17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse.
The ubiquitin-proteasome system (UPS) is the principal protein degradation system that tags and targets short-lived proteins, as well as damaged or misfolded proteins, for destruction. In spinal and bulbar muscular atrophy (SBMA), the androgen receptor (AR), an Hsp90 client protein, is such a misfolded protein that tends to aggregate in neurons. Hsp90 inhibitors promote the degradation of Hsp90 client proteins via the UPS. In a transgenic mouse model of SBMA, we examined whether a functioning UPS is preserved, if it was capable of degrading polyglutamine-expanded mutant AR, and what might be the therapeutic effects of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), an oral Hsp90 inhibitor. Ubiquitin-proteasomal function was well preserved in SBMA mice and was even increased during advanced stages when the mice developed severe phenotypes. Administration of 17-DMAG markedly ameliorated motor impairments in SBMA mice without detectable toxicity and reduced amounts of monomeric and nuclear-accumulated mutant AR. Mutant AR was preferentially degraded in the presence of 17-DMAG in both SBMA cell and mouse models when compared with wild-type AR. 17-DMAG also significantly induced Hsp70 and Hsp40. Thus, 17-DMAG would exert a therapeutic effect on SBMA via preserved proteasome function.
Tokui
Keisuke
K
Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Adachi
Hiroaki
H
Waza
Masahiro
M
Katsuno
Masahisa
M
Minamiyama
Makoto
M
Doi
Hideki
H
Tanaka
Keiji
K
Hamazaki
Jun
J
Murata
Shigeo
S
Tanaka
Fumiaki
F
Sobue
Gen
G
D000818:Animals; D016227:Benzoquinones / Q000008:administration & dosage*; D004195:Disease Models, Animal; D047029:Lactams, Macrocyclic / Q000008:administration & dosage*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
C410798:AR protein, human; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D010455:Peptides; D011944:Receptors, Androgen; D025801:Ubiquitin; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex