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...  Read more

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.

View all comments by Paul J. Muchowski

In this article, Kazantsev, Housman, and colleagues screened for molecules that promote inclusion formation. They used an N-terminal fragment of huntingtin fused to GFP and a cell-based assay to screen the effects of a 37,000-compound library. Five compounds increased overall fluorescence, and when the investigators examined their effects more closely, they found that two of these clearly promoted inclusion formation and an improvement in proteasome function. They found these compounds also promoted inclusion formation by the Parkinson disease-causing polypeptide, α-synuclein, and a reduction in associated cytotoxicity.

These results are important for several reasons. First, they offer independent evidence for the idea that inclusion formation can be a beneficial cellular coping response in diseases such as Huntington and Parkinson disease (Arrasate et al., 2004). Second, the results bear on the utility of using aggregation or inclusion formation as a primary measure of pathology.

Previously, other small molecules had been...  Read more

In this article, Kazantsev, Housman, and colleagues screened for molecules that promote inclusion formation. They used an N-terminal fragment of huntingtin fused to GFP and a cell-based assay to screen the effects of a 37,000-compound library. Five compounds increased overall fluorescence, and when the investigators examined their effects more closely, they found that two of these clearly promoted inclusion formation and an improvement in proteasome function. They found these compounds also promoted inclusion formation by the Parkinson disease-causing polypeptide, α-synuclein, and a reduction in associated cytotoxicity.

These results are important for several reasons. First, they offer independent evidence for the idea that inclusion formation can be a beneficial cellular coping response in diseases such as Huntington and Parkinson disease (Arrasate et al., 2004). Second, the results bear on the utility of using aggregation or inclusion formation as a primary measure of pathology.

Previously, other small molecules had been found which mitigate toxicity but interfere with inclusion formation. The compounds in this study also reduce toxicity but promote inclusion formation. The seemingly paradoxical results could both be true. They could indicate that such small molecules that influence toxicity do so by regulating other processes inside cells besides aggregation. Determining the intracellular targets of these small molecules and establishing their specificity will be an important future goal. Another explanation could be that the aggregation process is complex, with toxic aggregation intermediates becoming less toxic as they become more aggregated, as has been previously proposed. In this model, small molecules that inhibit an early step in the process might prevent the toxic forms from ever developing and prevent inclusion formation. On the other hand, small molecules that act to promote final steps in the process might also reduce toxicity by sequestering more toxic forms.

In any case, these results indicate that aggregation per se may not be the most informative or interpretable feature to follow as an indicator of pathogenesis. Third, they offer hope that the mechanisms by which inclusions form can be regulated by small molecules and therefore offer a new therapeutic strategy. That the small molecule they found works for both a huntingtin fragment and synuclein suggests that neurons may respond in a common fashion to aggregation-prone proteins. As such, a therapy that targeted these common mechanisms might work for other diseases such as Alzheimer disease, prion diseases, and ALS. In this regard, an important future goal will be to determine whether these or follow-on compounds have efficacy in vivo.

View all comments by Steven Finkbeiner