Identification of potential therapeutic drugs for huntington's disease using Caenorhabditis elegans

PLoS One. 2007 Jun 6;2(6):e504. doi: 10.1371/journal.pone.0000504.


Background: The prolonged time course of Huntington's disease (HD) neurodegeneration increases both the time and cost of testing potential therapeutic compounds in mammalian models. An alternative is to initially assess the efficacy of compounds in invertebrate models, reducing time of testing from months to days.

Methodology/principal findings: We screened candidate therapeutic compounds that were identified previously in cell culture/animal studies in a C. elegans HD model and found that two FDA approved drugs, lithium chloride and mithramycin, independently and in combination suppressed HD neurotoxicity. Aging is a critical contributor to late onset neurodegenerative diseases. Using a genetic strategy and a novel assay, we demonstrate that lithium chloride and mithramycin remain neuroprotective independent of activity of the forkhead transcription factor DAF-16, which mediates the effects of the insulin-like signaling pathway on aging.

Conclusions/significance: These results suggest that pathways involved in polyglutamine-induced degeneration are distinct from specific aging pathways. The assays presented here will be useful for rapid and inexpensive testing of other potential HD drugs and elucidating pathways of drug action. Additionally, the neuroprotection conferred by lithium chloride and mithramycin suggests that these drugs may be useful for polyglutamine disease therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Animals
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / growth & development*
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / metabolism
  • Disease Models, Animal
  • Drug Combinations
  • Forkhead Transcription Factors
  • Huntington Disease / drug therapy*
  • Lithium Chloride / therapeutic use*
  • Longevity / drug effects
  • Neuroprotective Agents / therapeutic use*
  • Peptides / metabolism
  • Plicamycin / therapeutic use*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism


  • Caenorhabditis elegans Proteins
  • Drug Combinations
  • Forkhead Transcription Factors
  • Neuroprotective Agents
  • Peptides
  • Transcription Factors
  • daf-16 protein, C elegans
  • polyglutamine
  • Lithium Chloride
  • Plicamycin