RRC ID 2390
Author Adachi H, Katsuno M, Minamiyama M, Sang C, Pagoulatos G, Angelidis C, Kusakabe M, Yoshiki A, Kobayashi Y, Doyu M, Sobue G.
Title 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.
Journal 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.
Volume 23(6)
Pages 2203-11
Published 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
Times Cited 191
Mice RBRC00344 RBRC00373