| Project/Area Number |
17209031
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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 | Tokyo Medical and Dental University |
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Principal Investigator |
MIZUSAWA Hidehiro Tokyo Medical and Dental University, Dept Neural, Professor (30144091)
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| Co-Investigator(Kenkyū-buntansha) |
YOKOTA Takanori Tokyo Medical and Dental University, Dept Neural, Associate Professor (90231688)
WATASE Kei Tokyo Medical and Dental University, 21st Cent COE program, Lecturer/Associate Prof (30376800)
ISHIKAWA Kinya Tokyo Medical and Dental University, Dept Neural, Lecturer (30313240)
常深 泰司 東京医科歯科大学, 大学院医歯学総合研究科, 助手 (50401344)
融 衆太 東京医科歯科大学, 医学部附属病院, 助手 (50376711)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥50,050,000 (Direct Cost: ¥38,500,000、Indirect Cost: ¥11,550,000)
Fiscal Year 2007: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2006: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000)
Fiscal Year 2005: ¥26,910,000 (Direct Cost: ¥20,700,000、Indirect Cost: ¥6,210,000)
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| Keywords | polyglutamine disease / SCA6 / P / Q type calcium channel / gene therapy / neurodegeneration / splicing / 脊髄小脳変性症6型 / SCA6 / Caチャンネル / RNAi / 動物モデル / 培養細胞 |
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| Research Abstract |
1. In order to model SCA6 in mice, we generated three strains of knock-in (KI) mice carrying normal, expanded, or hyper-expanded CAG repeat tracts in Cacna1a locus. Based on the analysis of these animals, we found that the expanded CAG repeat per se does not affect the intrinsic electrophysiological properties of the channel and the pathogenesis of SCA6 was apparently linked to an age-dependent process accompanied with accumulation of mutant Cav2.1 channel protein.
2. Using cellular models, KI cerebella, and postmortem patients' samples, we revealed that expansion of the CAG repeat tract affected splice-site selection at CACNA1A exon 47 locus, leading to the increased relative abundance of polyglutamine-containing Cav2.1 channels in cerebellar Purkinje neurons. Thus, the SCA6 mutation not only gives rise to transcripts encoding glutamine-expanded channel proteins, but also upregulates their expression, possibly by regulating splicing events.
3. We confirmed that the Cav2.1 channel underg
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oes cleavage at its C-terminal portion in SCA6 cerebella. The role of the cleaved fragment in SCA6 pathogenesis is now being examined.
4. Using cellular models expressing C-terminal fragment of ataxin-3 containing expanded polyglutamine, we demonstrated that the inhibition of Bax by BIPs (Bax-inhibiting polypepdides), which were developed as a series of cytoprotective membrane -permeable pentapeprides, markedly protected cells from polyglutamine-induced toxicity. Thus, Bax may be a key mediator of polyglutamine-induced toxicity and BIPs may provide a new strategy for developing therapeutics for polyglutamine diseases.
5. We developed a new RNA interference strategy for treating dominantly inherited neurodegenerative diseases. We found that SCA6 allele could be selectively suppressed with this method in cells.
6. We treated SCA6 patients with a potassium channel blocker 4-diaminopyridine (4-AP), which has been shown to increase the excitability of cerebellar Purkinje cells. These patients showed significant improvement in several aspects of clinical symptoms, suggesting that 4-AP may be useful for treating the disease. Less
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