Tag: inhibitors

Publication: Impact of aggregation inhibitors on protein aggregation and aggregate toxicity.

Congratulations to Greeshma Jain, Marina Trombetta-Lima and the whole team of co-authors for the publication of our most recent paper on Huntington’s disease (HD), in the journal Nature Communications. This paper is actually the fourteenth peer-reviewed publication from the lab on HD research, since our first paper in 2011. It was enabled by crucial funding from the CampagneTeam Huntington foundation, who supported our HD research program when the Van der Wel group moved back to the Netherlands.

In this new report we describe our use of structural analysis (NMR and EM) to look how aggregation-inhibiting small molecules (polyphenols) change the structure of protein aggregates formed by fragments of the huntingtin protein. We observed that these molecules are effective at slowing down huntingtin exon 1 aggregation, even at sub-stoichiometric concentrations. However, aggregates still formed. Notably, these ‘break-through’ aggregates seem to adopt a different conformation, resulting from a change in the aggregation mechanism. Moreover, we saw that the apparent toxic or pathogenic effects of these aggregates differ from normal aggregates, when we exposed neuronal cells to them. What precisely makes the differ in the reduced toxicity remains a bit unclear, requiring further research.

However, a notable and more general finding is that we need to pay attention to changes in aggregate polymorphs when developing aggregation inhibitors. Here we see a reduced toxic effect, but it seems conceivable that certain inhibitors may redirect the aggregation pathway to more toxic species. Further research would be important for better understanding the interplay of delayed aggregation, changes in aggregate morphology and cellular impacts of protein aggregates.

For more info, please see the actual paper at the journal, with citation below:

Jain G, Trombetta-Lima M, Matlahov I, Ribas HT, Chen T, Parlato R, Portale G, Dolga AM, Van der Wel PCA. Inhibitor-based modulation of huntingtin aggregation mechanisms mitigates fibril-induced cellular stress. Nat Commun. 2025 Apr 15;16(1):3588.