TAU IN FRONTOTEMPORAL DEMENTIA--REGULATION OF EXON 10

描述（改编自申请人摘要）：细胞骨架的组织 元素对于细胞迁移和形态至关重要。Tau蛋白， 结合并组织微管，有助于形成和维持 神经轴突。tau蛋白表达的干扰导致了 神经元细胞骨架和病理性tau结构的形成 在痴呆症患者的大脑中发现的（神经系统缠结）。的 神经元特异性tau转录物通过发育产生多种亚型 阶段和组织特异性可变剪接。特别是，亲和力 微管的tau蛋白的表达因成人特异性外显子10的表达而增加， 其编码微管结合重复序列（其它三个重复序列是 由组成型外显子9、11和12编码）。遗传性额颞性痴呆 帕金森综合征（FTDP）是由tau基因突变引起的。一些血统 在微管结合重复序列中或附近含有错义突变。然而，在这方面， 大多数家系携带影响外显子10剪接的突变。在这些 在某些情况下，尽管产生的tau蛋白是野生型，但同种型的转变 比例足以导致疾病。在拨款中，我们建议探索 外显子10剪接的调控机制和因素。从我们的工作， 以及FTDP突变体的表型，我们得出结论，该外显子是 主要通过抑制来调节。我们发现了已知的 抑制外显子10包含的调节子，并发现了新的实体， 与外显子结合。本研究的具体目标是：1）对小说进行隔离 抑制外显子10剪接的因子; 2）表征位点和模式 抑制外显子10包含的已知和新因子的作用; 和3）确定外显子10的剪接是否部分受 消音器和一个拟议的茎环，其形成将拮抗结合 剪接体成分。

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.