Protein misfolding and aggregation is associated with several human diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD) and dementia. Structured fibrillar aggregates called amyloid are pathological hallmarks of these diseases. Amyloid formation is inhibited by a class of molecular chaperones known as small heat-shock proteins (sHsps) (1). sHsps typically assemble into large oligomers that are formed from the association of smaller dimeric building blocks, however, their inherent heterogeneity has confounded mechanistic and biophysical characterization (2). This study has compared the activities on two amyloid forming systems of WT sHsps, with variant constructs of sHsps that are engineered to form only dimers (2).
WT sHsps were more effective inhibitors of total amyloid formation against both apolipoprotein C-II (apoC-II), a constituent of atherosclerotic plaques, and α-synuclein (α-syn), which forms Lewy Body deposits in PD and dementia. Dimeric sHsp variants primarily reduced the rate of the elongation phase of fibril assembly.
Though WT sHsps are known to bind stably to amyloid fibrils formed from a variety of precursors, sHsp constructs lacking the variable N-terminal domain and C-terminal extension regions did not bind stably to apoC-II fibrils or α-syn fibrils, providing insight into the mechanisms of fibril binding. The novel discovery of the inhibition of fibril end-to-end rejoining by a dimeric form of αB-C supports the hypothesis that sHsps bind and cap the ends of proto-fibrils to inhibit further elongation.
We demonstrate that WT and variant sHsps are active against amyloid formation during all stages of fibril assembly, however WT sHsps possess additional important chaperone activities, highlighting the importance of sequences outside of the core α-crystallin domain for the chaperone activity of sHsps. These findings demonstrate the potential of targeting sHsps in the treatment of diseases involving amyloid deposition.