Structural remodeling during amyloidogenesis of physiological Nα-acetylated α-synuclein

GALLEA JI; SARROUKH R; YUNES-QUARTINO P; RUYSSCHAERT JM; RAUSSENS V; CELEJ MS

BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2016 vol. 864 p. 501 - 510

1570-9639

The misfolding and aggregation of the presynaptic protein α-synuclein (AS) intoamyloid fibrils is pathognomonic of Parkinson's disease, though the mechanism by which this structural conversion occurs is largely unknown.Soluble oligomeric species that accumulate as intermediates in the process of fibril formation are thought to be highly cytotoxic. Recent studies indicate that oligomer-to-fibril AS transition plays a key role in cell toxicityand progression of neurodegeneration. We previously demonstrated that a subgroup of oligomeric AS species are ordered assemblies possessing a well-defined pattern of intermolecular contacts which are arranged into a distinctive antiparallel β-sheet structure, as opposed to the parallel fibrillar fold. Recently, it was demonstrated that the physiological form of AS is N-terminally acetylated (Ac-AS). Here, we first showed that wellcharacterized conformational ensembles of Ac-AS, namely monomers, oligomers and fibrils, recapitulate manybiophysical features of the nonacetylated protein, such as hydrodynamic, tinctorial, structural and membraneleakage properties. Then, we relied on ATR-FTIR spectroscopy to explore the structural reorganization during Ac-AS fibrillogenesis. We found that antiparallel β-sheet transient intermediates are built-up at early stages of aggregation, which then evolve to parallel β-sheet fibrils through helix-rich/disordered species. The results are discussed in termsof regions of the protein that might participate in this structural rearrangement. Our work provides new insights into the complex conformational reorganization occurring during Ac-AS amyloid formation.