Identification of tau stem loop RNA stabilizers
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences
Medical Subject Headings
Aminoglycosides; Base Sequence; Binding, Competitive; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Models, Biological; Nucleic Acid Conformation; Pyrenes; RNA Splicing; RNA Stability; RNA, Messenger; tau Proteins
Life Sciences | Medicine and Health Sciences
Alternative splicing of tau exon 10 produces tau isoforms with either 3 (3R) or 4 (4R) repeated microtubule-binding domains. Increased ratios of 4R to 3R tau expression, above the physiological 1:1, leads to neurofibrillary tangles and causes neurodegenerative disease. An RNA stem loop structure plays a significant role in determining the ratio, with decreasing stability correlating with an increase in 4R tau mRNA expression. Recent studies have shown that aminoglycosides are able to bind and stabilize the tau stem loop in vitro, suggesting that other druglike small molecules could be identified and that such molecules might lead to decreased exon 10 splicing in vivo. The authors have developed a fluorescent high-throughput fluorescent binding assay and screened a library of approximately 110,000 compounds to identify candidate drugs that will bind the tau stem loop in vitro. In addition, they have developed a fluorescent-based RNA probe to assay the stabilizing effects of candidate drugs on the tau stem loop RNA. These assays should be applicable to the general problem of identifying small molecules that interact with mRNA secondary structures.
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Citation: J Biomol Screen. 2007 Sep;12(6):789-99. Epub 2007 May 24. Link to article on publisher's site
Journal of biomolecular screening : the official journal of the Society for Biomolecular Screening
Donahue, Christine Patricia; Ni, Jake; Rozners, Eriks; Glicksman, Marcie A.; and Wolfe, Michael S., "Identification of tau stem loop RNA stabilizers" (2007). GSBS Student Publications. 431.