. Intranuclear ataxin1 inclusions contain both fast- and slow-exchanging components. Nat Cell Biol. 2002 Oct;4(10):806-10. PubMed.

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  1. Two new papers demonstrate several interesting findings that demonstrate that components of aggregated, polyglutamine-containing inclusions seen in certain neurodegenerative diseases are highly dynamic. Stenoien, et al., used fluorescence recovery after photobleaching (FRAP) to show that the ataxin 1 protein, when tagged with green fluorescent protein (GFP) can be present in small or large aggregates within cells. With either short or long polyglutamine stretches, the protein aggregates though there were generally smaller inclusions with transfection of the shorter polyglutamine stretches and larger inclusions with the longer stretches. Interestingly, the ataxin 1 present in aggregates was shown to be highly dynamic with a half-life in small aggregates of only seconds and a half life in larger aggregates of 20 seconds. This dynamic equilibrium of misfolded proteins (felt previously to be somewhat static) is fascinating and suggests that molecular chaperones for these proteins play an important role in both the aggregation and disaggregation process. Further supporting that idea, the authors also found that the presence of ubiquitin associated with aggregates was linked with a longer half life of aggregates and the presence of a proteasome component was linked was a shorter half life.

    Kim, et al., used similar approaches such as FRAP as well as fluorescence loss in photobleaching (FLIP) and found that the interaction between molecular chaperones for polyglutamine-containing proteins such as Hsp70 were very different than the interaction between the polyglutamine-containing aggregates with themselves. They showed that while the polyglutamine aggegrates were “relatively” stable, the interactions of Hsp70 were very transient with the aggregates. They also found different aggregate dynamics and interaction with other proteins associated with the aggregates. These results demonstrate highly dynamic interactions with molecular chaperones and aggregates and that different classes of proteins interact in distinct ways with aggregates.

    In total, these two papers show that modification of aggegrated proteins in neurodegenerative diseases (e.g. Aβ, tau, polyglutamine proteins, synuclein, superoxide dismutase) is likely to be a dynamic process and that proteins are not irreversibly sequestered into these structures. Further, the results suggest that molecular chaperones (e.g. apoE, ubiquitin, heat shock proteins, etc.) and their modifiers would be good drug targets in that modification of their expression or function may be able to reverse the process of protein aggregation and its consequences faster than we previously thought.

    View all comments by David Holtzman

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