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bioRxiv · 10.1101/629238

Heme minimizes Parkinson’s disease-associated toxicity by inducing a conformational distortion in the oligomers of alpha-Synuclein

Chakraborty, R.·Dey, S.·Paul, S. S.·Sil, P.·Sengupta, J.·Chattopadhyay, K.
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Abstract

Aggregation of the intrinsically disordered protein alpha-Synuclein (-Syn) into insoluble fibrils with a cross-{beta} sheet amyloid structure plays a key role in the neuronal pathology of Parkinsons disease (PD). The fibrillation pathway of -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 -Syn contains the core residues of the protein arranged into in-register parallel {beta} 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 -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 -Syn oligomers. We believe that this study provides a novel strategy of developing a therapeutic solution of PD, which has been elusive so far.

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Chakraborty, R., Dey, S., Paul, S. S., Sil, P., Sengupta, J., Chattopadhyay, K.. 2019-05-07. Heme minimizes Parkinson’s disease-associated toxicity by inducing a conformational distortion in the oligomers of alpha-Synuclein. https://doi.org/10.1101/629238

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