. A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):892-7. PubMed.


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  1. This paper is a nice example of a collaborative
    research approach leading to the identification of small molecules that
    may be useful for future characterization in Huntington disease animal
    models. The authors screened a library of 16,000 compounds in a yeast
    model, out of which they identified nine compounds that increased yeast
    growth. These compounds, and structural analogs derived from these
    compounds, were subsequently tested in cell culture models, in vitro in a
    polyglutamine aggregation assay, in a brain slice model, and one compound
    was tested in a fly model.

    One compound that was effective in all of the
    systems appeared to modulate polyglutamine aggregation, although it is
    likely that this effect was mediated via inhibition of an unidentified
    cellular target, as it only had a modest effect in vitro on polyglutamine
    aggregation at very high concentrations. Unfortunately, the authors did
    not comment on whether or not this compound inhibited polyglutamine
    aggregation in the fly model, because if it did, this data would have
    further bolstered their claim that inhibition of aggregation is a useful
    pharmacological target for Huntington disease.

    It will be very
    interesting to determine the cellular target for this compound, as well as
    others obtained in the screen, as this information could then be combined
    with current genetic screens that are published or underway using model
    organisms including the same yeast model that was described for the
    chemical screen.

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This paper appears in the following:


  1. Inclusions: Part of the Problem, or the Solution?
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