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

Nat Med. 2005 Oct;11(10):1088-95. doi: 10.1038/nm1298. Epub 2005 Sep 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoquinones
  • Cell Line
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Lactams, Macrocyclic
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Neurons / drug effects*
  • Motor Neurons / pathology*
  • Muscular Atrophy, Spinal / drug therapy
  • Muscular Atrophy, Spinal / genetics*
  • Muscular Atrophy, Spinal / pathology*
  • Mutation
  • Peptides / genetics*
  • Phenotype
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Rifabutin / analogs & derivatives*
  • Rifabutin / pharmacology
  • Rifabutin / therapeutic use
  • Trinucleotide Repeat Expansion / genetics


  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Peptides
  • Receptors, Androgen
  • Rifabutin
  • polyglutamine
  • tanespimycin