Interaction of the molecular chaperone αB-crystallin with α-Synuclein: Effects on amyloid fibril formation and chaperone activity
Rekas A., Adda CG., Andrew Aquilina J., Barnham KJ., Sunde M., Galatis D., Williamson NA., Masters CL., Anders RF., Robinson CV., Cappai R., Carver JA.
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.