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Investigating the Presence of Doubly‐phosphorylated α‐Synuclein at Tyrosine 125 and Serine 129 In Idiopathic Lewy Body Diseases

Lookup NU author(s): Dr Daniel Erskine, Dr Christopher Morris, Professor Johannes Attems

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

Aggregation of the protein α‐synuclein (α‐syn) into insoluble intracellular assemblies termed Lewy bodies (LBs) is thought to be a critical pathogenic event in LB diseases such as Parkinson’s disease and dementia with LBs. In LB diseases, the majority of α‐syn is phosphorylated at serine 129 (pS129), suggesting this is an important disease‐related post‐translational modification (PTM). However, PTMs do not typically occur in isolation, and phosphorylation at the proximal tyrosine 125 (pY125) residue has received considerable attention and has been inconsistently reported to be present in LBs. Furthermore, the proximity of Y125 to S129 means that some pS129 antibodies may have epitopes that include Y125, in which case phosphorylation of Y125 will impede recognition of α‐syn. This would potentially lead to underestimating LB pathology burdens if pY125 occurs alongside pS129. To address the apparent controversy in the literature regarding the detection of pY125, we investigated its presence in LB pathology. We generated pS129 antibodies whose epitope includes or does not include Y125 and compared the extent of α‐syn pathology recognized in mouse models of α‐synucleinopathies, human brain tissue lysates and fixed post‐mortem brain tissues. Our study demonstrated no difference in α‐syn pathology recognized between pS129 antibodies, irrespective of whether Y125 was part of the epitope or not. Furthermore, evaluation with pY125 antibodies whose epitope does not include S129 demonstrated no labelling of LB pathology. This study reconciles disparate results in the literature and demonstrates pY125 is not a key component of LB pathology in murine models or human tissues in idiopathic LB diseases.


Publication metadata

Author(s): Fayyad M, Erskine D, Majbour NK, Vaikath NV, Ghanem SS, Sudhakaran IP, Abdesselem H, Lamprokostopoulou A, Vekrellis K, Morris CM, Attems J, El-Agnaf OMA

Publication type: Article

Publication status: Published

Journal: Brain Pathology

Year: 2020

Pages: epub ahead of print

Online publication date: 23/04/2020

Acceptance date: 16/04/2020

Date deposited: 24/04/2020

ISSN (electronic): 1750-3639

Publisher: Wiley-Blackwell Publishing, Inc.

URL: https://doi.org/10.1111/bpa.12845

DOI: 10.1111/bpa.12845


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