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Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites

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  • Andres Binolfi

    (In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)
    Present address: Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR-UNR), Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR-CONICET), 27 de Febrero 210 bis, S2002LRK Rosario, Argentina)

  • Antonio Limatola

    (In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)
    University of Naples 'Federico II', Via Domenico Montesanto 49, Naples 80131, Italy.)

  • Silvia Verzini

    (In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin))

  • Jonas Kosten

    (In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin))

  • Francois-Xavier Theillet

    (In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)
    Present address: Institute for Integrative Biology of the Cell (I2BC), UMR9198 CNRS, Université Paris-Sud, CEA Batiment 144, Gif-sur-Yvette, F-91191, France)

  • Honor May Rose

    (In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin))

  • Beata Bekei

    (In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin))

  • Marchel Stuiver

    (In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin))

  • Marleen van Rossum

    (In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin))

  • Philipp Selenko

    (In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin))

Abstract

Cellular oxidative stress serves as a common denominator in many neurodegenerative disorders, including Parkinson’s disease. Here we use in-cell NMR spectroscopy to study the fate of the oxidation-damaged Parkinson’s disease protein alpha-synuclein (α-Syn) in non-neuronal and neuronal mammalian cells. Specifically, we deliver methionine-oxidized, isotope-enriched α-Syn into cultured cells and follow intracellular protein repair by endogenous enzymes at atomic resolution. We show that N-terminal α-Syn methionines Met1 and Met5 are processed in a stepwise manner, with Met5 being exclusively repaired before Met1. By contrast, C-terminal methionines Met116 and Met127 remain oxidized and are not targeted by cellular enzymes. In turn, persisting oxidative damage in the C-terminus of α-Syn diminishes phosphorylation of Tyr125 by Fyn kinase, which ablates the necessary priming event for Ser129 modification by CK1. These results establish that oxidative stress can lead to the accumulation of chemically and functionally altered α-Syn in cells.

Suggested Citation

  • Andres Binolfi & Antonio Limatola & Silvia Verzini & Jonas Kosten & Francois-Xavier Theillet & Honor May Rose & Beata Bekei & Marchel Stuiver & Marleen van Rossum & Philipp Selenko, 2016. "Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites," Nature Communications, Nature, vol. 7(1), pages 1-10, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10251
    DOI: 10.1038/ncomms10251
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