GSBS Student Publications

Title

Identification of tau stem loop RNA stabilizers

GSBS Program

Biochemistry & Molecular Pharmacology

UMMS Affiliation

Graduate School of Biomedical Sciences

Date

5-26-2007

Document Type

Article

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

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: J Biomol Screen. 2007 Sep;12(6):789-99. Epub 2007 May 24. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal Title

Journal of biomolecular screening : the official journal of the Society for Biomolecular Screening

PubMed ID

17525136