Abstract
A wide variety of oligomeric structures are formed during the aggregation of proteins associated with neurodegenerative diseases. Such soluble oligomers are believed to be key toxic species in the related disorders; therefore, identification of the structural determinants of toxicity is of upmost importance. Here, we analysed toxic oligomers of α-synuclein and its pathological variants in order to identify structural features that could be related to toxicity and found a novel structural polymorphism within G51D oligomers. These G51D oligomers can adopt a variety of β-sheet-rich structures with differing degrees of α-helical content, and the helical structural content of these oligomers correlates with the level of induced cellular dysfunction in SH-SY5Y cells. This structure–function relationship observed in α-synuclein oligomers thus presents the α-helical structure as another potential structural determinant that may be linked with cellular toxicity in amyloid-related proteins.
Highlights
The misfolding of proteins and their aggregation into amyloid fibrils has been implicated in numerous neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD) [1]
Deconvolution of circular dichroism (CD) spectra of WT oligomers suggests that they contain around 11% of α-helical structure, which was not detected by solid-state NMR analysis [13], indicating that the percentage of α-helical content we report here should only be used as a relative quantification between oligomer samples
Detailed work on the WT oligomers generated through our methods has identified the mechanistic features of α-synuclein oligomer-induced membrane disruption: first, the disordered N-terminal regions of the oligomers were found to act as anchors to the membrane by folding into α-helices, allowing the structured hydrophobic β-sheet core of the oligomer to insert into the interior of the lipid bilayer [13]
Summary
The misfolding of proteins and their aggregation into amyloid fibrils has been implicated in numerous neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD) [1]. Α-synuclein is intrinsically disordered; upon interaction with membranes, the protein has been observed to adopt an α-helical structure [2], associated with the functional role of the protein in neuronal cells [3]. Oligomeric species with varying degrees of β-sheet structure are observable in the early stages of aggregation [7]. It is these early oligomeric species, rather than the mature amyloid fibrils, that are believed to be key toxic species in the context of disease [1,8,9,10,11]. While a range of mechanisms have been proposed by which the toxic effect could be mediated, interactions with cell membranes are likely to be a main contributor to the observed cytotoxicity [12,13,14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
