Identification of tau stem loop RNA stabilizers.
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.
Donahue
Christine P
CP
Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Ni
Jake
J
Rozners
Eriks
E
Glicksman
Marcie A
MA
Wolfe
Michael S
MS
D000617:Aminoglycosides / Q000494:pharmacology; D001483:Base Sequence; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008954:Models, Biological; D009690:Nucleic Acid Conformation; D011721:Pyrenes / Q000494:pharmacology; D012326:RNA Splicing / Q000502:physiology; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
D000617:Aminoglycosides; D011721:Pyrenes; D012333:RNA, Messenger; D016875:tau Proteins