17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse
In: Human Molecular Genetics, Jg. 18 (2008-12-09), S. 898-910
Online
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Zugriff:
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.
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17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse
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Autor/in / Beteiligte Person: | Adachi, Hiroaki ; Tanaka, Keiji ; Hamazaki, Jun ; Waza, Masahiro ; Tanaka, Fumiaki ; Tokui, Keisuke ; Minamiyama, Makoto ; Doi, Hideki ; Sobue, Gen ; Murata, Shigeo ; Katsuno, Masahisa |
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Zeitschrift: | Human Molecular Genetics, Jg. 18 (2008-12-09), S. 898-910 |
Veröffentlichung: | Oxford University Press (OUP), 2008 |
Medientyp: | unknown |
ISSN: | 1460-2083 (print) ; 0964-6906 (print) |
DOI: | 10.1093/hmg/ddn419 |
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