Small Heat-shock Proteins Prevent α-synuclein aggregation via transient interactions and their efficacy is affected by the rate of aggregation

Dezerae Cox, Emily Selig, Michael D.W. Griffin, John A. Carver, Heath Ecroyd*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    90 Citations (Scopus)

    Abstract

    The aggregation of α-synuclein (α-syn) into amyloid fibrils is associated with neurodegenerative diseases, collectively referred to as the α-synucleinopathies. In vivo, molecular chaperones, such as the small heat-shock proteins (sHsps), normally act to prevent protein aggregation; however, it remains to be determined how aggregation-prone α-syn evades sHsp chaperone action leading to its disease-associated deposition. This work examines the molecular mechanism by which two canonical sHsps, αB-crystallin (αB-c) and Hsp27, interact with aggregation-prone α-syn to prevent its aggregation in vitro. Both sHsps are very effective inhibitors of α-syn aggregation, but no stable complex between the sHsps and α-syn was detected, indicating that the sHsps inhibit α-syn aggregation via transient interactions. Moreover, the ability of these sHsps to prevent α-syn aggregation was dependent on the kinetics of aggregation; the faster the rate of aggregation (shorter the lag phase), the less effective the sHsps were at inhibiting fibril formation of α-syn. Thus, these findings indicate that the rate at which α-syn aggregates in cells may be a significant factor in how it evades sHsp chaperone action in the α-synucleinopathies.

    Original languageEnglish
    Pages (from-to)22618-22629
    Number of pages12
    JournalJournal of Biological Chemistry
    Volume291
    Issue number43
    DOIs
    Publication statusPublished - 21 Oct 2016

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