Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases (original) (raw)

• Ross, C. A. & Poirier, M. A. Protein aggregation and neurodegenerative disease. Nature Med. 10, S10–S17 (2004).
  Article CAS PubMed Google Scholar
• Zhang, Q. C. et al. A compact β model of huntingtin toxicity. J. Biol. Chem. 286, 8188–8196 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nature Rev. Mol. Cell Biol. 8, 101–112 (2007).
  Article CAS Google Scholar
• Muchowski, P. J. Protein misfolding, amyloid formation, and neurodegeneration: a critical role for molecular chaperones? Neuron 35, 9–12 (2002).
  Article CAS PubMed Google Scholar
• Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R. & Finkbeiner, S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805–810 (2004).
  Article CAS PubMed Google Scholar
• Fiumara, F., Fioriti, L., Kandel, E. R. & Hendrickson, W. A. Essential role of coiled coils for aggregation and activity of Q/N-rich prions and polyQ proteins. Cell 143, 1121–1135 (2010). This study demonstrated that coiled-coil motifs in polyQ proteins contribute to the aggregation and cytotoxicity of these proteins.
  Article CAS PubMed PubMed Central Google Scholar
• Cookson, M. R. The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nature Rev. Neurosci. 11, 791–797 (2010).
  Article CAS Google Scholar
• Jankovic, J. Parkinson's disease: clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatr. 79, 368–376 (2008).
  Article CAS Google Scholar
• Buschert, V., Bokde, A. L. W. & Hampel, H. Cognitive intervention in Alzheimer disease. Nature Rev. Neurol. 6, 508–517 (2010).
  Article CAS Google Scholar
• Carter, M. D., Simms, G. A. & Weaver, D. F. The development of new therapeutics for Alzheimer's disease. Clin. Pharmacol. Ther. 88, 475–486 (2010).
  Article CAS PubMed Google Scholar
• Boillée, S., Vande Velde, C. & Cleveland, D. W. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52, 39–59 (2006).
  Article CAS PubMed Google Scholar
• Verity, N. C. & Mallucci, G. R. Rescuing neurons in prion disease. Biochem. J. 433, 19–29 (2010).
  Article CAS Google Scholar
• Walker, F. O. Huntington's disease. Lancet 369, 218–228 (2007).
  Article CAS PubMed Google Scholar
• Hartl, F. U. & Hayer-Hartl, M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295, 1852–1858 (2002).
  Article CAS PubMed Google Scholar
• Chai, Y., Koppenhafer, S. L., Bonini, N. M. & Paulson, H. L. Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. J. Neurosci. 19, 10338–10347 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Warrick, J. M. et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nature Genet. 23, 425–428 (1999).
  Article CAS PubMed Google Scholar
• Chan, H. Y., Warrick, J. M., Gray-Board, G. L., Paulson, H. L. & Bonini, N. M. Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum. Mol. Genet. 9, 2811–2820 (2000). This study showed that HSP40 and HSP70 synergize to ameliorate the cytotoxicity of polyQ proteins in fruitfly disease models by modulating the solubility of these proteins.
  Article CAS PubMed Google Scholar
• Auluck, P. K. & Bonini, N. M. Pharmacological prevention of Parkinson disease in Drosophila. Nature Med. 8, 1185–1186 (2002). This paper showed that pharmacological activation of HSF1 via the HSP90 inhibitor geldanamycin can ameliorate disease phenotypes in a fruitfly model of Parkinson's disease.
  Article CAS PubMed Google Scholar
• Auluck, P., Meulener, M. & Bonini, N. Mechanisms of suppression of α-synuclein neurotoxicity by geldanamycin in Drosophila. J. Biol. Chem. 280, 2873–2878 (2005).
  Article CAS PubMed Google Scholar
• Alavez, S., Vantipalli, M. C., Zucker, D. J., Klang, I. M. & Lithgow, G. J. Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature 472, 226–229 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Ben-Zvi, A., Miller, E. A. & Morimoto, R. I. Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc. Natl Acad. Sci. USA 106, 14914–14919 (2009). This study describes a widespread failure in protein folding that occurs in early adulthood and coincides with reduced activation of HSF1 and chaperone protein expression in C. elegans.
  Article CAS PubMed PubMed Central Google Scholar
• Fonte, V. et al. Interaction of intracellular β amyloid peptide with chaperone proteins. Proc. Natl Acad. Sci. USA 99, 9439–9444 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Satyal, S. H. et al. Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 97, 5750–5755 (2000). This study shows that the expression of polyQ proteins in C. elegans disrupts general protein folding, causes aggregation of otherwise soluble proteins and constitutively promotes the activation of HSF1 and chaperone proteins.
  Article CAS PubMed PubMed Central Google Scholar
• Teixeira-Castro, A. et al. Neuron-specific proteotoxicity of mutant ataxin-3 in C. elegans: rescue by the DAF-16 and HSF-1 pathways. Hum. Mol. Genet. 20, 2996–3009 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, J. et al. An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons of Caenorhabditis elegans. PLoS Genet. 5, e1000350 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Lanneau, D., de Thonel, A., Maurel, S., Didelot, C. & Garrido, C. Apoptosis versus cell differentiation: role of heat shock proteins HSP90, HSP70 and HSP27. Prion 1, 53–60 (2007).
  Article PubMed PubMed Central Google Scholar
• Batulan, Z. et al. High threshold for induction of the stress response in motor neurons is associated with failure to activate HSF1. J. Neurosci. 23, 5789–5798 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Bonelli, M. A. et al. Attenuated expression of 70-kDa heat shock protein in WI-38 human fibroblasts during aging in vitro. Exp. Cell Res. 252, 20–32 (1999).
  Article CAS PubMed Google Scholar
• Gutsmann-Conrad, A., Heydari, A. R., You, S. & Richardson, A. The expression of heat shock protein 70 decreases with cellular senescence in vitro and in cells derived from young and old human subjects. Exp. Cell Res. 241, 404–413 (1998).
  Article CAS PubMed Google Scholar
• Gutsmann-Conrad, A., Pahlavani, M. A., Heydari, A. R. & Richardson, A. Expression of heat shock protein 70 decreases with age in hepatocytes and splenocytes from female rats. Mech. Ageing Dev. 107, 255–270 (1999).
  Article CAS PubMed Google Scholar
• Fargnoli, J., Kunisada, T., Fornace, A. J., Schneider, E. L. & Holbrook, N. J. Decreased expression of heat shock protein 70 mRNA and protein after heat treatment in cells of aged rats. Proc. Natl Acad. Sci. USA 87, 846–850 (1990).
  Article CAS PubMed PubMed Central Google Scholar
• Fawcett, T. W., Sylvester, S. L., Sarge, K. D., Morimoto, R. I. & Holbrook, N. J. Effects of neurohormonal stress and aging on the activation of mammalian heat shock factor 1. J. Biol. Chem. 269, 32272–32278 (1994).
  CAS PubMed Google Scholar
• Pahlavani, M. A., Harris, M. D., Moore, S. A., Weindruch, R. & Richardson, A. The expression of heat shock protein 70 decreases with age in lymphocytes from rats and rhesus monkeys. Exp. Cell Res. 218, 310–318 (1995).
  Article CAS PubMed Google Scholar
• Bailey, C. K., Andriola, I. F. M., Kampinga, H. H. & Merry, D. E. 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, 515–523 (2002).
  Article CAS PubMed Google Scholar
• Fujimoto, M. et al. Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models. J. Biol. Chem. 280, 34908–34916 (2005). This study demonstrates that the expression of a constitutively active HSF1 allele ameliorates pathogenic phenotypes in a mouse model of Huntington's disease.
  Article CAS PubMed Google Scholar
• Muchowski, P. J. et al. Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl Acad. Sci. USA 97, 7841–7846 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Wacker, J. L., Zareie, M. H., Fong, H., Sarikaya, M. & Muchowski, P. J. Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nature Struct. Mol. Biol. 11, 1215–1222 (2004).
  Article CAS Google Scholar
• Wyttenbach, A. et al. Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease. Proc. Natl Acad. Sci. USA 97, 2898–2903 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Feder, J. H., Rossi, J. M., Solomon, J., Solomon, N. & Lindquist, S. The consequences of expressing hsp70 in Drosophila cells at normal temperatures. Genes Dev. 6, 1402–1413 (1992).
  Article CAS PubMed Google Scholar
• Dai, C., Whitesell, L., Rogers, A. B. & Lindquist, S. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130, 1005–1018 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Akerfelt, M., Morimoto, R. I. & Sistonen, L. Heat shock factors: integrators of cell stress, development and lifespan. Nature Rev. Mol. Cell Biol. 11, 545–555 (2010).
  Article CAS Google Scholar
• Gonsalves, S. E., Moses, A. M., Razak, Z., Robert, F. & Westwood, J. T. Whole-genome analysis reveals that active heat shock factor binding sites are mostly associated with non-heat shock genes in Drosophila melanogaster. PLoS ONE 6, e15934 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Hahn, J.-S., Hu, Z., Thiele, D. J. & Iyer, V. R. Genome-wide analysis of the biology of stress responses through heat shock transcription factor. Mol. Cell Biol. 24, 5249–5256 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Trinklein, N. D., Murray, J. I., Hartman, S. J., Botstein, D. & Myers, R. M. The role of heat shock transcription factor 1 in the genome-wide regulation of the mammalian heat shock response. Mol. Biol. Cell 15, 1254–1261 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Ostling, P., Björk, J. K., Roos-Mattjus, P., Mezger, V. & Sistonen, L. Heat shock factor 2 (HSF2) contributes to inducible expression of hsp genes through interplay with HSF1. J. Biol. Chem. 282, 7077–7086 (2007).
  Article CAS PubMed Google Scholar
• Sandqvist, A. et al. Heterotrimerization of heat-shock factors 1 and 2 provides a transcriptional switch in response to distinct stimuli. Mol. Biol. Cell 20, 1340–1347 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Shinkawa, T. et al. Heat shock factor 2 is required for maintaining proteostasis against febrile range thermal stress and polyglutamine aggregation. Mol. Biol. Cell 22, 3571–3583 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Abravaya, K., Myers, M. P., Murphy, S. P. & Morimoto, R. I. The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expression. Genes Dev. 6, 1153–1164 (1992).
  Article CAS PubMed Google Scholar
• Ali, A., Bharadwaj, S., O'Carroll, R. & Ovsenek, N. HSP90 interacts with and regulates the activity of heat shock factor 1 in Xenopus oocytes. Mol. Cell Biol. 18, 4949–4960 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Bharadwaj, S., Ali, A. & Ovsenek, N. Multiple components of the HSP90 chaperone complex function in regulation of heat shock factor 1 in vivo. Mol. Cell Biol. 19, 8033–8041 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Conde, R., Xavier, J., McLoughlin, C., Chinkers, M. & Ovsenek, N. Protein phosphatase 5 is a negative modulator of heat shock factor 1. J. Biol. Chem. 280, 28989–28996 (2005).
  Article CAS PubMed Google Scholar
• Guo, Y. et al. Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complex. J. Biol. Chem. 276, 45791–45799 (2001).
  Article CAS PubMed Google Scholar
• Shi, Y., Mosser, D. D. & Morimoto, R. I. Molecular chaperones as HSF1-specific transcriptional repressors. Genes Dev. 12, 654–666 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Zou, J., Guo, Y., Guettouche, T., Smith, D. F. & Voellmy, R. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94, 471–480 (1998).
  Article CAS PubMed Google Scholar
• Arlander, S. J. H. et al. Chaperoning checkpoint kinase 1 (Chk1), an Hsp90 client, with purified chaperones. J. Biol. Chem. 281, 2989–2998 (2006).
  Article CAS PubMed Google Scholar
• Hernández, M. P., Chadli, A. & Toft, D. O. HSP40 binding is the first step in the HSP90 chaperoning pathway for the progesterone receptor. J. Biol. Chem. 277, 11873–11881 (2002).
  Article CAS PubMed Google Scholar
• King, F. W., Wawrzynow, A., Höhfeld, J. & Zylicz, M. Co-chaperones Bag-1, Hop and Hsp40 regulate Hsc70 and Hsp90 interactions with wild-type or mutant p53. EMBO J. 20, 6297–6305 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Carmichael, J., Sugars, K. L., Bao, Y. P. & Rubinsztein, D. C. Glycogen synthase kinase-3β inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation. J. Biol. Chem. 277, 33791–33798 (2002).
  Article CAS PubMed Google Scholar
• Chu, B., Soncin, F., Price, B. D., Stevenson, M. A. & Calderwood, S. K. Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1. J. Biol. Chem. 271, 30847–30857 (1996).
  Article CAS PubMed Google Scholar
• Chu, B., Zhong, R., Soncin, F., Stevenson, M. A. & Calderwood, S. K. Transcriptional activity of heat shock factor 1 at 37 °C is repressed through phosphorylation on two distinct serine residues by glycogen synthase kinase 3 and protein kinases Cα and Cζ. J. Biol. Chem. 273, 18640–18646 (1998).
  Article CAS PubMed Google Scholar
• Hietakangas, V. et al. Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1. Mol. Cell Biol. 23, 2953–2968 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Kline, M. P. & Morimoto, R. I. Repression of the heat shock factor 1 transcriptional activation domain is modulated by constitutive phosphorylation. Mol. Cell Biol. 17, 2107–2115 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Knauf, U., Newton, E. M., Kyriakis, J. & Kingston, R. E. Repression of human heat shock factor 1 activity at control temperature by phosphorylation. Genes Dev. 10, 2782–2793 (1996).
  Article CAS PubMed Google Scholar
• Murshid, A. et al. Protein kinase A binds and activates heat shock factor 1. PLoS ONE 5, e13830 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, X. et al. Phosphorylation of HSF1 by MAPK-activated protein kinase 2 on serine 121, inhibits transcriptional activity and promotes HSP90 binding. J. Biol. Chem. 281, 782–791 (2006).
  Article CAS PubMed Google Scholar
• Pelham, H. R. A regulatory upstream promoter element in the Drosophila Hsp 70 heat-shock gene. Cell 30, 517–528 (1982).
  Article CAS PubMed Google Scholar
• Pelham, H. R. & Bienz, M. A synthetic heat-shock promoter element confers heat-inducibility on the herpes simplex virus thymidine kinase gene. EMBO J. 1, 1473–1477 (1982).
  Article CAS PubMed PubMed Central Google Scholar
• Perisic, O., Xiao, H. & Lis, J. T. Stable binding of Drosophila heat shock factor to head-to-head and tail-to-tail repeats of a conserved 5 bp recognition unit. Cell 59, 797–806 (1989).
  Article CAS PubMed Google Scholar
• Clos, J. et al. Molecular cloning and expression of a hexameric Drosophila heat shock factor subject to negative regulation. Cell 63, 1085–1097 (1990).
  Article CAS PubMed Google Scholar
• Sorger, P. K. & Nelson, H. C. Trimerization of a yeast transcriptional activator via a coiled-coil motif. Cell 59, 807–813 (1989).
  Article CAS PubMed Google Scholar
• Ahn, S.-G. & Thiele, D. J. Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress. Genes Dev. 17, 516–528 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Neef, D. W., Turski, M. L. & Thiele, D. J. Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease. PLoS Biol. 8, e1000291 (2010). In this study the authors generated a humanized HSF1-based yeast screen to identify HSF1A, a novel pharmacological activator of HSF1 that is efficacious in ameliorating polyQ protein-associated protein aggregation and cytotoxicity in cell culture and fruitfly disease models.
  Article CAS PubMed PubMed Central Google Scholar
• Trott, A. et al. Activation of heat shock and antioxidant responses by the natural product celastrol: transcriptional signatures of a thiol-targeted molecule. Mol. Biol. Cell 19, 1104–1112 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Rabindran, S. K., Haroun, R. I., Clos, J., Wisniewski, J. & Wu, C. Regulation of heat shock factor trimer formation: role of a conserved leucine zipper. Science 259, 230–234 (1993).
  Article CAS PubMed Google Scholar
• Guettouche, T., Boellmann, F., Lane, W. S. & Voellmy, R. Analysis of phosphorylation of human heat shock factor 1 in cells experiencing a stress. BMC Biochem. 6, 4 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Holmberg, C. I. et al. Phosphorylation of serine 230 promotes inducible transcriptional activity of heat shock factor 1. EMBO J. 20, 3800–3810 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, S.-A., Yoon, J.-H., Lee, S.-H. & Ahn, S.-G. Polo-like kinase 1 phosphorylates heat shock transcription factor 1 and mediates its nuclear translocation during heat stress. J. Biol. Chem. 280, 12653–12657 (2005).
  Article CAS PubMed Google Scholar
• Westerheide, S. D., Anckar, J., Stevens, S. M., Sistonen, L. & Morimoto, R. I. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323, 1063–1066 (2009). This study demonstrated that the DNA binding activity of HSF1 is inhibited by acetylation within the DNA binding domain, and HSF1 is maintained in a deacetylated state via SIRT1.
  Article CAS PubMed PubMed Central Google Scholar
• Yang, J., Bridges, K., Chen, K. Y. & Liu, A. Y.-C. Riluzole increases the amount of latent HSF1 for an amplified heat shock response and cytoprotection. PLoS ONE 3, e2864 (2008). This work reported that riluzole, which is a treatment for ALS, promotes an increase in steady-state HSF1 levels potentially via the inhibition of chaperone-mediated autophagy.
  Article CAS PubMed PubMed Central Google Scholar
• Trepel, J., Mollapour, M., Giaccone, G. & Neckers, L. Targeting the dynamic HSP90 complex in cancer. Nature Rev. Cancer 10, 537–549 (2010).
  Article CAS Google Scholar
• Dickey, C. A. et al. HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites. FASEB J. 20, 753–755 (2006).
  Article CAS PubMed Google Scholar
• Dickey, C. A. et al. Development of a high throughput drug screening assay for the detection of changes in tau levels — proof of concept with HSP90 inhibitors. Curr. Alzheimer Res. 2, 231–238 (2005).
  Article CAS PubMed Google Scholar
• Dou, F. et al. Chaperones increase association of tau protein with microtubules. Proc. Natl Acad. Sci. USA 100, 721–726 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Petrucelli, L. et al. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum. Mol. Genet. 13, 703–714 (2004).
  Article CAS PubMed Google Scholar
• Flower, T. R., Chesnokova, L. S., Froelich, C. A., Dixon, C. & Witt, S. N. Heat shock prevents α-synuclein-induced apoptosis in a yeast model of Parkinson's disease. J. Mol. Biol. 351, 1081–1100 (2005).
  Article CAS PubMed Google Scholar
• Shen, H.-Y., He, J.-C., Wang, Y., Huang, Q.-Y. & Chen, J.-F. Geldanamycin induces heat shock protein 70 and protects against MPTP-induced dopaminergic neurotoxicity in mice. J. Biol. Chem. 280, 39962–39969 (2005).
  Article CAS PubMed Google Scholar
• Agrawal, N. et al. Identification of combinatorial drug regimens for treatment of Huntington's disease using Drosophila. Proc. Natl Acad. Sci. USA 102, 3777–3781 (2005). This study demonstrated that the HSP90 inhibitor geldanamycin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid have combinatorial efficacy in ameliorating cytotoxicity in a fruitfly model of neurodegenerative disease.
  Article CAS PubMed PubMed Central Google Scholar
• Fujikake, N. et al. Heat shock transcription factor 1-activating compounds suppress polyglutamine-induced neurodegeneration through induction of multiple molecular chaperones. J. Biol. Chem. 283, 26188–26197 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Hay, D. G. 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. Hum. Mol. Genet. 13, 1389–1405 (2004).
  Article CAS PubMed Google Scholar
• Sittler, A. et al. Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease. Hum. Mol. Genet. 10, 1307–1315 (2001).
  Article CAS PubMed Google Scholar
• Marcu, M. G., Chadli, A., Bouhouche, I., Catelli, M. & Neckers, L. M. The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone. J. Biol. Chem. 275, 37181–37186 (2000).
  Article CAS PubMed Google Scholar
• Yu, X. M. et al. Hsp90 inhibitors identified from a library of novobiocin analogues. J. Am. Chem. Soc. 127, 12778–12779 (2005).
  Article CAS PubMed Google Scholar
• Ansar, S. et al. A non-toxic Hsp90 inhibitor protects neurons from Aβ-induced toxicity. Bioorg. Med. Chem. Lett. 17, 1984–1990 (2007).
  Article CAS PubMed Google Scholar
• Kimura, H. et al. ITZ-1, a client-selective Hsp90 inhibitor, efficiently induces heat shock factor 1 activation. Chem. Biol. 17, 18–27 (2010).
  Article CAS PubMed Google Scholar
• Salehi, A. H. et al. AEG3482 is an antiapoptotic compound that inhibits Jun kinase activity and cell death through induced expression of heat shock protein 70. Chem. Biol. 13, 213–223 (2006).
  Article CAS PubMed Google Scholar
• Schnaider, T., Somogyi, J., Csermely, P. & Szamel, M. The Hsp90-specific inhibitor, geldanamycin, blocks CD28-mediated activation of human T lymphocytes. Life Sci. 63, 949–954 (1998).
  Article CAS PubMed Google Scholar
• Westerheide, S. et al. Celastrols as inducers of the heat shock response and cytoprotection. J. Biol. Chem. 279, 56053–56060 (2004).
  Article CAS PubMed Google Scholar
• Hieronymus, H. et al. Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell 10, 321–330 (2006).
  Article CAS PubMed Google Scholar
• Zhang, T. et al. A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Mol. Cancer Ther. 7, 162–170 (2008).
  Article CAS PubMed Google Scholar
• Yang, H., Chen, D., Cui, Q. C., Yuan, X. & Dou, Q. P. Celastrol, a triterpene extracted from the Chinese “Thunder of God Vine,” is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res. 66, 4758–4765 (2006).
  Article CAS PubMed Google Scholar
• Kiaei, M. et al. Celastrol blocks neuronal cell death and extends life in transgenic mouse model of amyotrophic lateral sclerosis. Neurodegener. Dis. 2, 246–254 (2005).
  Article CAS PubMed Google Scholar
• Allison, A. C., Cacabelos, R., Lombardi, V. R., Alvarez, X. A. & Vigo, C. Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 25, 1341–1357 (2001).
  Article CAS PubMed Google Scholar
• Wang, J., Gines, S., MacDonald, M. E. & Gusella, J. F. Reversal of a full-length mutant huntingtin neuronal cell phenotype by chemical inhibitors of polyglutamine-mediated aggregation. BMC Neurosci. 6, 1 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, Y.-Q. & Sarge, K. D. Celastrol inhibits polyglutamine aggregation and toxicity though induction of the heat shock response. J. Mol. Med. 85, 1421–1428 (2007).
  Article CAS PubMed Google Scholar
• Cleren, C., Calingasan, N. Y., Chen, J. & Beal, M. F. Celastrol protects against MPTP- and 3-nitropropionic acid-induced neurotoxicity. J. Neurochem. 94, 995–1004 (2005).
  Article CAS PubMed Google Scholar
• Faust, K. et al. Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson's disease. BMC Neurosci. 10, 109 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hansen, J. & Bross, P. A cellular viability assay to monitor drug toxicity. Methods Mol. Biol. 648, 303–311 (2010).
  Article CAS PubMed Google Scholar
• Kalmar, B. & Greensmith, L. Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration — evidence for neuroprotective and neurotoxic effects. Cell. Mol. Biol. Lett. 14, 319–335 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, S., Liu, K., Wang, X., He, Q. & Chen, X. Toxic effects of celastrol on embryonic development of zebrafish (Danio rerio). Drug Chem. Toxicol. 34, 61–65 (2011).
  Article CAS PubMed Google Scholar
• Ohtsuka, K., Kawashima, D., Gu, Y. & Saito, K. Inducers and co-inducers of molecular chaperones. Int. J. Hyperthermia 21, 703–711 (2005).
  Article CAS PubMed Google Scholar
• Hirakawa, T., Rokutan, K., Nikawa, T. & Kishi, K. Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa. Gastroenterology 111, 345–357 (1996).
  Article CAS PubMed Google Scholar
• Katsuno, M. et al. Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease. Proc. Natl Acad. Sci. USA 102, 16801–16806 (2005). This work demonstrated that pharmacological activation of HSF1 via geranylgeranylacetone promotes the activation of chaperone protein expression and ameliorates cytotoxicity in a mouse model of spinal and bulbar muscular atrophy.
  Article CAS PubMed PubMed Central Google Scholar
• Otaka, M. et al. The induction mechanism of the molecular chaperone HSP70 in the gastric mucosa by geranylgeranylacetone (HSP-inducer). Biochem. Biophys. Res. Commun. 353, 399–404 (2007).
  Article CAS PubMed Google Scholar
• Patury, S., Miyata, Y. & Gestwicki, J. E. Pharmacological targeting of the Hsp70 chaperone. Curr. Top. Med. Chem. 9, 1337–1351 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hirota, K. et al. Geranylgeranylacetone enhances expression of thioredoxin and suppresses ethanol-induced cytotoxicity in cultured hepatocytes. Biochem. Biophys. Res. Commun. 275, 825–830 (2000).
  Article CAS PubMed Google Scholar
• Okada, S. et al. Geranylgeranylacetone induces apoptosis in HL-60 cells. Cell Struct. Funct. 24, 161–168 (1999).
  Article CAS PubMed Google Scholar
• Endo, S. et al. Geranylgeranylacetone, an inducer of the 70-kDa heat shock protein (HSP70), elicits unfolded protein response and coordinates cellular fate independently of HSP70. Mol. Pharmacol. 72, 1337–1348 (2007).
  Article CAS PubMed Google Scholar
• Tam, S., Geller, R., Spiess, C. & Frydman, J. The chaperonin TRiC controls polyglutamine aggregation and toxicity through subunit-specific interactions. Nature Cell Biol. 8, 1155–1162 (2006). This study shows that the TRIC cytosolic chaperone complex binds to the pathogenic huntingtin protein and reduces huntingtin-mediated cytotoxicity.
  Article CAS PubMed Google Scholar
• Tam, S. et al. The chaperonin TRiC blocks a huntingtin sequence element that promotes the conformational switch to aggregation. Nature Struct. Mol. Biol. 16, 1279–1285 (2009).
  Article CAS Google Scholar
• Hargitai, J. et al. Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1. Biochem. Biophys. Res. Commun. 307, 689–695 (2003).
  Article CAS PubMed Google Scholar
• Vígh, L. et al. Bimoclomol: a nontoxic, hydroxylamine derivative with stress protein-inducing activity and cytoprotective effects. Nature Med. 3, 1150–1154 (1997).
  Article PubMed Google Scholar
• Török, Z. et al. Heat shock protein coinducers with no effect on protein denaturation specifically modulate the membrane lipid phase. Proc. Natl Acad. Sci. USA 100, 3131–3136 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Nánási, P. P. & Jednákovits, A. Multilateral in vivo and in vitro protective effects of the novel heat shock protein coinducer, bimoclomol: results of preclinical studies. Cardiovasc. Drug Rev. 19, 133–151 (2001).
  Article PubMed Google Scholar
• Kalmar, B. et al. Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1G93A mouse model of ALS. J. Neurochem. 107, 339–350 (2008).
  Article CAS PubMed Google Scholar
• Kieran, D. et al. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nature Med. 10, 402–405 (2004). This study demonstrates that pharmacological activation of HSF1 via arimoclomol ameliorates pathogenic phenotypes and extends lifespan in a mouse model of ALS.
  Article CAS PubMed Google Scholar
• Lanka, V., Wieland, S., Barber, J. & Cudkowicz, M. Arimoclomol: a potential therapy under development for ALS. Expert Opin. Investig. Drugs 18, 1907–1918 (2009).
  Article CAS PubMed Google Scholar
• Liu, A. Y. C. et al. Neuroprotective drug riluzole amplifies the heat shock factor 1 (HSF1)- and glutamate transporter 1 (GLT1)-dependent cytoprotective mechanisms for neuronal survival. J. Biol. Chem. 286, 2785–2794 (2011).
  Article CAS PubMed Google Scholar
• Jurivich, D. A., Sistonen, L., Kroes, R. A. & Morimoto, R. I. Effect of sodium salicylate on the human heat shock response. Science 255, 1243–1245 (1992).
  Article CAS PubMed Google Scholar
• Lee, B. S., Chen, J., Angelidis, C., Jurivich, D. A. & Morimoto, R. I. Pharmacological modulation of heat shock factor 1 by antiinflammatory drugs results in protection against stress-induced cellular damage. Proc. Natl Acad. Sci. USA 92, 7207–7211 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Winegarden, N. A., Wong, K. S., Sopta, M. & Westwood, J. T. Sodium salicylate decreases intracellular ATP, induces both heat shock factor binding and chromosomal puffing, but does not induce hsp 70 gene transcription in Drosophila. J. Biol. Chem. 271, 26971–26980 (1996).
  Article CAS PubMed Google Scholar
• Housby, J. N. et al. Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. Cytokine 11, 347–358 (1999).
  Article CAS PubMed Google Scholar
• Palayoor, S. T., Youmell, M. Y., Calderwood, S. K., Coleman, C. N. & Price, B. D. Constitutive activation of IκB kinase α and NF-κB in prostate cancer cells is inhibited by ibuprofen. Oncogene 18, 7389–7394 (1999).
  Article CAS PubMed Google Scholar
• Stevenson, M. A., Zhao, M. J., Asea, A., Coleman, C. N. & Calderwood, S. K. Salicylic acid and aspirin inhibit the activity of RSK2 kinase and repress RSK2-dependent transcription of cyclic AMP response element binding protein- and NF-κ B-responsive genes. J. Immunol. 163, 5608–5616 (1999).
  CAS PubMed Google Scholar
• Ishihara, K., Yamagishi, N. & Hatayama, T. Suppression of heat- and polyglutamine-induced cytotoxicity by nonsteroidal anti-inflammatory drugs. Eur. J. Biochem. 271, 4552–4558 (2004).
  Article CAS PubMed Google Scholar
• Ianaro, A. et al. Anti-inflammatory activity of 15-deoxy-δ12,14-PGJ2 and 2-cyclopenten-1-one: role of the heat shock response. Mol. Pharmacol. 64, 85–93 (2003).
  Article CAS PubMed Google Scholar
• Rossi, A., Elia, G. & Santoro, M. G. 2-cyclopenten-1-one, a new inducer of heat shock protein 70 with antiviral activity. J. Biol. Chem. 271, 32192–32196 (1996).
  Article CAS PubMed Google Scholar
• Zhou, Y. et al. Chloro-oxime derivatives as novel small molecule chaperone amplifiers. Bioorg. Med. Chem. Lett. 19, 3128–3135 (2009).
  Article CAS PubMed Google Scholar
• Zhou, Y. et al. Pyrimido[5,4-e][1,2,4]triazine-5,7(1_H_,6_H_)-dione derivatives as novel small molecule chaperone amplifiers. Bioorg. Med. Chem. Lett. 19, 4303–4307 (2009).
  Article CAS PubMed Google Scholar
• Zhang, B. et al. Identification of small-molecule HSF1 amplifiers by high content screening in protection of cells from stress induced injury. Biochem. Biophys. Res. Commun. 390, 925–930 (2009).
  Article CAS PubMed Google Scholar
• Hayashida, N. et al. Heat shock factor 1 ameliorates proteotoxicity in cooperation with the transcription factor NFAT. EMBO J. 29, 3459–3469 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Batista-Nascimento, L., Neef, D. W., Liu, P. C. C., Rodrigues-Pousada, C. & Thiele, D. J. Deciphering human heat shock transcription factor 1 regulation via post-translational modification in yeast. PLoS ONE 6, e15976 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Rimoldi, M., Servadio, A. & Zimarino, V. Analysis of heat shock transcription factor for suppression of polyglutamine toxicity. Brain Res. Bull. 56, 353–362 (2001). This study shows that constitutively active HSF1, via loss of repressive phosphorylation events, prevents protein aggregation in cell culture models of polyglutamine disease.
  Article CAS PubMed Google Scholar
• Banerjee Mustafi, S., Chakraborty, P. K. & Raha, S. Modulation of Akt and ERK1/2 pathways by resveratrol in chronic myelogenous leukemia (CML) cells results in the downregulation of Hsp70. PLoS ONE 5, e8719 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Khaleque, M. A. et al. Induction of heat shock proteins by heregulin β1 leads to protection from apoptosis and anchorage-independent growth. Oncogene 24, 6564–6573 (2005).
  Article CAS PubMed Google Scholar
• Xavier, I. et al. Glycogen synthase kinase 3β negatively regulates both DNA-binding and transcriptional activities of heat shock factor 1. J. Biol. Chem. 275, 29147–29152 (2000).
  Article CAS PubMed Google Scholar
• Anckar, J. et al. Inhibition of DNA binding by differential sumoylation of heat shock factors. Mol. Cell Biol. 26, 955–964 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Bernier-Villamor, V., Sampson, D. A., Matunis, M. J. & Lima, C. D. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1. Cell 108, 345–356 (2002).
  Article CAS PubMed Google Scholar
• Brunet Simioni, M. et al. Heat shock protein 27 is involved in SUMO-2/3 modification of heat shock factor 1 and thereby modulates the transcription factor activity. Oncogene 28, 3332–3344 (2009).
  Article CAS PubMed Google Scholar
• Fukuda, I. et al. Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate. Chem. Biol. 16, 133–140 (2009).
  Article CAS PubMed Google Scholar
• Parker, J. A. et al. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nature Genet. 37, 349–350 (2005). This study shows that activation of SIR-2 (the C. elegans homolog of SIRT1) via resveratrol rescues neuronal dysfunction in C. elegans and mouse models of polyQ disease.
  Article CAS PubMed Google Scholar
• Kim, D. et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169–3179 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Ladiwala, A. R. A. et al. Resveratrol selectively remodels soluble oligomers and fibrils of amyloid Aβ into off-pathway conformers. J. Biol. Chem. 285, 24228–24237 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Marambaud, P., Zhao, H. & Davies, P. Resveratrol promotes clearance of Alzheimer's disease amyloid-β peptides. J. Biol. Chem. 280, 37377–37382 (2005).
  Article CAS PubMed Google Scholar
• Lu, K.-T. et al. Neuroprotective effects of resveratrol on MPTP-induced neuron loss mediated by free radical scavenging. J. Agric. Food Chem. 56, 6910–6913 (2008).
  Article CAS PubMed Google Scholar
• Zhang, F. et al. Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions. Mol. Pharmacol. 78, 466–477 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Salamanca, H. H., Fuda, N., Shi, H. & Lis, J. T. An RNA aptamer perturbs heat shock transcription factor activity in Drosophila melanogaster. Nucleic Acids Res. 39, 6729–6740 (2011). This work describes an RNA aptamer that interacts with the DNA binding domain of HSF1 and inhibits its binding to promoter heat shock elements.
  Article CAS PubMed PubMed Central Google Scholar
• Liu, P. C. & Thiele, D. J. Modulation of human heat shock factor trimerization by the linker domain. J. Biol. Chem. 274, 17219–17225 (1999).
  Article CAS PubMed Google Scholar
• Finkbeiner, S. Bridging the Valley of Death of therapeutics for neurodegeneration. Nature Med. 16, 1227–1232 (2010).
  Article CAS PubMed Google Scholar
• Aguzzi, A. & O'Connor, T. Protein aggregation diseases: pathogenicity and therapeutic perspectives. Nature Rev. Drug Discov. 9, 237–248 (2010).
  Article CAS Google Scholar
• Hampel, H. et al. Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives. Nature Rev. Drug Discov. 9, 560–574 (2010).
  Article CAS Google Scholar
• Schapira, A. H. V. Challenges to the development of disease-modifying therapies in Parkinson's disease. Eur. J. Neurol. 18 (Suppl. 1), 16–21 (2011).
  Article PubMed Google Scholar
• Murray, A. N., Solomon, J. P., Wang, Y. J., Balch, W. E. & Kelly, J. W. Discovery and characterization of a mammalian amyloid disaggregation activity. Protein Sci. 19, 836–846 (2010). This work describes the discovery of a mammalian disaggregase with the ability to disaggregate β-amyloid aggregates.
  Article CAS PubMed PubMed Central Google Scholar
• Opar, A. Hope builds for earlier detection of Alzheimer's disease. Nature Rev. Drug Discov. 9, 579–581 (2010).
  Article CAS Google Scholar
• Nielsen, P. A., Andersson, O., Hansen, S. H., Simonsen, K. B. & Andersson, G. Models for predicting blood–brain barrier permeation. Drug Discov. Today 16, 472–475 (2011).
  Article CAS PubMed Google Scholar
• Pardridge, W. M. Alzheimer's disease drug development and the problem of the blood-brain barrier. Alzheimers Dement. 5, 427–432 (2009).
  Article PubMed PubMed Central Google Scholar
• Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3–26 (2001).
  Article CAS PubMed Google Scholar
• Cudkowicz, M. E. et al. Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis. Muscle Nerve 38, 837–844 (2008).
  Article CAS PubMed Google Scholar
• Milane, A. et al. Brain and plasma riluzole pharmacokinetics: effect of minocycline combination. J. Pharm. Pharm. Sci. 12, 209–217 (2009).
  Article CAS PubMed Google Scholar
• Kumar, S. et al. Extracellular phosphorylation of the amyloid β-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease. EMBO J. 30, 2255–2265 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Williams, T. L. & Serpell, L. C. Membrane and surface interactions of the Alzheimer's Aβ peptide: insights into the mechanism of cytotoxicity. FEBS J. 278, 3905–3917 (2011).
  Article CAS PubMed Google Scholar
• Cohen, F. E. & Kelly, J. W. Therapeutic approaches to protein-misfolding diseases. Nature 426, 905–909 (2003).
  Article CAS PubMed Google Scholar
• Labbadia, J. et al. Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease. J. Clin. Invest. 121, 3306–3319 (2011). This study demonstrates that activation of HSF1-dependent chaperone protein expression via an HSP90 inhibitor transiently ameliorates disease phenotypes in a mouse model of polyQ-based disease as a result of decreased promoter acetylation.
  Article CAS PubMed PubMed Central Google Scholar
• Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).
  Article CAS PubMed Google Scholar
• Biamonte, M. A. et al. Heat shock protein 90: inhibitors in clinical trials. J. Med. Chem. 53, 3–17 (2010).
  Article CAS PubMed Google Scholar
• Lancet, J. E. et al. Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia. Leukemia 24, 699–705 (2010).
  Article CAS PubMed Google Scholar
• Nowakowski, G. S. et al. A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer. Clin. Cancer Res. 12, 6087–6093 (2006).
  Article CAS PubMed Google Scholar
• Brandt, G. E. L., Schmidt, M. D., Prisinzano, T. E. & Blagg, B. S. J. Gedunin, a novel Hsp90 inhibitor: semisynthesis of derivatives and preliminary structure–activity relationships. J. Med. Chem. 51, 6495–6502 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kikuchi, T. et al. Cytotoxic and apoptosis-inducing activities of limonoids from the seeds of Azadirachta indica (neem). J. Nat. Prod. 74, 866–870 (2011).
  Article CAS PubMed Google Scholar
• Traynor, B. J. et al. Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology 67, 20–27 (2006).
  Article CAS PubMed Google Scholar
• Bensimon, G. et al. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study. Brain 132, 156–171 (2009).
  Article PubMed Google Scholar
• Nanke, Y. et al. Geranylgeranylacetone, a non-toxic inducer of heat shock protein, induces cell death in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Mod. Rheumatol. 19, 379–383 (2009).
  Article CAS PubMed Google Scholar
• Nishida, T. et al. Geranylgeranylacetone protects against acetaminophen-induced hepatotoxicity by inducing heat shock protein 70. Toxicology 219, 187–196 (2006).
  Article CAS PubMed Google Scholar
• Shirakabe, H. et al. Clinical evaluation of teprenone, a mucosal protective agent, in the treatment of patients with gastric ulcers: a nationwide, multicenter clinical study. Clin. Ther. 17, 924–935 (1995).
  Article CAS PubMed Google Scholar