Alpha-synuclein amyloid oligomers exhibit beta-sheet antiparallel structure as revealed by FTIR spectroscopy.

CELEJ MS; SARROUKH R; GOORMAGHTIGH E; FIDELIO FD; RUYSSCHAERT JM; RAUSSENS V

San Diego, CA

Congreso; Biophysical Society 56th Annual Meeting; 2012

Parkinson’s disease is an aged-related movement disorder characterized by the presence in the mid-brain of amyloid deposits of the 140-aa protein alpha-synuclein (AS). AS amyloid fibrils consist of interwound protofilaments with a cross beta-sheet secondary structure. Fibrillation of AS follows a nucleation polymerization pathway involving major structural rearrangements and the population of diverse transient prefibrillar species varying in size and morphology. It is currently believed that citotoxicity relies on these prefibrillar species rather than on the final insoluble aggregates, although the underlying molecular mechanism remains elusive. Structural studies may contribute to the understanding of both amyloid aggregation mechanism and oligomer-induced toxicity.It is already recognized that soluble oligomeric AS species already contain b-sheet structural elements that differ from the typical fibrillar structure. However, more detailed information on the origin of this difference is still lacking.  In the present work we ATR-FTIR, a technique especially sensitive to beta-sheet structure, to discriminate between the beta-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel b-sheet structure, as opposed to the parallel arrangement present in fibrils. We discuss possible regions that may be involved in such early b-sheet interactions based on available data.We hypothesize that antiparallel beta-sheet structure might represent distinctive signature of amyloid oligomers underlying their common membrane-disrupting pathogenic action.