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

被引：305

作者：

Waza, M ^{[1
]}

Adachi, H ^{[1
]}

Katsuno, M ^{[1
]}

Minamiyama, M ^{[1
]}

Sang, C ^{[1
]}

Tanaka, F ^{[1
]}

Inukai, A ^{[1
]}

Doyu, M ^{[1
]}

Sobue, G ^{[1
]}

机构：

[1] Nagoya Univ, Grad Sch Med, Dept Neurol, Showa Ku, Nagoya, Aichi 4668550, Japan

来源：

NATURE MEDICINE | 2005年 / 11卷 / 10期

关键词：

D O I：

10.1038/nm1298

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1088 / 1095

页数：8

共 52 条

[1] Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients [J].

Adachi, H ;

Katsuno, M ;

Minamiyama, M ;

Waza, M ;

Sang, C ;

Nakagomi, Y ;

Kobayashi, Y ;

Tanaka, F ;

Doyu, M ;

Inukai, A ;

Yoshida, M ;

Hashizume, Y ;

Sobue, G .

BRAIN, 2005, 128 :659-670

[2]

Adachi H, 2003, J NEUROSCI, V23, P2203

[3] Pharmacological prevention of Parkinson disease in Drosophila [J].

Auluck, PK ;

Bonini, NM .

NATURE MEDICINE, 2002, 8 (11) :1185-1186

[4]

Bagatell R, 2001, CLIN CANCER RES, V7, P2076

[5] Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy [J].

Bailey, CK ;

Andriola, IFM ;

Kampinga, HH ;

Merry, DE .

HUMAN MOLECULAR GENETICS, 2002, 11 (05) :515-523

[6]

Beliakoff J, 2003, CLIN CANCER RES, V9, P4961

[7] Mutant conformation of p53 translated in vitro or in vivo requires functional HSP90 [J].

Blagosklonny, MV ;

Toretsky, J ;

Bohen, S ;

Neckers, L .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (16) :8379-8383

[8] Ubiquitination and proteasomal degradation of nucleophosmin-anaplastic lymphoma kinase induced by 17-allylamino-demethoxygeldanamycin: Role of the co-chaperone carboxyl heat shock protein 70-interacting protein [J].

Bonvini, P ;

Dalla Rosa, H ;

Vignes, N ;

Rosolen, A .

CANCER RESEARCH, 2004, 64 (09) :3256-3264

[9] Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1 [J].

Cummings, CJ ;

Mancini, MA ;

Antalffy, B ;

DeFranco, DB ;

Orr, HT ;

Zoghbi, HY .

NATURE GENETICS, 1998, 19 (02) :148-154

[10] Chaperones increase association of tau protein with microtubules [J].

Dou, F ;

Netzer, WJ ;

Tanemura, K ;

Li, F ;

Hartl, FU ;

Takashima, A ;

Gouras, GK ;

Greengard, P ;

Xu, HX .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (02) :721-726

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