Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT, McLean PJ, Young AB, Housman DE, Kazantsev AG. Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases. Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4246-51. PubMed.
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University of California, San Francisco
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.
References:
Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature. 2004 Oct 14;431(7010):805-10. PubMed.
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