Toxic prefibrillar α-synuclein amyloid oligomers adopt a distinctive antiparallel β-sheet structure.
Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-brain of amyloid deposits of the 140-amino-acid protein AS (α-synuclein). AS fibrillation follows a nucleation polymerization pathway involving diverse transient prefibrillar species varying in size and morphology. Similar to other neurodegenerative diseases, cytotoxicity is currently attributed to these prefibrillar species rather than to the insoluble aggregates. Nevertheless, the underlying molecular mechanisms responsible for cytotoxicity remain elusive and structural studies may contribute to the understanding of both the amyloid aggregation mechanism and oligomer-induced toxicity. It is already recognized that soluble oligomeric AS species adopt β-sheet structures that differ from those characterizing the fibrillar structure. In the present study we used ATR (attenuated total reflection)-FTIR (Fourier-transform infrared) spectroscopy, a technique especially sensitive to β-sheet structure, to get a deeper insight into the β-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel β-sheet structure, whereas fibrils adopt a parallel arrangement. The results are discussed in terms of regions of the protein involved in the early β-sheet interactions and the implications of such conformational arrangement for the pathogenicity associated with AS oligomers.
Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC, UNC-CONICET), Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina. mcelej@mail.fcq.unc.edu.ar
María Soledad
MS
Celej
Rabia
R
Sarroukh
Erik
E
Goormaghtigh
Gerardo D
GD
Fidelio
Jean-Marie
JM
Ruysschaert
Vincent
V
Raussens
D000682:Amyloid / Q000737:chemistry*; D001704:Biopolymers / Q000737:chemistry*; D004591:Electrophoresis, Polyacrylamide Gel; D046529:Microscopy, Electron, Transmission; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D051844:alpha-Synuclein / Q000737:chemistry*
D000682:Amyloid; D001704:Biopolymers; D051844:alpha-Synuclein