TAU IN FRONTOTEMPORAL DEMENTIA--REGULATION OF EXON 10

描述(改编自申请者摘要)：细胞骨架组织 元素是细胞迁移和形态的关键。Tau蛋白，它 结合和组织微管，有助于形成和维持 神经元轴突。Tau基因表达紊乱导致细胞外信号转导中断 神经元细胞骨架与病理性tau结构的形成 (神经原纤维缠结)在痴呆症患者的大脑中发现。这个 神经元特异性tau转录本通过发育产生多种异构体 特定阶段和特定组织的选择性剪接。尤其是亲和力 微管中tau的表达通过成体特异性外显子10的表达而增加， 微管结合重复序列的哪些编码(其他三个重复序列是 由构成外显子9、11和12编码)。遗传性额颞叶痴呆 患有帕金森综合症(FTDP)的患者是由tau基因突变引起的。一些家谱 在微管结合重复序列中或其附近包含错义突变。然而， 大多数家系携带影响外显子10剪接的突变。 病例中，尽管所产生的tau蛋白是野生型的，但其亚型的转变 比例足以导致这种疾病。在拨款中，我们建议探索 调节外显子10剪接的机制和因素。我们的工作如下 根据FTDP突变体的表型，我们得出结论：这个外显子是 主要由抑制来调节。我们发现了已知的剪接 抑制外显子10包含的调节器，并发现新的实体 与外显子结合。本研究的具体目的是：1)分离小说 抑制外显子10剪接的因素；2)表征位点和方式 抑制外显子10包含的已知和新因素的作用； 以及3)确定外显子10的剪接是否部分受 消音器和拟议的茎环，其形成将拮抗结合 剪接体组分。

DESCRIPTION (Adapted from applicant's abstract): Organization of cytoskeletal elements is critical for cellular migration and morphology. Tau protein, which binds to and organizes microtubules, is instrumental in forming and maintaining the neuronal axon. Disturbances in tau expression result in disruption of the neuronal cytoskeleton and formation of pathological tau structures (neurofibrillary tangles) found in brains of dementia sufferers. The neuron-specific tau transcript produces multiple isoforms via developmental stage- and tissue- specific alternative splicing. In particular, the affinity of tau for microtubules is increased by expression of adult-specific exon 10, which codes for a microtubule binding repeat (the other three repeats are encoded by constitutive exons 9, 11, and 12). Inherited frontotemporal dementia with Parkinsonism (FTDP) is cased by mutations in the tau gene. Some pedigrees contain missense mutations in or near the microtubule-binding repeats. However, most pedigrees carry mutations which affect the splicing of exon 10. In these cases, although the resulting tau protein is wild type, the shift in isoform ratios is sufficient to cause the disease. In the grant, we propose to explore the mechanisms and factors which regulate splicing of exon 10. From our work as well as the phenotypes of the FTDP mutants we concluded that this exon is primarily regulated by inhibition. We identified already known splicing regulators which suppress inclusion of exon 10, and found novel entities which bind to the exon. The specific goals of this study are: 1) to isolate the novel factors which inhibit splicing of exon 10; 2) to characterize the site and mode of action of both known and novel factors that suppress inclusion of exon 10; and 3) to determine if the splicing of exon 10 is partly regulated by a silencer and a proposed stem-loop, whose formation would antagonize binding of spliceosomal components.