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Sci Rep. 2016 Dec 16;6:39171. doi: 10.1038/srep39171.

The involvement of dityrosine crosslinking in α-synuclein assembly and deposition in Lewy Bodies in Parkinson's disease.

Author information

1
School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
2
College of Sciences, Chemistry Department, Al-Mustansiriyah University, Baghdad, Iraq.
3
School of Biosciences, University of Kent, Canterbury, CT2 7NJ, UK.
4
Laboratory of Molecular Biology, MRC Centre, Hills Rd, Cambridge, CB2 OQH, UK.

Abstract

Parkinson's disease (PD) is characterized by intracellular, insoluble Lewy bodies composed of highly stable α-synuclein (α-syn) amyloid fibrils. α-synuclein is an intrinsically disordered protein that has the capacity to assemble to form β-sheet rich fibrils. Oxidiative stress and metal rich environments have been implicated in triggering assembly. Here, we have explored the composition of Lewy bodies in post-mortem tissue using electron microscopy and immunogold labeling and revealed dityrosine crosslinks in Lewy bodies in brain tissue from PD patients. In vitro, we show that dityrosine cross-links in α-syn are formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress by fluorescence and confirmed using mass-spectrometry. A covalently cross-linked dimer isolated by SDS-PAGE and mass analysis showed that dityrosine dimer was formed via the coupling of Y39-Y39 to give a homo dimer peptide that may play a key role in formation of oligomeric and seeds for fibril formation. Atomic force microscopy analysis reveals that the covalent dityrosine contributes to the stabilization of α-syn assemblies. Thus, the presence of oxidative stress induced dityrosine could play an important role in assembly and toxicity of α-syn in PD.

PMID:
27982082
PMCID:
PMC5159849
DOI:
10.1038/srep39171
[Indexed for MEDLINE]
Free PMC Article

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