Interaction of the molecular chaperone alphaB-crystallin with alpha-synuclein: effects on amyloid fibril formation and chaperone activity.

Journal article

alpha-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, alpha-synuclein spontaneously forms amyloid fibrils. Here, we report that alphaB-crystallin, a molecular chaperone found in Lewy bodies that are characteristic of Parkinson's disease (PD), is a potent in vitro inhibitor of alpha-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 alpha-synuclein and alphaB-crystallin are formed implying that alphaB-crystallin redirects alpha-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. alpha-Synuclein acts as a molecular chaperone to prevent the stress-induced, amorphous aggregation of target proteins. Compared to wild-type alpha-synuclein, both mutant forms have decreased chaperone activity in vitro against the aggregation of reduced insulin at 37 degrees C and the thermally induced aggregation of betaL-crystallin at 60 degrees C. Wild-type alpha-synuclein abrogates the chaperone activity of alphaB-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, alpha-synuclein and alphaB-crystallin interact readily with each other and affect each other's properties, in particular alpha-synuclein fibril formation and alphaB-crystallin chaperone action.

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

• Journal: Journal of molecular biology
• Volume: 340
• Issue: 5
• Pages: 1167-1183
• Publication date: 2004-07-01
• DOI: 10.1016/j.jmb.2004.05.054
• EISSN: 1089-8638
• ISSN: 0022-2836
• Language: English
• Keywords: Nerve Tissue Proteins; Protein Denaturation; Humans; Synucleins; Microscopy, Electron; Amyloid; Magnetic Resonance Spectroscopy; Temperature; Spectrometry, Fluorescence; Mass Spectrometry; alpha-Crystallin B Chain; alpha-Synuclein; Protein Binding