| Project/Area Number |
15209031
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Nagoya University |
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Principal Investigator |
SOBUE Gen Nagoya University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (20148315)
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| Co-Investigator(Kenkyū-buntansha) |
DOYU Manabu Nagoya University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (90293703)
INUKAI Akira Nagoya University, University Hospital, Assistant Professor, 医学部附属病院, 講師 (30314016)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥50,440,000 (Direct Cost: ¥38,800,000、Indirect Cost: ¥11,640,000)
Fiscal Year 2004: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
Fiscal Year 2003: ¥36,010,000 (Direct Cost: ¥27,700,000、Indirect Cost: ¥8,310,000)
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| Keywords | Neurodegeneration / motor neuron / polyglutamine / androgen receptor / histone / heat shock protein / geranylgeranylaceone / テストステロン / LHRHアナログ / フルタミド / HSP |
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| Research Abstract |
Spinal and bulbar muscular atrophy(SBMA), a hereditary motor neuron disease affecting adult males, is caused by expansion of CAG trinucleotide repeat in the androgen receptor(AR) gene. Histopathological analysis of the spinal cord from SBMA patients demonstrated that the extent of diffuse nuclear accumulation of mutant AR in motor and sensory neurons of the spinal cord was closely related to CAG repeat length. A transgenic mouse model of SBMA carrying full-length human AR gene containing 97 CAGs showed significant sexual differences in phenotypes which was more progressive in males than females. Testosterone deprivation with either surgical castration or LHRH analogue treatment suppressed nuclear accumulation of mutant AR protein and thereby significantly improved neurological phenotypes and histopathological abnormalities in SBMA mice. Clinical trial of LHRH analogue for SBMA patients is currently being conducted.
Cross-breeding of SBMA transgenic mice with mice overexpressing human Hsp70 resulted in inhibition of nuclear accumulation of mutant AR as well as marked amelioration of the motor function. Hsp70 did not only inhibit aggregation of mutant AR but also facilitated degradation of this protein. In a cell culture model of SBMA, geranylgeranylacetone, Hsp70 inducer enhanced suppressed nuclear accumulation of mutant AR, resulting in mitigation of neurotoxicity exerted by expanded polyglutamine. Oral administration of GGA also alleviated neuronal dysfunction in SBMA mice.
Oral administration of sodium butyrate, a histone deacetylase inhibitor, upregulated histone acetylation and ameliorated phenotypes of SBMA mice, although therapeutic window of sodium butyrate was narrow.
Our results suggest that inhibition of nuclear AR accumulation, enhancement of AR degradation, and restoration of transcription are the targets in pathogenesis-based therapeutic strategies for SBMA. (266 words)
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