2004 Fiscal Year Final Research Report Summary
Development of Pathogenesis-based treatment for spinal and bulbar muscular atrophy
| 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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| Keywords | Neurodegeneration / motor neuron / polyglutamine / androgen receptor / histone / heat shock protein / geranylgeranylaceone |
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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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Research Products
(59 results)
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[Journal Article] Gene expression profile of motor neurons in sporadic amyotrophic lateral sclerosis.2005
Author(s)
Jiang YM, Yamamoto M, Kobayashi Y, Yoshihara T, Liang Y, Terao S, Takeuchi H, Ishigaki S, Katsuno M, Adachi H, Niwa J, Tanaka F, Doyu M, Yoshida M, Hashizume Y, Sobue G
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Journal Title
Ann Neurol 57
Pages: 236-251
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients.2005
Author(s)
Adachi H, Katsuno M, Minamiyama M, Sang C, Nakagomi Y, Kobayashi Y, Tanaka F, Doyu M, Inukai A, Yoshida M, Hashizume Y, Sobue G
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[Journal Article] Pathology of early-vs late-onset TTR Met30 familial amyloid polyneuropathy.2004
Author(s)
Koike H, Misu K, Sugiura M, Iijima M, Mori K, Yamamoto M, Hattori N, Mukai E, Ando Y, Dceda S, Sobue G
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Journal Title
Neurology 63
Pages: 129-138
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22,MPZ and Cx32) : a clinicopathological study of 205 Japanese patients.2003
Author(s)
Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa N, Yoshikawa H, Ohnishi A, Hayasaka K, Onodera O, Baba M, Yasuda H, Saito T, Nakashima K, Kira J, Kaji R, Oka N, Sobue G, the Study Group for Hereditary Neuropathy in Japan
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[Journal Article] 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.2003
Author(s)
Adachi H, Katsuno M, Minamiyama M, Sang C, Pagoulatous G, Angelidis C, Kusakabe M, Yoshiki A, Kobayashi Y, Doyu M, Sobue G
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Journal Title
J Neurosci 23(6)
Pages: 2203-2211
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Nerve excitability properties in Charcot-Marie-Tooth disease type 1A.2003
Author(s)
Nodera H, Bostock H, Kuwabara S, Sakamoto T, Asanuma K, Jia-Ying S, Ogawara K, Hattori N, Hirayama M, Sobue G, Kaji R
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「研究成果報告書概要(欧文)」より
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