【摘 要】
：
Microtubule-binding protein Tau is critical for neuronal function.Expression and function of human tau gene are under complex regulation by alternative splicing.Exclusion or inclusion of exon 10 leads
【机 构】
：
Charles Louis Mix Professor of Neurology, Northwestern University Medical School, USA
【出 处】
：
2005 WHTS3rd Annual Congress of International Drug Discovery
论文部分内容阅读
Microtubule-binding protein Tau is critical for neuronal function.Expression and function of human tau gene are under complex regulation by alternative splicing.Exclusion or inclusion of exon 10 leads to the formation of tau proteins containing either 3 or 4 microtubule-binding repeats (Tau3R or Tau4R).In the normal human brain, the ratio of Tau4R to Tau3R is approximately one.Mutations that disrupt this delicate balance lead to tauopathies including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17).Using a tau minigene system, we have been investigating mechanisms regulating tau exon 10 alternative splicing.Cis-acting regulatory elements important for exon 10 splicing have been identified in both intronic and exonic regions (Jiang et al.,2000; 2003).To develop a strategy that allows us to systematically screen for genes regulating alternative splicing,we established tau-GFP reporters to screen for factors either enhance or suppress exon 10 splicing.Using these reporter genes in expression cloning screening of cDNA libraries, we have identified several genes encoding trans acting factors that regulate tau exon 10 splicing.These splicing regulators are being characterized and their potential mechanisms will be discussed.Using a similar tau-luciferase reporter gene, we have begun to screen chemical libraries for compounds that activate or suppress tau exon 10 inclusion.Promising candidate lead compounds are being further characterized and analyzed.
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