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

Andres Binolfi, Antonio Limatola, Silvia Verzini, Jonas Kosten, Francois-Xavier Theillet, Honor May Rose, Beata Bekei, Marchel Stuiver, Marleen van Rossum and Philipp Selenko ()
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Andres Binolfi: In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)
Antonio Limatola: In-Cell NMR Laboratory, Leibniz Institute of Molecular Pharmacology (FMP Berlin)
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)
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)

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10251

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