Interaction of the molecular chaperone alpha B-crystallin with alpha-synuclein: Effects on amyloid fibril formation and chaperone activity

Journal article

α-Synuclein is a pre-synaptic protein, the function of which is not completely understood, but its pathological form is involved in neurodegenerative diseases. In vitro, α-synuclein spontaneously forms amyloid fibrils. Here, we report that αB-crystallin, a molecular chaperone found in Lewy bodies that are characteristic of Parkinson's disease (PD), is a potent in vitro inhibitor of α-synuclein fibrillization, both of wild-type and the two mutant forms (A30P and A53T) that cause familial, early onset PD. In doing so, large irregular aggregates of α-synuclein and αB-crystallin are formed implying that αB-crystallin redirects α-synuclein from a fibril-formation pathway towards an amorphous aggregation pathway, thus reducing the amount of physiologically stable amyloid deposits in favor of easily degradable amorphous aggregates. α-Synuclein acts as a molecular chaperone to prevent the stress-induced, amorphous aggregation of target proteins. Compared to wild-type α-synuclein, both mutant forms have decreased chaperone activity in vitro against the aggregation of reduced insulin at 37°C and the thermally induced aggregation of βL-crystallin at 60°C. Wild-type α-synuclein abrogates the chaperone activity of αB-crystallin to prevent the precipitation of reduced insulin. Interaction between these two chaperones and formation of a complex are also indicated by NMR spectroscopy, size-exclusion chromatography and mass spectrometry. In summary, α-synuclein and αB-crystallin interact readily with each other and affect each other's properties, in particular α-synuclein fibril formation and αB-crystallin chaperone action. © 2004 Elsevier Ltd. All rights reserved.

Authors: Rekas, A; Adda, C; Aquilina, J; Barnham, K; Sunde, M

• Publication status: Published
• Journal: JOURNAL OF MOLECULAR BIOLOGY
• Volume: 340
• Issue: 5
• Pages: 1167-1183
• Publication date: 2004-07-23
• DOI: 10.1016/jmb.2004.05.054
• ISSN: 0022-2836
• Language: English
• Keywords: alpha B-crystallin; amyloid; chaperone; protein aggregation; alpha-symiclein