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Mapping Surface Hydrophobicity of α-Synuclein Oligomers at the Nanoscale.

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Rodrigues, Margarida 
Carr, Alexander R 
Horrocks, Mathew H 


Proteins fold into a single structural ensemble but can also misfold into many diverse structures including small aggregates and fibrils, which differ in their toxicity. The aggregate surface properties play an important role in how they interact with the plasma membrane and cellular organelles, potentially inducing cellular toxicity, however, these properties have not been measured to date due to the lack of suitable methods. Here, we used a spectrally resolved, super-resolution imaging method combined with an environmentally sensitive fluorescent dye to measure the surface hydrophobicity of individual aggregates formed by the protein α-synuclein (αS), whose aggregation is associated with Parkinson's disease. We show that the surface of soluble oligomers is more hydrophobic than fibrils and populates a diverse range of coexisting states. Overall, our data show that the conversion of oligomers to fibril-like aggregates and ultimately to fibrils results in a reduction in both hydrophobicity and the variation in hydrophobicity. This funneling characteristic of the energy landscape explains many of the observed properties of αS aggregates and may be a common feature of aggregating proteins.



Nile red, Super-resolution spectroscopy, alpha-synuclein, hydrophobicity, protein aggregation, spectral imaging, Fluorescent Dyes, Humans, Hydrophobic and Hydrophilic Interactions, Optical Imaging, Parkinson Disease, Protein Aggregates, Protein Aggregation, Pathological, Protein Multimerization, Solubility, alpha-Synuclein

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Nano Lett

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American Chemical Society (ACS)
European Research Council (669237)
Wellcome Trust (094425/Z/10/Z)
Biotechnology and Biological Sciences Research Council (BB/H003843/1)
Medical Research Council (MR/K015850/1)
Engineering and Physical Sciences Research Council (EP/L504920/1)
Engineering and Physical Sciences Research Council (EP/N035003/1)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (701013)
C.M.D. is supported by the Wellcome Trust (094425/Z/10/Z) and the UK Biotechnology and Biochemical Sciences Research Council (BB/H003843/1). D.J.W. is supported by the UK Engineering and Physical Science Research Council (EP/L504920/1). S.F.L. is supported by the Royal Society (UF120277). D.K. is a Royal Society Professor of Molecular Medicine and funded by the European Research Council (669237) and MRC (MR/K015850/1). We thank the members of the Klenerman and Lee research groups for their input and discussion, in particular we would like to thank Dr. Juan Varela, Dr. Aleks Ponjavic, Dr. Marija Iljina, and Dr. Alex Herbert for their helpful discussion.