| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases, including Huntington's disease and spinocerebellar ataxias, which are caused by an abnormal expansion of the polyQ stretch in each unrelated disease-causing protein. It has been recently suggested that the neurological phenotypes of polyQ disease patients are caused by reversible neuronal dysfunction rather than neuronal cell death. However, the molecular mechanisms involved in polyQ-induced neuronal dysfunction are not fully understood so far. To investigate the molecular mechanisms of polyQ-induced neuronal dysfunction, we screened for modifier genes of premature death in a Drosophila polyQ disease model, which is a phenotype caused by neuronal dysfunction. We established a GS-polyQ fly line which conditionally expresses an expanded polyQ protein in the nervous system in an RU486-dependent manner using the GeneSwitch system. We then crossed this GS-polyQ fly line with various mutant fly lines which have a partial deletion in their chromosomes (Bloomington deficiency kit,220 lines), and evaluated the survival rate of their offspring. We successfully identified 11 suppressor lines, whose offspring exhibited an improved survival rate compared with the GS-polyQ line. Importantly, nine of these 11 lines did not suppress polyQ-induced neuronal cell death, suggesting that these deleted regions contain genes involved in polyQ-induced neuronal dysfunction but not neuronal cell death. We next screened for genes responsible for the improved survival rate within these 11 deleted chromosomal regions, and selected three candidate genes. We further evaluated the effects of knockdown of these candidate genes using RNAi, and identified a novel gene (Sup5) which is involved in polyQ-induced neuronal dysfunction. We therefore conclude that the Sup5 gene is involved in a novel mechanism of polyQ-induced reversible neuronal dysfunction, providing a novel therapeutic target for the polyQ diseases.
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