The involvement of dityrosine crosslinking in α-synuclein assembly and deposition in Lewy Bodies in Parkinson’s disease
Citations Over TimeTop 10% of 2016 papers
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.
Related Papers
- → Immunogold for Protein Location in Chromaffin Cells(2022)1 cited
- → Microwave Polymerization in Thin Layers of London Resin White Allows Selection of Specimens for Immunogold Labeling(2001)4 cited
- → Colour development of immunogold-labelled antibodies for light microscopy(1986)13 cited
- Immunogold and immunogold/silver staining in the ultrastructural localization of target molecules identified by monoclonal antibodies.(1989)
- → Polarized incident light microscopical enhancement of immunogold and immunogold–silver preparations: Its role in immunohistology(1989)6 cited