Establishment of a molecular therapy for neurodegenerative diseases including the polyglutamine diseases.
| Project/Area Number |
14570594
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Osaka University |
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Principal Investigator |
NAGAI Yoshitaka Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (60335354)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Gene / Neuroscience / Protein / Neurological diseases / Molecular therapy / Neurodegenerative diseases / Polyglutamine diseases / Amyloid |
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| Research Abstract |
The polyglutamine (polyQ) diseases are a class of inherited neurodegenerative diseases including Huntington s disease and the spinocerebellar ataxias, which are caused by abnormal expansions of the polyQ stretch within the disease proteins. Expansion of the polyQ stretch is thought to confer toxic properties on the disease proteins through a conformational transition, leading to pathogenic protein-protein interactions including aggregate formation. We previously identified QBP1, a peptide that preferentially binds the expanded polyQ stretch, and have shown that QBP1 inhibits polyQ protein aggregation in vitro and cytotoxicity in cellular models. In this study, 1) we show that co-expression of QBP1 suppresses polyQ protein aggregation and compound eye degeneration, and rescues premature death in Drosophila polyQ disease models, indicating that QBP1 prevents polyQ-induced neurodegeneration in vivo. 2) We utilized a protein transduction domain (PTD) to deliver QBP1 efficiently into cells, and show that long-term administration of PTD-QBP1 into the lateral ventricle of a mouse model of the polyQ diseases results in significant suppression of polyQ aggregation around the administration site. 3) By structural analysis using circular dichroism and electron microscopy, we demonstrate that QBP1 prevents the expanded polyQ protein from undergoing a toxic conformational transition to a β-sheet rich structure, resulting in inhibition of amyloid-like fibril formation. We conclude that the toxic conformational transition of the expanded polyQ protein is a therapeutic target, and QBP1 is a potential therapeutic candidate for the currently untreatable polyQ diseases.
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Report
(3 results)
Research Products
(17 results)
