In addition to amyloid and its proteolytic production, the lab has begun to combine chemistry and biology toward the study of another factor critical to the pathogenesis of dementias: the microtubule-associated protein tau. Filaments of tau are a common feature in a variety of different neurodegenerative diseases, including Alzheimer’s disease. Mutations in the gene encoding this protein are associated with dominant, familial forms of frontotemporal dementia, and many of these mutations alter pre-mRNA splicing to increase inclusion of exon 10. Alternative splicing of exon 10 leads to tau isoforms contain 3 or 4 repeated microtubule binding domains (3R and 4R, respectively). The Wolfe lab has recently validated the in vivo existence of a hypothetical stem loop at the end of exon 10, where many of the dementia-associated mutations occur (Donahue et al., J Biol Chem, 2006). These mutations destabilize this RNA stem loop structure, allowing more ready access to splicing factors. High-throughput screening has led to identification of small molecules that interact with and stabilize this structure (Donahue et al., J Biomol Screen, 2007), and efforts are ongoing to improve the potency and selectivity of these agents to provide new tools for chemical biology as well as new prototype therapeutics.
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