Human Molecular Genetics Advance Access published online on May 23, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl135
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1 Departments of Neurology, and Cellular and Molecular Pharmacology, UCSF, San Francisco, CA 94143-2280
* To whom correspondence should be addressed. Polyglutamine expansion in certain proteins causes neurodegeneration in inherited disorders such as Huntington disease and X-linked spinobulbar muscular atrophy. Polyglutamine tracts promote protein aggregation in vitro and in vivo with a strict length-dependence that strongly implicates alternative protein folding and/or aggregation as a proximal cause of cellular toxicity and neurodegeneration. We used an intracellular polyglutamine protein aggregation assay based on fluorescence resonance energy transfer (FRET) to identify inhibitors of androgen receptor (AR) aggregation in three libraries of biologically active small molecules: the Annotated Compound library, the NINDS Custom Collection and a kinase inhibitor collection. 10 compounds reduced AR aggregation in the primary screen. While 10/10 also reduced huntingtin (Htt) exon 1 aggregation, only 2/10 reduced aggregation of pure polyglutamine peptides. 9/10 compounds reduced aggregation in a PC-12 model. 5/9 compounds tested in an Htt exon 1 assay of neurodegeneration in Drosophila partially rescued the phenotype. 3/5 of the compounds effective in flies are FDA-approved drugs. These compounds provide new leads for therapeutic development for the polyglutamine diseases based on their efficacy in mammalian cells and a Drosophila model. The high predictive value of the primary screen suggests that the FRET-based screening assay may be useful for further primary and secondary screens for genes or small molecules that inhibit polyglutamine protein aggregation.
Received September 9, 2005
Revised May 18, 2006
Accepted May 18, 2006
Article
Biologically Active Molecules that Reduce Polyglutamine Aggregation and Toxicity
Urvee A. Desai 1,
Judit Pallos 2,
Brent R. Stockwell 3,
Leslie Michels Thompson 4,
J. Lawrence Marsh 2,
and
Marc I. Diamond 5 *
2 Department of Developmental and Cell Biology, UC Irvine, Irvine, CA 92697-2300
3 Departments of Biological Sciences, and Chemistry, Columbia University, New York, NY 10027
4 Department of Psychiatry and Human Behavior, Department of Biological Chemistry, UC Irvine, Irvine, CA 92697-4260
5 Departments of Neurology, and Cellular and Molecular Pharmacology, GH-S572B, UCSF, 600 16th Street, San Francisco, CA 94143-2280
Marc I. Diamond, E-mail: marcd{at}itsa.ucsf.edu
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