Originally published In Press as doi:10.1074/jbc.M710521200 on July 16, 2008

J. Biol. Chem., Vol. 283, Issue 38, 26188-26197, September 19, 2008


Nobuhiro Fujikake{ddagger}12, Yoshitaka Nagai{ddagger}123, H. Akiko Popiel{ddagger}2, Yuma Okamoto{ddagger}2, Masamitsu Yamaguchi§, and Tatsushi Toda{ddagger}

From the {ddagger}Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan and the §Department of Applied Biology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585, Japan


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.

Received for publication, December 26, 2007 , and in revised form, July 14, 2008.

* This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas (to Y. N.; Advanced Brain Science Project, Research on Patho-mechanisms of Brain Disorders, Life of Proteins, and Protein Community) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; by a Grant-in-Aid for the Research Committee for Ataxic Diseases (to Y. N.) from the Ministry of Health, Labor and Welfare, Japan; and by Grants-in-Aid for Scientific Research (B) (to Y. N.) and for Young Scientists (B) (to N. F.) from the Japan Society for the Promotion of Science. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked"advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 These authors contributed equally to this work.

2 Present address: Dept. of Degenerative Neurological Diseases, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.

3 To whom correspondence should be addressed. Tel.:               81-6-68...       ; Fax: 81-6-6879-3389; E-mail: nagai@....

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