| Co-Investigator(Kenkyū-buntansha) |
SOBUE Gen Nagoya University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (20148315)
INUKAI Akira Nagoya University, University Hospital, Research Associate, 医学部附属病院, 助手 (30314016)
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| Research Abstract |
Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract, in the androgen receptor (AR) gene. We generated transgenic mouse model expressing the full-length human AR containing either 24 or 97 CAG repeats under the control of a cytomegalovirus enhancer and a chicken β-actin promoter (AR-97Q mice). First, we castrated male AR-97Q mice. Castrated males showed profound improvement of their motor function, body weight, lifespan and nuclear accumulation of the mutant AR. On the other hand, testosterone administration caused a significant aggravation of their symptoms and enhanced nuclear accumulation of the mutant AR in female mice. Nuclear accumulation of the mutant protein with an expended polyQ tract is likely to be important in inducing neuronal cell dysfunction and degeneration in the majority of the polyQ diseases. Castration of the males pre
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vented the nuclear accumulation of the mutant AR by reducing the testosterone level, and improved their motor function. Similarly, testosterone blockade therapy, using leuprorelin, a LHRH analogue which reduces testosterone release from the testis, showed a marked amelioration of motor function and nuclear accumulation of the mutant AR. On the basis of these results, we started the double-blind clinical trial using leuprorelin.
Next, we cross-bred AR-97Q mice with mice over-expressing the inducible form of human HSP70. High expression of HSP70 markedly ameliorated motor function of AR-97Q mice. In double transgenic mice, nuclear mutant AR accumulation, particularly that of the large complex form, was significantly reduced. Monomeric mutant AR was also reduced in amount by HSP70 over-expression, suggesting the enhanced degradation of mutant AR. These findings suggest that HSP70 over-expression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR, which probably due to enhanced mutant AR degradation. Less
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