|
Sign In to gain access to subscriptions and/or personal tools.
|
Identification of Tau Stem Loop RNA Stabilizers
Christine P. Donahue
Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts
Jake Ni
Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital, Cambridge, Massachusetts
Eriks Rozners
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts
Marcie A. Glicksman
Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital, Cambridge, Massachusetts
Michael S. Wolfe
Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts, mwolfe{at}rics.bwh.harvard.edu
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  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 candiate 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. (Journal of Biomolecular Screening 2007:789-799)
Key Words: tau • alternative splicing • pyrene • aminoglycosides • RNA
References
- Lee VM, Goedert M., Trojanowski JQ: Neurodegenerative tauopathies. Annu Rev Neurosci 2001;24:1121-1159.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Neve R., Harris P., Kosik K., Kurnit D., Donlon T.: Identification of cDNA clones for the human microtubule-associated protein, tau, and chromosomal localization of the genes for tau and microtubule-associated protein 2. Mol Brain Res 1986;1:271-280.[Medline]
[Order article via Infotrieve]
- Kosik KS, Orecchio LD, Bakalis S., Neve RL: Developmentally regulated expression of specific tau sequences. Neuron 1989;2(4):1389-1397.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Andreadis A., Brown WM, Kosik KS: Structure and novel exons of the human tau gene. Biochemistry 1992;31(43):10626-10633.[CrossRef][Medline]
[Order article via Infotrieve]
- Gustke N., Trinczek B., Biernat J., Mandelkow EM, Mandelkow E.: Domains of tau protein and interactions with microtubules. Biochemistry 1994;33(32):9511-9522.[CrossRef][Medline]
[Order article via Infotrieve]
- Hutton M., Lendon CL, Rizzu P., Baker M., Froelich S., Houlden H., et al: Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393)6686):702-705.[CrossRef][Medline]
[Order article via Infotrieve]
- D'Souza I., Schellenberg GD: Regulation of tau isoform expression and dementia. Biochim Biophys Acta 2005;1739(2-3):104-115.[Medline]
[Order article via Infotrieve]
- Jiang Z., Cote J., Kwon JM, Goate AM, Wu JY: Aberrant splicing of tau pre-mRNA caused by intronic mutations associated with the inherited dementia frontotemporal dementia with parkinsonism linked to chromosome 17. Mol Cell Biol 2000;20(11):4036-4048.[Abstract/Free Full Text]
- Varani L., Hasegawa M., Spillantini MG, et al: Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17. Proc Natl Acad Sci U S A 1999;96(14):8229-8234.[Abstract/Free Full Text]
- Donahue CP, Muratore C., Wu JY, Kosik KS, Wolfe MS: Stabilization of the tau exon 10 stem loop alters pre-mRNA splicing. J Biol Chem 2006; 281(33):23302-23306.[Abstract/Free Full Text]
- Varani L., Spillantini MG, Goedert M., Varani G.: Structural basis for recognition of the RNA major groove in the tau exon 10 splicing regulatory element by aminoglycoside antibiotics. Nucleic Acids Res 2000; 28(3):710-719.[Abstract/Free Full Text]
- Hannon GJ, Rossi JJ: Unlocking the potential of the human genome with RNA interference. Nature 2004;431(7006):371-378.[CrossRef][Medline]
[Order article via Infotrieve]
- Tor Y.: Targeting RNA with small molecules. Chembiochem 2003;4(10): 998-1007.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Zaman GJ, Michiels PJ, van Boeckel CA: Targeting RNA: new opportunities to address drugless targets. Drug Discov Today 2003;8(7):297-306.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Thomas JR, Liu X., Hergenrother PJ: Biochemical and thermodynamic characterization of compounds that bind to RNA hairpin loops: toward an understanding of selectivity. Biochemistry 2006;45(36):10928-10938.[CrossRef][Medline]
[Order article via Infotrieve]
- Michael K., Wang H., Tor Y.: Enhanced RNA binding of dimerized aminoglycosides. Bioorg Med Chem 1999;7(7):1361-1371.[CrossRef][Medline]
[Order article via Infotrieve]
- Kirk SR, Luedtke NW, Tor Y.: Neomycin-acridine conjugate: a potent inhibitor of Rev-RRE binding. Bioorg Med Chem 2000;122:980-981.
- Hamasaki K., Rando RR: A high-throughput fluorescence screen to monitor the specific binding of antagonists to RNA targets. Anal Biochem 1998;261(2):183-190.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Xue CB, Voss ME, Nelson DJ, et al: Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo. J Med Chem 2001; 44(16):2636-2360.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Zhang JH, Chung TD, Oldenburg KR: A simple statistical parameter for use in evaluation and validation of high-throughput screening assays. J Biomol Screen 1999;4(2):67-73.[Abstract/Free Full Text]
- Lee J., Kwon M., Lee KH, et al: An approach to enhance specificity against RNA targets using heteroconjugates of aminoglycosides and chloramphenicol (or linezolid). J Am Chem Soc 2004;126(7):1956-1957.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Xue L., Charles I., Arya DP: Pyrene-neomycin conjugate: dual recognition of a DNA triple helix. Chem Commun (Camb) 2002;1:70-71.[Medline]
[Order article via Infotrieve]
- Arya DP, Micovic L., Charles I., Coffee RL Jr, Willis B., Xue L.: Neomycin binding to Watson-Hoogsteen (W-H) DNA triplex groove: a model. J Am Chem Soc 2003;125(13):3733-3744.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Arya DP, Xue L., Willis B.: Aminoglycoside (neomycin) preference is for A-form nucleic acids, not just RNA: results from a competition dialysis study. J Am Chem Soc 2003;125(34):10148-10149.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hermann T.: Chemical and functional diversity of small molecule ligands for RNA. Biopolymers 2003;70(1):4-18.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Buratti E., Baralle FE: Influence of RNA secondary structure on the pre-mRNA splicing process. Mol Cell Biol 2004;24(24):10505-10514.[Free Full Text]
- Tucker BJ, Breaker RR: Riboswitches as versatile gene control elements. Curr Opin Struct Biol 2005;15(3):342-348.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Mandal M., Breaker RR: Gene regulation by riboswitches. Nat Rev Mol Cell Biol 2004;5(6):451-463.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Lipscombe D.: Neuronal proteins custom designed by alternative splicing. Curr Opin Neurobiol 2005;15(3):358-363.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Blencowe BJ: Splicing on the brain. Nat Genet 2005;37(8):796-797.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Krawczak M., Reiss J., Cooper DN: The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 1992;90(1-2):41-54.[Web of Science][Medline]
[Order article via Infotrieve]
- Stamm S., Ben-Ari S., Rafalska I., et al: Function of alternative splicing. Gene 2005;344:1-20.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
This version was published on September
1, 2007
Journal of Biomolecular Screening, Vol. 12, No. 6,
789-799 (2007)
DOI: 10.1177/1087057107302676
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
T. Rodriguez-Martin, K. Anthony, M. A. Garcia-Blanco, S. G. Mansfield, B. H. Anderton, and J.-M. Gallo
Correction of tau mis-splicing caused by FTDP-17 MAPT mutations by spliceosome-mediated RNA trans-splicing
Hum. Mol. Genet.,
September 1, 2009;
18(17):
3266 - 3273.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
