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• W2943846912 abstract "Abstract Aggregation of the intrinsically disordered protein alpha-Synuclein (α-Syn) into insoluble fibrils with a cross-β sheet amyloid structure plays a key role in the neuronal pathology of Parkinson’s disease (PD). The fibrillation pathway of α-Syn encompasses a multitude of transient oligomeric forms differing in size, secondary structure, hydrophobic exposure and toxicity. According to a recent solid state NMR study, the fibrillating unit of α-Syn contains the core residues of the protein arranged into in-register parallel β sheets with a unique Greek key topology. Here, we have shown that the physiologically available small molecule heme (hemin chloride) when added at sub-stoichiometric ratios to either monomeric or aggregated α-Syn, arrests its aggregation in an oligomeric state, which is minimally toxic. Using cryo-EM, we observed that these heme-induced oligomers are ‘mace’-shaped and consist of approximately four monomers. However, the presence of a crucial twist or contortion in their Greek key structural architecture prevents further hierarchical appending into annular oligomers and protofilament formation. We confirm using a His50Gln mutant that the binding of heme onto His50 is crucial in inflicting the structural distortion and is responsible for the stabilization of the non-toxic and off-pathway α-Syn oligomers. We believe that this study provides a novel strategy of developing a therapeutic solution of PD, which has been elusive so far." @default.
• W2943846912 created "2019-05-16" @default.
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• W2943846912 date "2019-05-07" @default.
• W2943846912 modified "2023-10-18" @default.
• W2943846912 title "Heme minimizes Parkinson’s disease-associated toxicity by inducing a conformational distortion in the oligomers of alpha-Synuclein" @default.
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• W2943846912 doi "https://doi.org/10.1101/629238" @default.
• W2943846912 hasPublicationYear "2019" @default.
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