Toxic prefibrillar alpha-synuclein amyloid oligomers adopt a distinctive antiparallel beta-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-aa protein alpha-synuclein (AS). AS fibrillation follows a nucleation polymerization pathway involving diverse transient prefibrillar species varying in size and morphology. Like for 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 amyloid aggregation mechanism and oligomer-induced toxicity. It is already recognized that soluble oligomeric AS species adopt beta-sheet structures that differ from those characterizing the fibrillar structure. In the present work we used ATR-FTIR spectroscopy, a technique especially sensitive to beta-sheet structure, to get deeper insight into the beta-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel beta-sheet structure whereas fibrils, a parallel arrangement. The data are discussed in terms of regions of the protein involved in the early beta-sheet interactions and the implications of such conformational arrangement for the pathogenicity associated to AS oligomers.
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[Show abstract] [Hide abstract] ABSTRACT: Alpha synuclein (αsyn) fibrils are found in the Lewy Bodies of patients with Parkinson's disease (PD). The aggregation of the αsyn monomer to soluble oligomers and insoluble fibril aggregates is believed to be one of the causes of PD. Recently, the view of the native state of αsyn as a monomeric ensemble was challenged by a report suggesting that αsyn exists in its native state as a helical tetramer. This review reports on our current understanding of αsyn within the context of these recent developments and describes the work performed by a number of groups to address the monomer/tetramer debate. A number of in depth studies have subsequently shown that both non-acetylated and acetylated αsyn purified under mild conditions are primarily monomer. A description of the accessible states of acetylated αsyn monomer and the ability of αsyn to self-associate is explored.0Comments 14Citations
- "This would imply reorientation of monomer units as an obligatory step before formation of the fibril. However , at least one report demonstrates that toxic prefibrillar amyloid aggregates adopt an antiparallel orientation , and in this sense we cannot draw any analogy to this pseudo-equilibrium dimer population that exists with the fibril accessible monomer ensemble, and how the monomers therein may interact with it. As the monomeric ensemble is shifted towards more fibril prone conditions, previously described conformational changes (Section 2.1), as well as changes in population of oligomeric species occurs. "
- [Show abstract] [Hide abstract] ABSTRACT: The toxicity of amyloids is a subject under intense scrutiny. Many studies link this toxicity to the existence of various intermediate structures prior to the fiber formation and/or their specific interaction with membranes. Membranes can also be a catalyst of amyloidogenesis and the composition or the charge of membrane lipids may be of particular importance. Despite intensive research in the field, such intermediates are not yet fully characterized probably because of the lack of adapted methods for their analyses, and the mechanisms of interaction with the membrane are far to be understood. The purpose of this mini-review is to highlight some in vitro characteristics that seem to be convergent to explain the toxicity observed for some amyloids. Based on a comparison between the behavior of a model non-toxic amyloid (the Prion Forming Domain of HET-s) and its toxic mutant (M8), we could establish that short oligomers and/or fibers assembled in antiparallel β-sheets strongly interact with membrane leading to its disruption. Many recent evidences are in favor of the formation of antiparallel toxic oligomers assembled in β-helices able to form pores. We may also propose a new model of amyloid interaction with membranes by a "raft-like" mode of insertion that could explain important destabilization of membranes and thus amyloid toxicity.0Comments 18Citations
- [Show abstract] [Hide abstract] ABSTRACT: Amyloid refers to insoluble protein aggregates that are responsible for amyloid diseases but are also implicated in important physiological functions (functional amyloids). The widespread presence of protein aggregates but also, in most of the cases, their deleterious effects explain worldwide efforts made to understand their formation, structure and biological functions. We emphasized the role of FTIR and especially ATR-FTIR techniques in amyloid protein and/or peptide studies. The multiple advantages provided by ATR-FTIR allow an almost continuous structural view of protein/peptide conversion during the aggregation process. Moreover, it is now well-established that infrared can differentiate oligomers from fibrils simply on their spectral features. ATR-FTIR is certainly the fastest and easiest method to obtain this information. ATR-FTIR occupies a key position in the analysis and comprehension of the complex aggregation mechanism(s) at the oligomer and/or fibril level. These mechanism(s) seem to present strong similarities between different amyloid proteins and might therefore be extremely important to understand for both disease-associated and functional amyloid proteins. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies.0Comments 39Citations