Abstract
Overwhelming experimental evidence supports the hypothesis that molecular chaperones are critical modulators of protein aggregation and toxicity in a number of protein misfolding diseases. However, the mechanism by which chaperone activity facilitates neuroprotection remains poorly understood. Early intermediates in the assembly process of Aβ aggregates have been found to be potent neurotoxins in vivo, and it is likely that prefibrillar intermediates of other disease proteins may have similar pathogenic effects. Accordingly, a key step in the pathogenesis of the various proteinopathies may stem from the aberrant interactions of altered protein conformations or prefibrillar intermediates with key cellular proteins, effectively sequestering their activity and triggering a cascade of events that culminates in neuronal dysfunction prior to the appearance of inclusions. The vast majority of animal studies have shown that chaperones facilitate neuroprotection in the absence of a visible effect on inclusion formation, suggesting that protective interactions may occur at the level of prefibrillar aggregation intermediates, or by preventing conformational changes that precede the formation of aggregation intermedites. It will be important to develop techniques that enable in vivo detection of early aggregation intermediates for the various protein misfolding diseases and determine how interaction of these intermediates with other cellular proteins, such as the molecular chaperones, alters pathogenesis. Ultimately, it is necessary to understand how the various components of the protein quality proteome work together to regulate the toxicity of misfolded proteins. Effective therapies will likely require the simultaneous modulation of numerous components of the cellular quality control apparatus, and the molecular chaperones will play a key role in these types of approaches. Because the molecular chaperones provide a first line of defense against misfolded proteins, and are likely to function at the earliest stages of disease pathogenesis, they are a particularly exciting prospect for therapeutic intervention.
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References
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Wacker, J.L., Muchowski, P.J. (2006). Chaperone Suppression of Aggregated Protein Toxicity. In: Uversky, V.N., Fink, A.L. (eds) Protein Misfolding, Aggregation, and Conformational Diseases. Protein Reviews, vol 4. Springer, Boston, MA. https://doi.org/10.1007/0-387-25919-8_8
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