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17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration

Nature Medicine volume 11, pages 1088–1095 (2005)Cite this article

Abstract

Heat-shock protein 90 (Hsp90) functions as part of a multichaperone complex that folds, activates and assembles its client proteins. Androgen receptor (AR), a pathogenic gene product in spinal and bulbar muscular atrophy (SBMA), is one of the Hsp90 client proteins. We examined the therapeutic effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a potent Hsp90 inhibitor, and its ability to degrade polyglutamine-expanded mutant AR. Administration of 17-AAG markedly ameliorated motor impairments in the SBMA transgenic mouse model without detectable toxicity, by reducing amounts of monomeric and aggregated mutant AR. The mutant AR showed a higher affinity for Hsp90-p23 and preferentially formed an Hsp90 chaperone complex as compared to wild-type AR; mutant AR was preferentially degraded in the presence of 17-AAG in both cells and transgenic mice as compared to wild-type AR. 17-AAG also mildly induced Hsp70 and Hsp40. 17-AAG would thus provide a new therapeutic approach to SBMA and probably to other related neurodegenerative diseases.

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Figure 1: Effect of 17-AAG on the AR or chaperones in cultured-cell models.
Figure 2: Immunoprecipitation of wild-type and mutant AR in cultured-cell models.
Figure 3: Pharmacological change in the AR-Hsp90 complex, and the correlation to proteasomal degradation.
Figure 4: Effects of 17-AAG on behavioral and visible phenotypes in male AR-97Q mice.
Figure 5: Effects of 17-AAG on the histopathology of male AR-97Q mice.
Figure 6: Effects of 17-AAG on AR expression in male AR-24Q or 97Q mice.

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Acknowledgements

We thank National Cancer Institute and Kosan Biosciences for kindly providing 17-AAG. This work was supported by a Center of Excellence (COE) grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and by grants from the Ministry of Health, Labor and Welfare, Japan.

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Author notes

  1. Masahiro Waza and Hiroaki Adachi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Masahiro Waza, Hiroaki Adachi, Masahisa Katsuno, Makoto Minamiyama, Chen Sang, Fumiaki Tanaka, Akira Inukai, Manabu Doyu & Gen Sobue

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Supplementary information

Supplementary Fig. 1

Effect of 17-AAG on th expression of mutant AR under the inhibition of the heat-shock response. (PDF 152 kb)

Supplementary Fig. 2

The hematological examination of male AR-97Q mice treated with 17-AAG. (PDF 349 kb)

Supplementary Fig. 3

Quantification of large aggregated and soluble monomeric mutant AR protein by filter-trap assay. (PDF 793 kb)

Supplementary Fig. 4

Effect of 17-AAG on the expression of each chaperone in male AR-97Q mice. (PDF 579 kb)

Supplementary Methods (PDF 149 kb)

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Waza, M., Adachi, H., Katsuno, M. et al. 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat Med 11, 1088–1095 (2005). https://doi.org/10.1038/nm1298

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