The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

Dezerae Cox, Daniel R Whiten, James Brown, Mathew H Horrocks, Rebecca San Gil, Christopher M. Dobson, David Klenerman, Antoine M. Van Oijen, Heath Ecroyd

Research output: Contribution to journalArticlepeer-review

Abstract

Proteostasis, or protein homeostasis, encompasses the maintenance of the
conformational and functional integrity of the proteome and involves an integrated network of cellular pathways. Molecular chaperones, such as the small heat shock proteins (sHsps), are a key element of the proteostasis network that have crucial roles in inhibiting the aggregation of misfolded proteins. Failure of the proteostasis network can lead to the accumulation of misfolded proteins into intra- and extracellular deposits. Deposits containing fibrillar forms of α-synuclein (α-syn) are characteristic of neurodegenerative disorders including Parkinson’s disease and dementia with Lewy bodies. Here we show that the sHsp Hsp27 (HSPB1) binds to α-syn fibrils, inhibiting fibril growth by preventing elongation. Using total internal reflection fluorescence (TIRF)-based
imaging methods, we show that Hsp27 binds along the surface of α-syn fibrils, decreasing their hydrophobicity. Binding of Hsp27 also inhibits
cytotoxicity of α-syn fibrils. Our results demonstrate that the ability of sHsps, such as Hsp27, to bind fibrils represents an important mechanism through which they may mitigate cellular toxicity associated with aberrant protein
aggregation. Fibril binding may represent a generic mechanism by which chaperone-active sHsps interact with aggregation-prone proteins, highlighting the potential to target sHsp activity to prevent or disrupt the onset and progression of α-syn aggregation associated with α-
synucleinopathies.
Original languageEnglish
Pages (from-to)jbc.M117.813865
JournalJournal of Biological Chemistry
Early online date30 Jan 2018
DOIs
Publication statusE-pub ahead of print - 30 Jan 2018
Externally publishedYes

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