Human Molecular Genetics Advance Access originally published online on May 23, 2006
Human Molecular Genetics 2006 15(13):2114-2124; doi:10.1093/hmg/ddl135
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Biologically active molecules that reduce polyglutamine aggregation and toxicity
1 Department of Neurology and Cellular and Molecular Pharmacology, GH-S572B, UCSF, 600 16th street, San Francisco, CA 94143-2280, USA, 2 Department of Developmental and Cell Biology, 3 Department of Psychiatry and Human Behavior, Department of Biological Chemistry, UC Irvine, Irvine, CA 92697-2300, USA and 4 sDepartments of Biological Sciences and Chemistry, Columbia University, New York, NY 10027, USA
* To whom correspondence should be addressed. Tel: +1 4155143646; fax: +1 4155144112; Email: marc.diamond{at}ucsf.edu
Received September 9, 2005; Accepted May 18, 2006
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. In the primary screen 10 compounds reduced AR aggregation. While 10/10 also reduced huntingtin (Htt) exon 1 aggregation, only 2/10 reduced aggregation of pure polyglutamine peptides. In a PC-12 model 9/10 compounds reduced aggregation. Five out of nine compounds tested in an Htt exon 1 assay of neurodegeneration in Drosophila partially rescued the phenotype. Three of the five 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.
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