Interaction of the Molecular Chaperone αB-Crystallin with α-Synuclein: Effects on Amyloid Fibril Formation and Chaperone Activity

• Published in: Journal of molecular biology 2004-07, Vol.340 (5), p.1167-1183
• Main Authors: Rekas, Agata, Adda, Christopher G, Andrew Aquilina, J, Barnham, Kevin J, Sunde, Margaret, Galatis, Denise, Williamson, Nicholas A, Masters, Colin L, Anders, Robin F, Robinson, Carol V, Cappai, Roberto, Carver, John A
• Format: Article
• Language: English
• Subjects: amyloid; chaperone; protein aggregation; α-synuclein; αB-crystallin
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2004.05.054

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.