Journal Article

17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse

Keisuke Tokui, Hiroaki Adachi, Masahiro Waza, Masahisa Katsuno, Makoto Minamiyama, Hideki Doi, Keiji Tanaka, Jun Hamazaki, Shigeo Murata, Fumiaki Tanaka and Gen Sobue

in Human Molecular Genetics

Volume 18, issue 5, pages 898-910
Published in print March 2009 | ISSN: 0964-6906
Published online December 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn419
17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse

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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.

Journal Article.  8598 words.  Illustrated.

Subjects: Genetics and Genomics

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