A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo

Xiaoqian Zhang, Donna L. Smith, Anatoli B. Meriin, Sabine Engemann, Deborah E. Russel, Margo Roark, Shetia L. Washington, Michele M. Maxwell, J. Lawrence Marsh, Leslie Michels Thompson, Erich E. Wanker, Anne B. Young, David E. Housman, Gillian P. Bates, Michael Y. Sherman, Aleksey G. Kazantsev

Research output: Contribution to journalArticlepeer-review

237 Scopus citations

Abstract

Polyglutamine (polyQ) disorders, including Huntington's disease (HD), are caused by expansion of polyQ-encoding repeats within otherwise unrelated gene products. In polyQ diseases, the pathology and death of affected neurons are associated with the accumulation of mutant proteins in insoluble aggregates. Several studies implicate polyQ-dependent aggregation as a cause of neurodegeneration in HD, suggesting that inhibition of neuronal polyQ aggregation may be therapeutic in HD patients. We have used a yeast-based high-throughput screening assay to identify small-molecule inhibitors of polyQ aggregation. We validated the effects of four hit compounds in mammalian cell-based models of HD, optimized compound structures for potency, and then tested them in vitro in cultured brain slices from HD transgenic mice. These efforts identified a potent compound (IC50 = 10 nM) with long-term inhibitory effects on polyQ aggregation in HD neurons. Testing of this compound in a Drosophila HD model showed that it suppresses neurodegeneration in vivo, strongly suggesting an essential role for polyQ aggregation in HD pathology. The aggregation inhibitors identified in this screen represent four primary chemical scaffolds and are strong lead compounds for the development of therapeutics for human polyQ diseases.

Original languageEnglish
Pages (from-to)892-897
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number3
DOIs
StatePublished - 18 Jan 2005
Externally publishedYes

Keywords

  • Drosophila
  • Genetic disease
  • High-throughput screen
  • R6/2 brain slices
  • Small-molecule therapeutics

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