Chaperone proteins protect against desmin fragment amyloid aggregation

In desmin-related cardiomyopathy, cellular stresses cause desmin to cleave and aggregate in vivo. Cleaved desmin fragments are amyloidogenic and induce misfolding, aggregation, and amyloid fibril formation of full-length wild-type desmin. Alongside this disease condition, cells overexpress αB-crystallin and heat shock protein (HSP) 27 as cardioprotective chaperones. Chaperone proteins may refold, sequester, or disaggregate misfolded or aggregating client proteins. Previously, little was known about the protective influence of chaperone proteins on desmin fragment amyloid formation. Here, we studied the secondary structure changes, kinetics, and morphology of desmin fragment amyloid formation with and without chaperone proteins αB-crystallin and HSP27. We found that both of these proteins prevent or delay amyloid formation in a concentration-dependent manner, but we did not observe amyloid disaggregation. We discovered better chaperone activity by αB-crystallin than HSP27 toward desmin fragment, correlated to increased binding sites between αB-crystallin and desmin fragment. Our interaction studies demonstrated that monomers or amorphous oligomers were likely reversibly captured by these chaperone proteins, whereas desmin fragment amyloid fibrils were likely irreversibly capped by chaperone proteins. Overall, αB-crystallin and HSP27 recognized and interacted with both desmin fragment monomer and desmin fragment amyloid at distinct sites to prevent further amyloid formation.