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.
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.
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Adachi
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.forename: Makoto
authors.initials: M
authors.lastname: Minamiyama
authors.forename: Chen
authors.initials: C
authors.lastname: Sang
authors.forename: Gerassimos
authors.initials: G
authors.lastname: Pagoulatos
authors.forename: Charalampos
authors.initials: C
authors.lastname: Angelidis
authors.forename: Moriaki
authors.initials: M
authors.lastname: Kusakabe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yoshiki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Manabu
authors.initials: M
authors.lastname: Doyu
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000096:biosynthesis* / Q000235:genetics; D009043:Motor Activity / Q000235:genetics; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009154:Mutation; D010641:Phenotype; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D018840:HSP70 Heat-Shock Proteins; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D011944:Receptors, Androgen