title: Interaction of the molecular chaperone alphaB-crystallin with alpha-synuclein: effects on amyloid fibril formation and chaperone activity.
abstract: 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.affiliation: Department of Chemistry, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia.
authors.forename: Agata
authors.initials: A
authors.lastname: Rekas
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Adda
authors.forename: J
authors.initials: J
authors.lastname: Andrew Aquilina
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Margaret
authors.initials: M
authors.lastname: Sunde
authors.forename: Denise
authors.initials: D
authors.lastname: Galatis
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Williamson
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Robin F
authors.initials: RF
authors.lastname: Anders
authors.forename: Carol V
authors.initials: CV
authors.lastname: Robinson
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.forename: John A
authors.initials: JA
authors.lastname: Carver
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding; D011489:Protein Denaturation; D013050:Spectrometry, Fluorescence; D051843:Synucleins; D013696:Temperature; D038203:alpha-Crystallin B Chain / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D051844:alpha-Synuclein
chemical_list: D000682:Amyloid; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D038203:alpha-Crystallin B Chain; D051844:alpha-Synuclein