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

Al-Hilaly, Youssra K, Biasetti, Luca, Brakeman, Ben J, Pollack, Saskia J, Zibaee, Shahin, Abdul-Sada, Alaa, Thorpe, Julian R, Xue, Wei-Feng and Serpell, Louise C (2016) The involvement of dityrosine crosslinking in α-synuclein assembly and deposition in Lewy Bodies in Parkinson’s disease. Scientific Reports, 6. p. 39171. ISSN 2045-2322

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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.

Item Type: Article
Keywords: Alpha-synuclein, Parkinson's disease, oxidative stress, Copper, Dityrosine
Schools and Departments: School of Life Sciences > Biochemistry
Research Centres and Groups: Sussex Neuroscience
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Youssra Al-Hilaly
Date Deposited: 19 Dec 2016 09:44
Last Modified: 07 Mar 2017 18:10
URI: http://sro.sussex.ac.uk/id/eprint/65921

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