| RRC ID |
2390
|
| 著者 |
Adachi H, Katsuno M, Minamiyama M, Sang C, Pagoulatos G, Angelidis C, Kusakabe M, Yoshiki A, Kobayashi Y, Doyu M, Sobue G.
|
| タイトル |
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.
|
| ジャーナル |
J Neurosci
|
| Abstract |
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.
|
| 巻・号 |
23(6)
|
| ページ |
2203-11
|
| 公開日 |
2003-3-15
|
| DOI |
10.1523/JNEUROSCI.23-06-02203.2003
|
| PII |
23/6/2203
|
| PMID |
12657679
|
| PMC |
PMC6742038
|
| MeSH |
Animals
Blotting, Western
Cell Nucleus / metabolism*
Cell Nucleus / pathology
Crosses, Genetic
Disease Models, Animal
Disease Progression
Gene Expression
HSP70 Heat-Shock Proteins / biosynthesis*
HSP70 Heat-Shock Proteins / genetics
Humans
Immunohistochemistry
Macromolecular Substances
Male
Mice
Mice, Transgenic
Molecular Chaperones / biosynthesis*
Molecular Chaperones / genetics
Motor Activity / genetics
Muscular Atrophy, Spinal / genetics
Muscular Atrophy, Spinal / pathology
Muscular Atrophy, Spinal / physiopathology*
Mutation
Phenotype
Receptors, Androgen / genetics
Receptors, Androgen / metabolism*
Trinucleotide Repeat Expansion / genetics
|
| IF |
5.674
|
| 引用数 |
191
|
|
WOS 分野
|
NEUROSCIENCES
|
| リソース情報 |
| 実験動物マウス |
RBRC00344
RBRC00373 |
