17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration.
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.
Waza
Masahiro
M
Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Adachi
Hiroaki
H
Katsuno
Masahisa
M
Minamiyama
Makoto
M
Sang
Chen
C
Tanaka
Fumiaki
F
Inukai
Akira
A
Doyu
Manabu
M
Sobue
Gen
G
D000818:Animals; D016227:Benzoquinones; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047029:Lactams, Macrocyclic; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology*; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D010455:Peptides / Q000235:genetics*; D010641:Phenotype; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D010455:Peptides; D011944:Receptors, Androgen; D017828:Rifabutin; C097188:polyglutamine; C112765:tanespimycin