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

Al-Hilaly, Youssra K, Biasetti, Luca, Blakeman, Ben J F, Pollack, Saskia J, Zibaee, Shahin, Abdul-Sada, Alaa, Thorpe, Julian R, Xue, Wei-Feng, Serpell, Louise C (2016) The involvement of dityrosine crosslinking in ?-synuclein assembly and deposition in Lewy Bodies in Parkinson's disease. Scientific Reports, 6 . Article Number 39171. ISSN 2045-2322. (doi:10.1038/srep39171) (KAR id:59869)


Parkinson's disease (PD) is characterized by intracellular, insoluble Lewy bodies composed of highly stable ?-synuclein (?-syn) amyloid fibrils. ?-synuclein is an intrinsically disordered protein that has the capacity to assemble to form ?-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 ?-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 ?-syn assemblies. Thus, the presence of oxidative stress induced dityrosine could play an important role in assembly and toxicity of ?-syn in PD.

Item Type: Article
DOI/Identification number: 10.1038/srep39171
Subjects: Q Science
Q Science > QP Physiology (Living systems) > QP517 Biochemistry
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Wei-Feng Xue
Date Deposited: 16 Jan 2017 16:37 UTC
Last Modified: 04 Mar 2024 18:08 UTC
Resource URI: (The current URI for this page, for reference purposes)

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