Al-Hilaly et al-2016.pdf (1.96 MB)
The involvement of dityrosine crosslinking in a-synuclein assembly and deposition in Lewy Bodies in Parkinson’s disease
journal contribution
posted on 2023-06-09, 04:25 authored by Youssra Al-Hilaly, Luca Biasetti, Ben J Brakeman, Saskia J Pollack, Shahin Zibaee, Alaa Abdul-Sada, Julian R Thorpe, Wei-Feng Xue, Louise SerpellLouise SerpellParkinson’s disease (PD) is characterized by intracellular, insoluble Lewy bodies composed of highly stable a-synuclein (a-syn) amyloid fibrils. a-synuclein is an intrinsically disordered protein that has the capacity to assemble to form ß-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 a-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 a-syn assemblies. Thus, the presence of oxidative stress induced dityrosine could play an important role in assembly and toxicity of a-syn in PD.
History
Publication status
- Published
File Version
- Published version
Journal
Scientific ReportsISSN
2045-2322Publisher
Nature Publishing GroupExternal DOI
Volume
6Page range
39171Department affiliated with
- Biochemistry Publications
Research groups affiliated with
- Sussex Neuroscience Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-12-19First Open Access (FOA) Date
2016-12-19First Compliant Deposit (FCD) Date
2016-12-19Usage metrics
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