–64 [Google Scholar]
  54. Adachi H, Katsuno M, Minamiyama M, Waza M, Sang C. 54.  et al. 2005. Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain 128:659–70 [Google Scholar]
  55. Taylor JP, Tanaka F, Robitschek J, Sandoval CM, Taye A. 55.  et al. 2003. Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum. Mol. Genet. 12:749–57 [Google Scholar]
  56. Kopito RR. 56.  2000. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 10:524–30 [Google Scholar]
  57. Waza M, Adachi H, Katsuno M, Minamiyama M, Sang C. 57.  et al. 2005. 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat. Med. 11:1088–95 [Google Scholar]
  58. Pratt WB, Galigniana MD, Harrell JM, DeFranco DB. 58.  2004. Role of hsp90 and the hsp90-binding immunophilins in signaling protein movement. Cell Signal. 16:857–72 [Google Scholar]
  59. Tokui K, Adachi H, Waza JM, Katsuno M, Minamiyama M. 59.  et al. 2009. 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse. Hum. Mol. Genet. 18:898–910 [Google Scholar]
  60. Stenoien DL, Cummings CJ, Adams HP, Mancini MG, Patel K. 60.  et al. 1999. Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone. Hum. Mol. Genet. 8:731–41 [Google Scholar]
  61. Abel A, Walcott J, Woods J, Duda J, Merry DE. 61.  2001. Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum. Mol. Genet. 10:107–16 [Google Scholar]
  62. Kobayashi Y, Kume A, Li M, Doyu M, Hata M. 62.  et al. 2000. Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J. Biol. Chem. 275:8772–78 [Google Scholar]
  63. Adachi H, Katsuno M, Minamiyama M, Sang C, Pagoulatos G. 63.  et al. 2003. 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. J. Neurosci. 23:2203–11 [Google Scholar]
  64. Adachi H, Waza M, Takui K, Katsuno M, Minamiyama M. 64.  et al. 2007. CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model. J. Neurosci. 27:5115–26 [Google Scholar]
  65. Imarisio S, Carmichael J, Korolchuk V, Chen CW, Saiki S. 65.  et al. 2008. Huntington's disease: from pathology and genetics to potential therapies. Biochem. J. 412:191–209 [Google Scholar]
  66. Truant R, Atwal RS, Burtnik A. 66.  2007. Nucleocytoplasmic trafficking and transcription effects of huntingtin in Huntington's disease. Prog. Neurobiol. 83:211–27 [Google Scholar]
  67. Gunawardena S, Her LS, Brusch RG, Layman RA, Niesman IR. 67.  et al. 2003. Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40:25–40 [Google Scholar]
  68. Gauthier LR, Charrin BC, Borrell-Pages M, Dumpierre JP, Rangone H. 68.  et al. 2004. Huntington controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118:127–38 [Google Scholar]
  69. Caviston JP, Ross JL, Antony SM, Tokito M, Holzbaur ELF. 69.  2007. Huntingtin facilitates dynein/dynactin-mediated vesicle transport. Proc. Natl. Acad. Sci. USA 104:10045–50 [Google Scholar]
  70. Caviston JP, Holzbaur ELF. 70.  2009. Huntingtin as an essential integrator of intracellular vesicular trafficking. Trends Cell Biol. 19:147–55 [Google Scholar]
  71. Lee WC, Yoshihara M, Littleton JJ. 71.  2004. Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease. Proc. Natl. Acad. Sci. USA 101:3224–29 [Google Scholar]
  72. Saudou F, Finkbeiner S, Devys D, Greenberg ME. 72.  1998. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95:55–66 [Google Scholar]
  73. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. 73.  2004. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431:805–10 [Google Scholar]
  74. Mukai H, Iregawa T, Goyama E, Tanaka S, Bence NF. 74.  et al. 2005. Formation of morphologically similar globular aggregates from diverse aggregation-prone proteins in mammalian cells. Proc. Natl. Acad. Sci. USA 102:10887–92 [Google Scholar]
  75. Menalled LB, Sison JD, Dragatsis I, Zeitlin S, Chesselet MF. 75.  2003. Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington's disease with 140 CAG repeats. J. Comp. Neurol. 465:11–26 [Google Scholar]
  76. Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH. 76.  et al. 1997. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:537–48 [Google Scholar]
  77. Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K. 77.  et al. 1999. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet. 8:397–407 [Google Scholar]
  78. Baldo B, Weiss A, Parker CN, Bibel M, Paganetti P, Kaupmann K. 78.  2012. A screen for enhancers of clearance identifies huntingtin as a heat shock protein 90 (Hsp90) client protein. J. Biol. Chem. 287:1406–14 [Google Scholar]
  79. Herbst M, Wanker EE. 79.  2007. Small molecule inducers of heat shock response reduce polyQ-mediated huntingtin aggregation. Neurodegener. Dis. 4:254–60 [Google Scholar]
  80. Fujikake N, Nagai Y, Popiel HA, Okamoto Y, Yamaguchi M, Toda T. 80.  2008. Heat shock transcription factor 1-activating compounds suppress polyglutamine-induced neurodegeneration through induction of multiple molecular chaperones. J. Biol. Chem. 283:26188–97 [Google Scholar]
  81. Labbadia J, Cunliffe H, Weiss A, Katsyuba E, Sathasivam K. 81.  et al. 2011. Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease. J. Clin. Invest. 121:3306–19 [Google Scholar]
  82. Krobitsch S, Lindquist S. 82.  2000. Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins. Proc. Natl. Acad. Sci. USA 97:1589–94 [Google Scholar]
  83. Muchowski PJ, Schaffar G, Sittler A, Wanker EE, Hayer-Hartl MK, Hartl U. 83.  2000. Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl. Acad. Sci. USA 97:7841–46 [Google Scholar]
  84. Chan HYE, Warrick JM, Gray-Board GL, Paulson HL, Bonini NM. 84.  2000. Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum. Mol. Genet. 9:2811–20 [Google Scholar]
  85. Kazemi-Esfarjani P, Benzer S. 85.  2000. Genetic suppression of polyglutamine toxicity in Drosophila. Science 287:1837–40 [Google Scholar]
  86. Hansson O, Nylandsted J, Castilho RF, Leist M, Jaattela M, Brundin P. 86.  2003. Overexpression of heat shock protein 70 in R6/2 Huntington's disease mice has only modest effects on disease progression. Brain Res. 970:47–57 [Google Scholar]
  87. Wacker JL, Huang SY, Steela AD, Aron R, Lotz GP. 87.  et al. 2009. Loss of Hsp70 exacerbates pathogenesis but not levels of fibrillar aggregates in a mouse model of Huntington's disease. J. Neurosci. 29:9104–14 [Google Scholar]
  88. Tsai YC, Fishman PS, Thakor NV, Oyler GA. 88.  2003. Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function. J. Biol. Chem. 278:22044–55 [Google Scholar]
  89. Jankovic J. 89.  2007. Parkinson's disease: clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 79:368–76 [Google Scholar]
  90. Obeso JA, Rodriguez-Oroz MC, Guetz CG, Marin C, Kordower JH. 90.  et al. 2010. Missing pieces in the Parkinson's disease puzzle. Nat. Med. 16:653–61 [Google Scholar]
  91. Farrer MJ. 91.  2006. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat. Rev. Genet. 7:306–18 [Google Scholar]
  92. Lee HJ, Lee SJ. 92.  2002. Characterization of cytoplasmic α-synuclein aggregates: Fibril formation is tightly linked to the inclusion-forming process in cells. J. Biol. Chem. 277:48976–83 [Google Scholar]
  93. Lansbury PT, Lashuel HA. 93.  2006. A century-old debate on protein aggregation and neurodegeneration enters the clinic. Nature 443:774–79 [Google Scholar]
  94. Bartels T, Chui JG, Selkoe DJ. 94.  2011. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477:107–10 [Google Scholar]
  95. Lee VM, Trojanowski JQ. 95.  2006. Mechanisms of Parkinson's disease linked to pathological α-synuclein: new targets for drug discovery. Neuron 52:33–38 [Google Scholar]
  96. Gupta A, Dawson VL, Dawson TM. 96.  2008. What causes cell death in Parkinson's disease?. Ann. Neurol. 64:S3–15 [Google Scholar]
  97. Uryu K, Richter-Landsberg C, Welch W, Sun E, Goldbaum O. 97.  et al. 2006. Convergence of heat shock protein 90 with ubiquitin in filamentous α-synuclein inclusions of α-synucleinopathies. Am. J. Pathol. 168:947–61 [Google Scholar]
  98. Liang J, Clark-Dixon C, Wang S, Flower TR, Williams-Hart T. 98.  et al. 2008. Novel suppressors of α-synuclein toxicity identified using yeast. Hum. Mol. Genet. 17:3784–95 [Google Scholar]
  99. Flower TR, Chesnokova LS, Froelich CA, Dixon C, Witt SN. 99.  2005. Heat shock prevents alpha-synuclein-induced apoptosis in a yeast model of Parkinson's disease. J. Mol. Biol. 351:1081–100 [Google Scholar]
  100. Auluck PK, Meulener MC, Bonini NM. 100.  2005. Mechanisms of suppression of α-synuclein neurotoxicity by geldanamycin in Drosophila. J. Biol. Chem. 280:2873–78 [Google Scholar]
  101. Putcha P, Danzer KM, Kranich LR, Scott A, Silinski M. 101.  et al. 2010. Brain-permeable, small-molecule inhibitors of Hsp90 prevent α-synuclein-induced toxicity. J. Pharmacol. Exp. Ther. 332:849–57 [Google Scholar]
  102. Dev KK, Hofele K, Barbieri S, Buchman VL, van der Putten H. 102.  2003. Part II: α-synuclein and its molecular pathophysiological role in neurodegenerative disease. Neuropharmacology 45:14–44 [Google Scholar]
  103. Auluck PK, Chan E, Trojanowski JQ, Lee VM, Bonini NM. 103.  2002. Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295:865–68 [Google Scholar]
  104. McLean PJ, Kawamata H, Shariff S, Hewett J, Sharma N. 104.  et al. 2002. Torsin A and heat shock proteins act as molecular chaperones: suppression of α-synuclein aggregation. J. Neurochem. 83:846–54 [Google Scholar]
  105. Zhou Y, Gu G, Goodlett DR, Zhang T, Pan C. 105.  et al. 2004. Analysis of α-synuclein-associated proteins by quantitative proteomics. J. Biol. Chem. 279:39155–64 [Google Scholar]
  106. Yu F, Xu HT, Zhuo M, Sun LY, Dong AW, Liu XY. 106.  2005. Impairment of redox state and dopamine level induced by α-synuclein aggregation and the preventive effect of hsp70. Biochem. Biophys. Res. Commun. 331:278–84 [Google Scholar]
  107. Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M. 107.  et al. 2008. Formation of toxic oligomeric α-synuclein species in living cells. PLOS ONE 3:e1867 [Google Scholar]
  108. Fan GH, Zhou HY, Yang H, Chen SD. 108.  2006. Heat shock proteins reduce α-synuclein aggregation induced by MPP+ in SK-N-SH cells. FEBS Lett. 580:3091–98 [Google Scholar]
  109. Shin Y, Klucken J, Patterson C, Hyman BT, McLean PJ. 109.  2005. The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates α-synuclein degradation decisions between proteasomal and lysosomal pathways. J. Biol. Chem. 280:23727–34 [Google Scholar]
  110. Kalia LV, Kalia SK, Chau H, Lozano AM, Hymen BJ, McLean PJ. 110.  2011. Ubiquitinylation of α-synuclein by carboxyl terminus Hsp70-interacting protein (CHIP) is regulated by Bcl-2-associated athanogene 5 (BAG5). PLOS ONE 6:e14695 [Google Scholar]
  111. Cummings JL. 111.  2004. Alzheimer's disease. N. Eng. J. Med. 351:56–67 [Google Scholar]
  112. Burns A, Iliffe S. 112.  2009. Alzheimer's disease. Br. Med. J. 338:467–71 [Google Scholar]
  113. Citron M. 113.  2010. Alzheimer's disease: strategies for disease modification. Nat. Rev. Drug Disc. 9:387–98 [Google Scholar]
  114. Hardy J, Selkoe DJ. 114.  2002. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353–56 [Google Scholar]
  115. Mesulam MM. 115.  1999. Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles. Neuron 24:521–29 [Google Scholar]
  116. Morris M, Maeda S, Vossel K, Mucke L. 116.  2011. The many faces of tau. Neuron 70:410–26 [Google Scholar]
  117. Lee VM, Goedert M, Trojanowski JQ. 117.  2001. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24:1121–59 [Google Scholar]
  118. Takei Y, Teng J, Harada A, Hirokawa N. 118.  2000. Defects in axonal elongation and neuronal migration in mice with disrupted tau and map1b genes. J. Cell Biol. 150:989–1000 [Google Scholar]
  119. Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B. 119.  et al. 1998. Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. J. Cell Biol. 143:777–94 [Google Scholar]
  120. Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM. 120.  2002. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J. Cell Biol. 156:1051–63 [Google Scholar]
  121. Dixit R, Ross JL, Goldman YE, Holzbaur ELF. 121.  2008. Differential regulation of dynein and kinesin motor proteins by tau. Science 319:1086–89 [Google Scholar]
  122. Feuillette S, Miguel L, Frébourg T, Campion D, Lecourtois M. 122.  2010. Drosophila models of human tauopathies indicate that Tau protein toxicity in vivo is mediated by soluble cytosolic phosphorylated forms of the protein. J. Neurochem. 113:895–903 [Google Scholar]
  123. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH. 123.  et al. 2007. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer's disease mouse model. Science 316:750–54 [Google Scholar]
  124. Dou F, Natzer WJ, Tanemura K, Li F, Hartl FU. 124.  et al. 2003. Chaperones increase association of tau protein with microtubules. Proc. Natl. Acad. Sci. USA 100:721–26 [Google Scholar]
  125. Luo W, Dou F, Rodina A, Chip S, Kim J. 125.  et al. 2007. Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies. Proc. Natl. Acad. Sci. USA 104:9511–16 [Google Scholar]
  126. Tortosa E, Santa-Maria I, Moreno F, Lim F, Perez M, Avila J. 126.  2009. Binding of Hsp90 to tau promotes a conformational change and aggregation of tau protein. J. Alzheimer's Dis. 17:319–25 [Google Scholar]
  127. Dicky CA, Dunmore J, Lu B, Wang JW, Lee WC. 127.  et al. 2006. HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites. FASEB J. 20:753–55 [Google Scholar]
  128. Dicky CA, Kamal A, Lundgren K, Klosak N, Bailey RM. 128.  et al. 2007. The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J. Clin. Invest. 117:648–58 [Google Scholar]
  129. Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H. 129.  et al. 2004. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum. Mol. Genet. 13:703–14 [Google Scholar]
  130. Shimura H, Schwartz D, Gygi SP, Kosik KS. 130.  2004. CHIP-Hsp70 complex ubiquitinates phosphorylated tau and enhances cell survival. J. Biol. Chem. 279:4869–76 [Google Scholar]
  131. Hatakeyama S, Matsumoto M, Kamura T, Murayama M, Chui DH. 131.  et al. 2004. U-box protein carboxyl terminus of Hsc70-interacting protein (CHIP) mediates poly-ubiquitination preferentially on four-repeat Tau and is involved in neurodegeneration of tauopathy. J. Neurochem. 91:299–307 [Google Scholar]
  132. Dickey CA, Yue M, Lin WL, Dickson DW, Dunmore JH. 132.  et al. 2006. Deletion of the ubiquitin ligase CHIP leads to the accumulation, but not the aggregation, of both endogenous phospho- and caspase-3-cleaved tau species. J. Neurosci. 26:6985–96 [Google Scholar]
  133. Sahara N, Murayama M, Mizoroki T, Urushitani M, Imai Y. 133.  et al. 2005. In vivo evidence of CHIP up-regulation attenuating tau aggregation. J. Neurochem. 94:1254–63 [Google Scholar]
  134. Abisambra J, Jinwal UK, Miyata Y, Rogers J, Blair L. 134.  et al. 2013. Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau. Biol. Psychiatry 74:367–74 [Google Scholar]

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