Alpha-Synuclein Amyloid Oligomers Exhibit Beta-Sheet Antiparallel Structure as Revealed by FTIR Spectroscopy

Abstract

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 α-synuclein (AS). AS amyloid fibrils consist of interwound protofilaments with a cross β-sheet conformation. 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 cytotoxicity relies on these prefibrillar species rather than on the 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 contain β-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 used ATR-FTIR spectroscopy, a technique especially sensitive to β-sheet structure, to discriminate between the β-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel β-sheet structure, as opposed to the parallel arrangement present in fibrils. We discussed about the possible regions that may be involved in such early β-sheet interactions.We suggest that antiparallel β-sheet structure might represent a distinctive signature of amyloid oligomers (Cerf et al, Biochem J, 2009, 421:415-23) underlying their common pathogenic action.