Abstract
BackgroundThe 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 FindingsWe 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/SignificanceThese 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.
Highlights
Drug discovery for late onset neurodegenerative diseases is a major challenge
We tested a collection of compounds that have been previously described to decrease degeneration in cell culture/animal models of polyQ toxicity for their ability to protect C. elegans neurons from the toxic effects of an expanded huntingtin polyglutamine fragment
¤ Current address: Department of Biochemistry, Northwestern University, Evanston, Illinois, United States of America pivotal role that growth and aging play in neurodegenerative disease, we found that lithium chloride (LiCl) and MTR protect C. elegans neurons in the absence of growth and through a daf-16 independent pathway suggesting that these compounds may target pathways that are specific to neurodegeneration
Summary
Drug discovery for late onset neurodegenerative diseases is a major challenge. In large part, the complexity of treating these disorders results from our insufficient understanding of the contributions of multiple pathways on disease pathophysiology. The development of rapid and inexpensive in vivo assays to evaluate the numerous candidate compounds identified in high-throughput screens is of paramount importance. Invertebrate model organisms such as C. elegans provide an attractive alternative for prioritizing lead compounds in the early stages of drug development for age-related diseases [1,2,3]. 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. The neuroprotection conferred by lithium chloride and mithramycin suggests that these drugs may be useful for polyglutamine disease therapy
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