Biologically active molecules that reduce polyglutamine aggregation and toxicity

• Published in: Human molecular genetics 2006-07, Vol.15 (13), p.2114-2124
• Main Authors: Desai, Urvee A., Pallos, Judit, Ma, Aye Aye K., Stockwell, Brent R., Thompson, Leslie Michels, Marsh, J. Lawrence, Diamond, Marc I.
• Format: Article
• Language: English
• Subjects: Androgen Receptor Antagonists; Animals; Biological and medical sciences; Biological Assay - methods; Cell Line; Dose-Response Relationship, Drug; Drosophila; Drosophila melanogaster - drug effects; Drosophila melanogaster - metabolism; Drug Evaluation, Preclinical - methods; Drugs, Investigational - chemistry; Drugs, Investigational - pharmacology; Drugs, Investigational - therapeutic use; Fluorescence Resonance Energy Transfer - methods; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Humans; Huntingtin Protein; Huntington Disease - drug therapy; Huntington Disease - metabolism; Molecular and cellular biology; Molecular Structure; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - metabolism; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - chemistry; Nuclear Proteins - metabolism; PC12 Cells; Peptides - antagonists & inhibitors; Peptides - chemistry; Peptides - metabolism; Protein Folding; Rats; Receptors, Androgen - chemistry; Receptors, Androgen - metabolism; Structure-Activity Relationship; Trinucleotide Repeat Expansion - drug effects
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddl135

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.