TAU IN FRONTOTEMPORAL DEMENTIA--REGULATION OF EXON 10

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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.