2006 Fiscal Year Final Research Report Summary
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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| Keywords | spinal and bulbar muscular atrophy / molecular chaperone / 17-AAG / GGA / ubiquitin-proteasome / heat shock protein / biomarker / dynactin1 |
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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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Research Products
(40 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
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