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Previous Article | Next Article
The Journal of Neuroscience, March 15, 2003, 23(6):2203
Heat Shock Protein 70 Chaperone Overexpression Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model by Reducing Nuclear-Localized Mutant Androgen Receptor Protein
Hiroaki Adachi1, Masahisa Katsuno1, Makoto Minamiyama1, Chen Sang1, Gerassimos Pagoulatos2, Charalampos Angelidis2, Moriaki Kusakabe3, Atsushi Yoshiki4, Yasushi Kobayashi1, Manabu Doyu1, and Gen Sobue1 1 Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya 466-8550, Japan, 2 Department of General Biology, University of Ioannina, School of Medicine, Ioannina GR-45110, Greece, 3 ANB Tsukuba Institute, ALOKA Company, Ltd., 1103 Fukaya, Kasumigaura, Niihari, Ibaraki 300-0134, Japan, and 4 Experimental Animal Division, Department of Biological Systems, BioResource Center, The Institute of Physical and Chemical Research (RIKEN) Tsukuba Institute 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan
Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR). The nuclear inclusions consisting of the mutant AR protein are characteristic and combine with many components of ubiquitin-proteasome and molecular chaperone pathways, raising the possibility that misfolding and altered degradation of mutant AR may be involved in the pathogenesis. We have reported that the overexpression of heat shock protein (HSP) chaperones reduces mutant AR aggregation and cell death in a neuronal cell model (Kobayashi et al., 2000). To determine whether increasing the expression level of chaperone improves the phenotype in a mouse model, we cross-bred SBMA transgenic mice with mice overexpressing the inducible form of human HSP70. We demonstrated that high expression of HSP70 markedly ameliorated the motor function of the SBMA model mice. In double-transgenic mice, the nuclear-localized mutant AR protein, particularly that of the large complex form, was significantly reduced. Monomeric mutant AR was also reduced in amount by HSP70 overexpression, suggesting the enhanced degradation of mutant AR. These findings suggest that HSP70 overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR, probably caused by enhanced mutant AR degradation. Our study may provide the basis for the development of an HSP70-related therapy for SBMA and other polyQ diseases.
Key words: HSP70; chaperone; polyglutamine; SBMA; transgenic mice; protein degradation
Copyright © 2003 Society for Neuroscience 0270-6474/03/2362203-09$05.00/0
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