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EGCG has Dual and Opposing Effects on the N-terminal Region of Self-associating α-synuclein Oligomers

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  • Anne Louise Grønnemose, Syddansk Universitet
  • ,
  • Eva Christina Østerlund, Syddansk Universitet
  • ,
  • Daniel Erik Otzen
  • Thomas J.D. Jørgensen, Syddansk Universitet

Oligomers of the protein α-synuclein (α-syn) are thought to be a major toxic species in Parkinson's disease, particularly through their ability to permeabilize cell membranes. The green tea polyphenol epigallocatechin gallate (EGCG) has been found to reduce this ability. We have analyzed α-syn oligomer dynamics and interconversion by H/D exchange monitored by mass spectrometry (HDX-MS). Our results show that the two oligomers OI and OII co-exist in equilibrium; OI is a multimer of OII and its dissociation can be followed by HDX-MS by virtue of the correlated exchange of the N-terminal region. Urea destabilizes the α-syn oligomers, dissociating OI to OII and monomers. Oligomers exposed to EGCG undergo Met oxidation. Intriguingly, EGCG induces an oxidation-dependent effect on the structure of the N-terminal region. For the non-oxidized N-terminal region, EGCG increases the stability of the folded structure as measured by a higher level of protection against H/D exchange. In contrast, protection is clearly abrogated in the Met oxidized N-terminal region. Having a non-oxidized and disordered N-terminal region is known to be essential for efficient membrane binding. Therefore, our results suggest that the combined effect of a structural stabilization of the non-oxidized N-terminal region and the presence of a disordered oxidized N-terminal region renders the oligomers less cytotoxic by decreasing the ability of the N-terminal region to bind to cell membranes and facilitate their permeabilization.

TidsskriftJournal of Molecular Biology
StatusUdgivet - dec. 2022

Bibliografisk note

Funding Information:
We are grateful to the Lundbeck Foundation for supporting this work through grant R183-2014-3545 to D.E.O.

Publisher Copyright:
© 2022 The Author(s)

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