Zhang X, Smith DL, Meriin AB, Engemann S, Russel DE, Roark M, Washington SL, Maxwell MM, Marsh JL, Thompson LM, Wanker EE, Young AB, Housman DE, Bates GP, Sherman MY, Kazantsev AG. 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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Comments
University of California, San Francisco
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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