Human Molecular Genetics Advance Access originally published online on December 9, 2008
Human Molecular Genetics 2009 18(5):898-910; doi:10.1093/hmg/ddn419
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse
1 Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan 2 Institute for Advanced Research, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan 3 Laboratory of Frontier Science, Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan 4 Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
* To whom correspondence should be addressed. Tel: +81 52-744-2385; Fax: +81 52-744-2384; Email: hadachi{at}med.nagoya-u.ac.jp; sobueg{at}med.nagoya-u.ac.jp
Received October 1, 2008; Revised November 13, 2008; Accepted December 5, 2008
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. P. Dantuma and K. Lindsten Stressing the ubiquitin-proteasome system Cardiovasc Res, January 15, 2010; 85(2): 263 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Maynard, C. Bottcher, Z. Ortega, R. Smith, B. I. Florea, M. Diaz-Hernandez, P. Brundin, H. S. Overkleeft, J.-Y. Li, J. J. Lucas, et al. Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment PNAS, August 18, 2009; 106(33): 13986 - 13991. [Abstract] [Full Text] [PDF]
|
|