Discovery of a novel small-molecule targeting selective clearance of mutant huntingtin fragments.
CAG-triplet repeat extension, translated into polyglutamines within the coding frame of otherwise unrelated gene products, causes 9 incurable neurodegenerative disorders, including Huntington's disease. Although an expansion in the CAG repeat length is the autosomal dominant mutation that causes the fully penetrant neurological phenotypes, the repeat length is inversely correlated with the age of onset. The precise molecular mechanism(s) of neurodegeneration remains elusive, but compelling evidence implicates the protein or its proteolytic fragments as the cause for the gain of novel pathological function(s). The authors sought to identify small molecules that target the selective clearance of polypeptides containing pathological polyglutamine extension. In a high-throughput chemical screen, they identified compounds that facilitate the clearance of a small huntingtin fragment with extended polyglutamines fused to green fluorescent protein reporter. Identified hits were validated in dose-response and toxicity tests. Compounds have been further tested in an assay for clearance of a larger huntingtin fragment, containing either pathological or normal polyglutamine repeats. In this assay, the authors identified compounds selectively targeting the clearance of mutant but not normal huntingtin fragments. These compounds were subjected to a functional assay, which yielded a lead compound that rescues cells from induced mutant polyglutamine toxicity.
Coufal
Myra
M
Massachusetts Institute of Technology, Cambridge, MA, USA.
Maxwell
Michele M
MM
Russel
Deborah E
DE
Amore
Allison M
AM
Altmann
Stephen M
SM
Hollingsworth
Zane R
ZR
Young
Anne B
AB
Housman
David E
DE
Kazantsev
Aleksey G
AG
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008970:Molecular Weight; D050505:Mutant Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides; D051381:Rats; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013379:Substrate Specificity
D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010455:Peptides; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C097188:polyglutamine