Key points are not available for this paper at this time.
Many neurodegenerative diseases including Alzheimer, Parkinson, and polyglutamine (polyQ) diseases are thought to be caused by protein misfolding. The polyQ diseases, including Huntington disease and spinocerebellar ataxias (SCAs), are caused by abnormal expansions of the polyQ stretch in disease-causing proteins, which trigger misfolding of these proteins, resulting in their deposition as inclusion bodies in affected neurons. Although genetic expression of molecular chaperones has been shown to suppress polyQ protein misfolding and neurodegeneration, toward developing a therapy, it is ideal to induce endogenous molecular chaperones by chemical administration. In this study, we assessed the therapeutic effects of heat shock transcription factor 1 (HSF1)-activating compounds, which induce multiple molecular chaperones, on polyQ-induced neurodegeneration in vivo. We found that oral administration of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) markedly suppresses compound eye degeneration and inclusion body formation in a Drosophila model of SCA. 17-AAG also dramatically rescued the lethality of the SCA model (74.1% rescue) and suppressed neurodegeneration in a Huntington disease model (46.3% rescue), indicating that 17-AAG is widely effective against various polyQ diseases. 17-AAG induced Hsp70, Hsp40, and Hsp90 expression in a dose-dependent manner, and the expression levels correlated with its therapeutic effects. Furthermore, knockdown of HSF1 abolished the induction of molecular chaperones and the therapeutic effect of 17-AAG, indicating that its therapeutic effects depend on HSF1 activation. Our study indicates that induction of multiple molecular chaperones by 17-AAG treatment is a promising therapeutic approach for a wide range of polyQ diseases and possibly other neurodegenerative diseases. Many neurodegenerative diseases including Alzheimer, Parkinson, and polyglutamine (polyQ) diseases are thought to be caused by protein misfolding. The polyQ diseases, including Huntington disease and spinocerebellar ataxias (SCAs), are caused by abnormal expansions of the polyQ stretch in disease-causing proteins, which trigger misfolding of these proteins, resulting in their deposition as inclusion bodies in affected neurons. Although genetic expression of molecular chaperones has been shown to suppress polyQ protein misfolding and neurodegeneration, toward developing a therapy, it is ideal to induce endogenous molecular chaperones by chemical administration. In this study, we assessed the therapeutic effects of heat shock transcription factor 1 (HSF1)-activating compounds, which induce multiple molecular chaperones, on polyQ-induced neurodegeneration in vivo. We found that oral administration of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) markedly suppresses compound eye degeneration and inclusion body formation in a Drosophila model of SCA. 17-AAG also dramatically rescued the lethality of the SCA model (74.1% rescue) and suppressed neurodegeneration in a Huntington disease model (46.3% rescue), indicating that 17-AAG is widely effective against various polyQ diseases. 17-AAG induced Hsp70, Hsp40, and Hsp90 expression in a dose-dependent manner, and the expression levels correlated with its therapeutic effects. Furthermore, knockdown of HSF1 abolished the induction of molecular chaperones and the therapeutic effect of 17-AAG, indicating that its therapeutic effects depend on HSF1 activation. Our study indicates that induction of multiple molecular chaperones by 17-AAG treatment is a promising therapeutic approach for a wide range of polyQ diseases and possibly other neurodegenerative diseases. The accumulation and deposition of misfolded proteins in the brain has been recognized as a common molecular pathogenesis of various neurodegenerative diseases including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and the polyglutamine (polyQ) 4The abbreviations used are: polyQpolyglutamineSCAspinocerebellar ataxiaHSF1heat shock transcription factor 117-AAG17-(allylamino)-17-demethoxygeldanamycinGAgeldanamycinRAradicicolCLcelastrolSBsodium butyrateGGAgeranylgeranylacetoneHAhemagglutininSL2Schneider line 2HRPhorseradish peroxidaseRTreverse transcriptionRNAiRNA interference. diseases, and hence these diseases are called protein misfolding diseases (1Ross C.A. Poirier M.A. Nat. Rev. Mol. Cell Biol. 2005; 6: 891-898Crossref PubMed Scopus (521) Google Scholar). Indeed, most genetic mutations responsible for these diseases produce mutant proteins that are prone to be misfolded. These facts strongly indicate that protein misfolding commonly occurs as the initial step in the pathogenic cascade of neurodegenerative diseases, and hence protein misfolding is considered to be a common therapeutic target for these neurodegenerative diseases. polyglutamine spinocerebellar ataxia heat shock transcription factor 1 17-(allylamino)-17-demethoxygeldanamycin geldanamycin radicicol celastrol sodium butyrate geranylgeranylacetone hemagglutinin Schneider line 2 horseradish peroxidase reverse transcription RNA interference. The polyQ diseases are a group of inherited neurodegenerative diseases including Huntington disease, various types of spinocerebellar ataxia (SCA1, 2, 6, 7, and 17 and SCA3/MJD), dentatorubral-pallidoluysian atrophy, and spinobulbar muscular atrophy, all of which are caused by expansions of the polyQ stretch to greater than 35-40 repeats in each disease-causing protein (2Gusella J.F. MacDonald M.E. Nat. Rev. Neurosci. 2000; 1: 109-115Crossref PubMed Scopus (325) Google Scholar, 3Zoghbi H.Y. Orr H.T. Annu. Rev. Neurosci. 2000; 23: 217-247Crossref PubMed Scopus (1117) Google Scholar). These expanded polyQ stretches cause misfolding of the disease-causing proteins, leading to their pathogenic interactions with themselves (aggregation) or other cellular proteins, resulting in their deposition and recruitment as inclusion bodies in affected neurons (1Ross C.A. Poirier M.A. Nat. Rev. Mol. Cell Biol. 2005; 6: 891-898Crossref PubMed Scopus (521) Google Scholar). The pathogenic interactions of misfolded polyQ proteins with other cellular proteins such as transcription factors, proteasome subunits, and cytoskeletal proteins have been reported to cause dysfunction of these proteins, eventually leading to neuronal dysfunction (4Bence N.F. Sampat R.M. Kopito R.R. Science. 2001; 292: 1552-1555Crossref PubMed Scopus (1857) Google Scholar, 5Nagai Y. Onodera O. Chun J. Strittmatter W.J. Burke J.R. Exp. Neurol. 1999; 155: 195-203Crossref PubMed Scopus (21) Google Scholar, 6Steffan J.S. Kazantsev A. Spasic-Boskovic O. Greenwald M. Zhu Y.Z. Gohler H. Wanker E.E. Bates G.P. Housman D.E. Thompson L.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 6763-6768Crossref PubMed Scopus (888) Google Scholar). Although therapeutic approaches against the dysfunction of each of these cellular proteins have been proposed to date, such as histone deacetylase inhibitors to improve transcriptional dysregulation (7Steffan J.S. Bodai L. Pallos J. Poelman M. McCampbell A. Apostol B.L. Kazantsev A. Schmidt E. Zhu Y.Z. Greenwald M. Kurokawa R. Housman D.E. Jackson G.R. Marsh J.L. Thompson L.M. Nature. 2001; 413: 739-743Crossref PubMed Scopus (1060) Google Scholar), their therapeutic effects were limited because polyQ-induced neuronal dysfunction results from the dysfunction of multiple cellular proteins (2Gusella J.F. MacDonald M.E. Nat. Rev. Neurosci. 2000; 1: 109-115Crossref PubMed Scopus (325) Google Scholar). In contrast, misfolding of the polyQ protein is likely the initial event in the pathogenic cascade, and hence suppression of protein misfolding is expected to inhibit a wide range of multiple downstream events, resulting in the most effective suppression of neuronal dysfunction. Molecular chaperones are known to suppress protein misfolding by synergistically assisting misfolded proteins in the refolding process, as well as newly synthesized proteins in the folding process. For example, Hsp70 has been reported to act in concert with Hsp40 to suppress misfolding of various polyQ proteins in vitro, resulting in suppression of their aggregation (8Kobayashi Y. Kume A. Li M. Doyu M. Hata M. Ohtsuka K. Sobue G. J. Biol. Chem. 2000; 275: 8772-8778Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 9Muchowski P.J. Schaffar G. Sittler A. Wanker E.E. Hayer-Hartl M.K. Hartl F.U. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 7841-7846Crossref PubMed Scopus (552) Google Scholar). In a Drosophila model of the polyQ diseases, co-expression of Hsp70 and Hsp40 has been reported to synergistically suppress misfolding of the polyQ protein, resulting in remarkable suppression of polyQ-induced neurodegeneration, although expression of Hsp70 or Hsp40 alone exhibits weaker suppression (10Chan H.Y. Warrick J.M. Gray-Board G.L. Paulson H.L. Bonini N.M. Hum. Mol. Genet. 2000; 9: 2811-2820Crossref PubMed Scopus (278) Google Scholar, 11Kazemi-Esfarjani P. Benzer S. Science. 2000; 287: PubMed Scopus Google Scholar, J.M. H.Y. Gray-Board G.L. Y. Paulson H.L. Bonini N.M. Nat. Genet. 1999; 23: PubMed Scopus Google Scholar). Furthermore, genetic expression of Hsp70 or Hsp40 alone is known to cause to which is chaperones are (10Chan H.Y. Warrick J.M. Gray-Board G.L. Paulson H.L. Bonini N.M. Hum. Mol. Genet. 2000; 9: 2811-2820Crossref PubMed Scopus (278) Google Scholar, P. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), that the of the of molecular chaperones is for their P.J. J.L. Nat. Rev. Neurosci. 2005; 6: PubMed Scopus Google Scholar). In expression of other molecular chaperones such as and is also reported to suppress polyQ-induced in K. Y. H. Y. Sobue G. Ohtsuka K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. H. M. K. K. J. Neurosci. PubMed Google Scholar, A. O. J. Hum. Mol. Genet. PubMed Scopus Google Scholar). on these expression of multiple molecular chaperones is expected to synergistically suppress polyQ-induced neurodegeneration and to have to of molecular chaperones to various types of cellular is known to be by heat shock transcription factor 1 HSF1 is in the and is in a protein including Hsp90 J. Y. R. Full Text Full Text PDF PubMed Scopus Google Scholar). to HSF1 from the Hsp90 protein the and to the heat shock in the of various molecular to induce their expression R. G. R. Mol. Cell Biol. PubMed Scopus Google Scholar). of HSF1 is various such as as well as M.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. H. M. 2005; PubMed Scopus Google Scholar). In HSF1 is in to heat shock in and multiple molecular chaperones such as Hsp70 and Hsp40, which against heat shock on the M. A. L. Cell 2000; PubMed Scopus Google Scholar, J.L. R. Y. R. Cell 1999; PubMed Google Scholar). Furthermore, expression of a mutant of which the that to the Hsp90 protein has been reported to suppress polyQ protein misfolding induction of molecular chaperones M. E. Y. Y. S. A. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). HSF1 has been considered to be therapeutic target for the polyQ diseases. Although genetic expression of molecular chaperones and a mutant of HSF1 polyQ-induced in P. Benzer S. Science. 2000; 287: PubMed Scopus Google Scholar, J.M. H.Y. Gray-Board G.L. Y. Paulson H.L. Bonini N.M. Nat. Genet. 1999; 23: PubMed Scopus Google Scholar, M. E. Y. Y. S. A. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), of the brain is a step toward developing a therapy, it is ideal to induce endogenous molecular chaperones by administration of chemical compounds, of to are known to HSF1 and to induce multiple endogenous molecular chaperones J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). These Hsp90 which HSF1 from the Hsp90 protein and protein which the of leading to of HSF1 J. Y. R. Full Text Full Text PDF PubMed Scopus Google Scholar, K. K. H. J. Mol. Cell Full Text Full Text PDF PubMed Scopus Google Scholar). In this study, we the therapeutic effects of administration of various on polyQ-induced neurodegeneration in vivo. We that oral administration of 17-(allylamino)-17-demethoxygeldanamycin a of markedly suppresses polyQ-induced neurodegeneration in Drosophila of polyQ diseases induction of multiple molecular Our study indicates the of as therapeutic for a wide range of polyQ diseases as well as other neurodegenerative diseases. and were and the or have been J.M. Paulson H.L. Gray-Board G.L. Bonini N.M. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The line the from the Drosophila The and a of the protein with the of and proteins, and the line of the protein with the of the For the the line and the line were used J.M. Paulson H.L. Gray-Board G.L. Bonini N.M. Full Text Full Text PDF PubMed Scopus Google Scholar). The chemical to be were in in and with Drosophila 17-AAG from geldanamycin and radicicol were from celastrol from and sodium butyrate from with by These were used for the 17-AAG, and and and and and These the the and of the For heat shock were for and for 1 and the therapeutic effects of on compound eye degeneration in the of the compound eye of were a model the therapeutic effects of on degeneration in the of with 17-AAG, or were in and and in were 1 and with were a model with a model and the of The of of degeneration by the in the of the and by the in the of in the The of in and were assessed for each for treatment The are as the For eye of the with 17-AAG were from and in The eye were with a as the to the protein and as the The were a model The of the eye with inclusion bodies of the protein and that of the with the protein were of The of in each eye to the of inclusion body were for each treatment The are as the the therapeutic effects of 17-AAG on the to of the protein in the we for the with the in to the of the are expected to the and the which the protein, of the are expected to the and which the The of the to the by the of by that of to the of the their to The of of the lethality by the in the the and by the in the of the were for each treatment and the were The are as the the effect of 17-AAG on the expression of the protein, of the with 17-AAG were in of and for The were on a and The were with a to the protein or a peroxidase or were used as the HSF1 protein in Schneider line 2 a and were The RNA from bodies or of of the and the protein alone the to the and reverse with We of Hsp70, Hsp40, and Hsp90 with the and and and and of protein a also with the and The were on a and by For with the and The of each by to to the the expression levels of each the of each of the the protein alone or the HSF1 by that of the The were The are as the and of expression of the HSF1 protein, a for the of Drosophila HSF1 Y. H. M. 2005; PubMed Scopus Google Scholar), with a the to the For the HSF1 knockdown the repeats to the to of the HSF1 by the of the HSF1 to the for HSF1 the by Cell and which were from were in with the of HSF1 were with the with the or as well as the as a to the The were and the were to 17-AAG polyQ-induced in the therapeutic effects of compounds, which induce multiple endogenous molecular chaperones, on polyQ-induced neurodegeneration, we the a the of a of resulting in of HSF1 J. Y. R. Full Text Full Text PDF PubMed Scopus Google Scholar). 17-AAG, a of the to inhibit Hsp90 has than J. J. R. E. E. J. A. L. Proc. Scholar). also the of Hsp90 S. S. L.M. Cell PubMed Scopus Google Scholar). a HSF1 G. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). protein leading to the and of HSF1 K. K. H. J. Mol. Cell Full Text Full Text PDF PubMed Scopus Google Scholar). We Drosophila polyQ disease to the therapeutic effects of oral administration of the compounds, because Drosophila has been shown to be a in model to study polyQ-induced neurodegeneration J.M. Paulson H.L. Gray-Board G.L. Bonini N.M. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). We the by in to the line which the protein in the eye the resulting in compound eye degeneration J.M. Paulson H.L. Gray-Board G.L. Bonini N.M. Full Text Full Text PDF PubMed Scopus Google Scholar). with the that 17-AAG is most effective against polyQ-induced compound eye degeneration 1 and 17-AAG treatment of and strongly suppressed polyQ-induced compound eye degeneration 2, treatment a therapeutic effect 17-AAG treatment to improve compound eye degeneration in the indicating that the therapeutic effect of 17-AAG is dose-dependent to with of and also suppression of polyQ-induced compound eye degeneration treatment and with from to also effective against polyQ-induced compound eye degeneration treatment with to or to and with the therapeutic effects of a histone deacetylase which reported to suppress polyQ-induced neurodegeneration (7Steffan J.S. Bodai L. Pallos J. Poelman M. McCampbell A. Apostol B.L. Kazantsev A. Schmidt E. Zhu Y.Z. Greenwald M. Kurokawa R. Housman D.E. Jackson G.R. Marsh J.L. Thompson L.M. Nature. 2001; 413: 739-743Crossref PubMed Scopus (1060) Google Scholar), 17-AAG a greater of polyQ-induced compound eye degeneration and suppresses polyQ-induced compound eye degeneration in a dose-dependent of the compound eye of with various of 17-AAG treatment of and strongly suppressed compound eye degeneration in the treatment 17-AAG treatment to improve compound eye degeneration in the These indicate that 17-AAG treatment to suppresses polyQ-induced neurodegeneration in a dose-dependent is are widely effective against various polyQ diseases, we 17-AAG, and to the line which the protein in the eye the resulting in degeneration M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The of neurons in the be as a in the of in each and which has We found that 17-AAG treatment markedly suppresses resulting in in the of from to in the and to a with and the of in the to rescue) and to rescue), and which were levels to treatment rescue) although the suppression the 17-AAG the most effective against degeneration in the with their therapeutic effects in the These indicate that 17-AAG widely suppresses eye degeneration induced by various polyQ We 17-AAG suppresses polyQ-induced neurodegeneration the because various of the are widely affected in of the protein the the the of their to because of neurodegeneration expression of the protein, which has a polyQ cause We found that 17-AAG treatment the of the to a of the These indicate that 17-AAG is effective against polyQ-induced neurodegeneration the and its is limited to compound eye We that 17-AAG, is effective against neurodegeneration in Drosophila of various polyQ diseases. 17-AAG of the polyQ the effect of 17-AAG on misfolding of the polyQ protein, we polyQ inclusion body formation 17-AAG treatment in a Drosophila polyQ disease polyQ proteins are known to and to eventually as inclusion bodies in also in Drosophila J.M. Paulson H.L. Gray-Board G.L. Bonini N.M. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). of the eye of the which the protein the inclusion bodies in the to the as reported J.M. Paulson H.L. Gray-Board G.L. Bonini N.M. Full Text Full Text PDF PubMed Scopus Google Scholar). We found that the with 17-AAG have inclusion bodies as with the and the and of inclusion bodies in the were by 17-AAG treatment and that 17-AAG suppresses polyQ inclusion body For of the effect of 17-AAG on inclusion body we the of the eye with inclusion bodies The of the with to the with of the protein has been shown to with disease J.M. L.M. J. Paulson H.L. Bonini N.M. Mol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), because of and hence expression of the protein in the of the eye and toward the We found that 17-AAG treatment the in the eye of the from to These indicate that 17-AAG inclusion body formation of the In the of the protein in the to that in and that the in inclusion body formation by 17-AAG treatment is to a in the expression of the that 17-AAG treatment the polyQ protein expression we protein expression by We found that the expression of the protein in the to that in These that 17-AAG suppresses polyQ inclusion body formation by suppression of protein misfolding than by the of the polyQ protein expression of 17-AAG on polyQ-induced with the of Molecular the therapeutic effects of 17-AAG on polyQ-induced neurodegeneration depend on induction of molecular chaperones, we assessed their expression levels 17-AAG We the expression levels of Hsp70, Hsp40, and Hsp90 in the by because these molecular chaperones are reported to suppress polyQ-induced P. Benzer S. Science. 2000; 287: PubMed Scopus Google Scholar, J.M. H.Y. Gray-Board G.L. Y. Paulson H.L. Bonini N.M. Nat. Genet. 1999; 23: PubMed Scopus Google Scholar, K. H. M. K. K. J. Neurosci. PubMed Google Scholar). We found that 17-AAG treatment to expression of Hsp70, Hsp40, and Hsp90 in the treatment For of the in the levels of these we We found that the expression levels of Hsp70 in the are by 17-AAG treatment from to in a dose-dependent and although the levels of induction are as as heat shock treatment 17-AAG treatment induce expression of Hsp70 all which is with the of a therapeutic effect on polyQ-induced neurodegeneration We also found that 17-AAG treatment to induced expression of Hsp40 in a dose-dependent and treatment The expression levels of Hsp90 were also by 17-AAG treatment to in a dose-dependent and and were to that heat shock treatment 17-AAG treatment induced expression of Hsp90 we that 17-AAG treatment to multiple molecular chaperones in a dose-dependent and that their expression levels with the therapeutic effects of 17-AAG on polyQ-induced of 17-AAG on polyQ-induced by HSF1 the therapeutic effects of 17-AAG on polyQ-induced neurodegeneration induction of multiple molecular chaperones are by HSF1 activation. For this we knockdown of endogenous HSF1 the therapeutic effects of 17-AAG on the We a RNA against HSF1 and its of HSF1 knockdown in Drosophila were with expression for the HSF1 protein and HSF1 and the were to In the with the HSF1 we found that the HSF1 as a because of as reported In contrast, the HSF1 protein in the with the HSF1 and the HSF1 indicating that this HSF1 expression of the HSF1 we HSF1 this HSF1 the and that these in their compound We these HSF1 with the to the effects of HSF1 knockdown on 17-AAG knockdown of endogenous HSF1 abolished the therapeutic effect of 17-AAG on compound eye degeneration in the 7, and The of compound eye degeneration in the the HSF1 to that in the 7, and These indicate that endogenous HSF1 is for the therapeutic effects of 17-AAG on polyQ-induced we the that knockdown of HSF1 the therapeutic effects of 17-AAG of the induction of molecular chaperones, because HSF1 knockdown polyQ-induced compound eye degeneration in the with a G. S. A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). the therapeutic effects of 17-AAG depend on induction of molecular chaperones, we the expression of Hsp70 in the the HSF1 We of the because the HSF1 is in the eye the We that 17-AAG treatment expression of Hsp70 in the of the as in their bodies knockdown of endogenous HSF1 dramatically the expression of Hsp70 in the which to that in the These indicate that endogenous HSF1 is for induction of molecular chaperones by 17-AAG and we that the therapeutic effects of 17-AAG on polyQ-induced neurodegeneration depend on induction of molecular neurodegenerative diseases including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and the polyQ diseases are thought to be caused by protein and hence suppression of protein misfolding by molecular chaperones is considered to be a common therapeutic approach for these neurodegenerative diseases P.J. J.L. Nat. Rev. Neurosci. 2005; 6: PubMed Scopus Google Scholar). In genetic expression of Hsp70, a molecular has been shown to suppress neurodegeneration in and of Parkinson disease, amyotrophic lateral sclerosis, and the polyQ diseases H.Y. Bonini N.M. Science. PubMed Scopus Google Scholar, J. J. 1999; PubMed Scopus Google Scholar, Y. P. R. Orr H.T. H.Y. Hum. Mol. Genet. 2001; PubMed Scopus Google Scholar). Furthermore, induction of multiple molecular chaperones including Hsp70 and Hsp40 by genetic expression of a mutant of HSF1 has been shown to be effective against amyotrophic lateral and the polyQ diseases with expression of Hsp70 alone M. E. Y. Y. S. A. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. PubMed Scopus Google Scholar). a step toward developing a therapy, we the therapeutic effects of induction of multiple endogenous molecular chaperones by in Drosophila of the polyQ diseases. In this study, we that 17-AAG treatment suppresses neurodegeneration induction of Hsp70, Hsp40 and Hsp90 in a Drosophila model of of the polyQ diseases 2, and 17-AAG also suppressed neurodegeneration in a model of Huntington disease, polyQ disease indicating that 17-AAG is widely effective against various polyQ diseases. In 17-AAG inclusion bodies of misfolded polyQ proteins with that co-expression of Hsp70 with Hsp40 synergistically suppresses polyQ inclusion body formation (8Kobayashi Y. Kume A. Li M. Doyu M. Hata M. Ohtsuka K. Sobue G. J. Biol. Chem. 2000; 275: 8772-8778Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, M.A. Exp. Cell PubMed Scopus Google Scholar). induction of Hsp70 by treatment has been reported to suppress neurodegeneration in a Drosophila model of Parkinson disease Bonini N.M. Nat. PubMed Scopus Google Scholar). of molecular chaperones by treatment with which is also known to has been reported to suppress neurodegeneration in a model of amyotrophic lateral J.R. J. G. L. Nat. PubMed Scopus Google Scholar). treatment with to induce multiple endogenous molecular chaperones is a promising therapeutic approach for the polyQ diseases as well as other neurodegenerative diseases. We that 17-AAG is the most effective against polyQ-induced neurodegeneration in Drosophila the we In to 17-AAG, and also weaker suppression of polyQ-induced neurodegeneration, with that and suppress polyQ protein misfolding in K. S. M. R. A. Bates G.P. Hum. Mol. Genet. PubMed Scopus Google Scholar). the other effective against polyQ-induced neurodegeneration in this study, although it has been reported to the of a model of spinobulbar muscular M. H. M. M. Doyu M. Sobue G. Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar). has been to HSF1 by the of Hsp70 M. S. K. Y. S. A. M. S. H. PubMed Scopus Google Scholar), which for the of its therapeutic effect in 17-AAG has been shown to be than J. J. R. E. E. J. A. L. Proc. Scholar), which and 17-AAG is in for the treatment of L. J. PubMed Scopus Google Scholar). In of 17-AAG has been reported to induce multiple molecular chaperones in their M. H. M. M. A. Doyu M. Sobue G. Nat. 2005; PubMed Scopus Google Scholar). 17-AAG is the most promising therapeutic for the polyQ diseases the 17-AAG has been reported to the of a model of spinobulbar muscular by of the mutant protein, Hsp90 protein, its Hsp90 than by induction of molecular chaperones M. H. M. M. A. Doyu M. Sobue G. Nat. 2005; PubMed Scopus Google Scholar). In Hsp90 inhibitors such as and have been reported to of the mutant protein in HSF1 M. J.M. Y. Hum. Mol. Genet. PubMed Scopus Google Scholar), the that the therapeutic effects of these Hsp90 inhibitors are by of HSF1 in the of spinobulbar muscular the of Hsp90 inhibitors has been considered to be limited to spinobulbar muscular In contrast, we that knockdown of HSF1 abolished the induction of molecular chaperones and therapeutic effect of 17-AAG on polyQ-induced neurodegeneration in a Drosophila model of indicating that the therapeutic effect of 17-AAG on induction of molecular chaperones and on of the mutant protein Furthermore, we that 17-AAG is also effective against neurodegeneration in a Drosophila model of Huntington disease with a that 17-AAG suppresses misfolding of the mutant protein its M. Wanker E.E. PubMed Scopus Google Scholar). we that 17-AAG is effective against a wide range of polyQ diseases induction of molecular In this study, we the therapeutic effects of on polyQ-induced neurodegeneration in vivo. We found that oral administration of 17-AAG markedly suppresses polyQ-induced neurodegeneration in Drosophila of polyQ diseases induction of multiple molecular we that 17-AAG is a promising therapeutic for the polyQ diseases as well as other neurodegenerative diseases caused by protein misfolding. We M. H. R. and for We for We also M. Bonini for with the and J. for the and the Drosophila and Drosophila of for the other
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