Treatment of polyglutamine disease using small molecular compound
| Project/Area Number |
17209032
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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 Aichi Medical University, School of Medicine, Professor, 医学部, 教授 (90293703)
TANAKA Fumiaki Nagoya University, Graduate School of Medicine COE Desearcher, Associate Professor, 大学院医学系研究科, COE特任助教授 (30378012)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥50,440,000 (Direct Cost: ¥38,800,000、Indirect Cost: ¥11,640,000)
Fiscal Year 2006: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2005: ¥33,150,000 (Direct Cost: ¥25,500,000、Indirect Cost: ¥7,650,000)
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| Keywords | spinal and bulbar muscular atrophy / molecular chaperone / 17-AAG / GGA / ubiquitin-proteasome / heat shock protein / biomarker / dynactin1 / アンドロゲン受容体 / 神経変性疾患 / 軸索輸送 / ポリグルタミン |
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| Research Abstract |
Spinal and bulbar atrophy (SBMA) is a motor neuron disease caused by a mutation of the gene coding androgen receptor (AR). We have delineated that the pathogenesis of this disease is androgen-dependent, and that androgen deprivation therapy suppresses neurodegeneration in SBMA. These results have now been verified in clinical trials.
In addition, we investigated alternative therapeutic strategies manipulating heat shock proteins (HSPs) which has been construed to be implicated in the pathogenesis of polyglutamine diseases. In a cellular model, 17-allylamino geldanamycin facilitated degradation of mutant AR protein in a dose dependent manner. This compound also improved muscular atrophy and motor weakness in a mouse model of SBMA. On the other hand, geranylgeranyl acetone, an HSP inducer, upregulated Hsp70 expression in the spinal cord, and ameliorated motor dysfunction in the same mouse model.
To carry out effective clinical trials for neurodegenerative diseases including SBMA, it is of importance to identify biomarkers which can be used as a surrogate endpoint. The degree of mutant AR accumulation in the scrotal skin reflected that in the spinal cord, and is correlated with clinical severity of SBMA patients. These findings suggest that mutant AR accumulation in the scrotal skin is a promising biomarker reflecting SBMA pathogenesis.
We have also demonstrated that nuclear accumulation of mutant AR causes transcriptional dysregulation of dynactin1, resulting in abnormal deposit of neurofilament in the distal axon in SBMA. Disruption of axonal transport thus is an important therapeutic target of motor neuron disease such as SBMA. (245 words)
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Report
(3 results)
Research Products
(55 results)
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[Journal Article] Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration2006
Author(s)
Katsuno M, Adachi H, Minamiyama M, Waza M, Tokui K, Banno H, Suzuki K, Onoda Y, Tanaka F, Doyu M, Sobue G
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Journal Title
J Neurosci 26
Pages: 12106-12117
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration.2006
Author(s)
Katsuno M, Adachi H, Minamiyama M, Waza M, Tokui K, Banno H, Suzuki K, Onoda Y, Tanaka F, Doyu M, Sobue G
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Journal Title
J Neurosci 26
Pages: 12106-12117
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration.2005
Author(s)
Waza M, Adachi H, Katsuno M, Minamiyama M, Sang C, Tanaka F, Inukai A, Doyu M, Sobue G
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Journal Title
Nature Med 11
Pages: 1088-1095
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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
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[Journal Article] Widespread nuclear and cytoplasmic mutant androgen receptor accum ulation in spinal and bulbar muscular atrophy.2005
Author(s)
Adachi H, Katsuno M, Minamiyama M, Waza M, Sang C, Nakagomi Y, Kobayashi Y, Tanaka F, Doyu M, Inukai A, Yoshida M, Hashizume Y, Sobue G
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Related Report
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[Journal Article] Neuronal intranuclear hyaline inclusion disease showing motor-sensory and autonomic neuropathy.2005
Author(s)
Sone J, Hishikawa N, Koike H, Hattori N, Hirayama M, Nagamatsu M, Yamamoto M, Tanaka F, Yoshida M, Hashizume Y, Imamura H, Yamada E, Sobue G
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Journal Title
Neurology 65
Pages: 1538-1543
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[Journal Article] The wide spectrum of clinical manifestations in Sjogren's syndrome-associated neuropathy.2005
Author(s)
Mori K, Iijima M, Koike H, Hattori N, Tanaka F, Watanabe H, Katsuno M, Fujita A, Aiba I, Ogata A, Saito T, Asakura K, Yoshida M, Hirayama M, Sobue G
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Journal Title
Brain 128
Pages: 2518-2534
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[Journal Article] Clinical and electrophysiologic correlates of IVIg responsiveness in CIDP.2005
Author(s)
Iijima M, Yamamoto M, Hirayama M, Tanaka F, Katsuno M, Mori K, Koike H, Hattori N, Arimura K, Nakagawa M, Yoshikawa H, Hayasaka K, Onodera O, Baba M, Yasuda H, Saito T, Nakazato M, Nakashima K, Kira J, Kaji R, Oka N, Sobue G
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Journal Title
Neurology 64
Pages: 1471-1475
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