Comparative Analysis of Total Alpha-Synuclein (αSYN) Immunoassays Reveals That They Do Not Capture the Diversity of Modified αSYN Proteoforms

Autor: Lara Petricca, Nour Chiki, Layane Hanna-El-Daher, Lorène Aeschbach, Ritwik Burai, Erik Stoops, Mohamed-Bilal Fares, Hilal A. Lashuel
Rok vydání: 2022
Předmět:
Zdroj: Journal of Parkinson's Disease. 12:1449-1462
ISSN: 1877-718X
1877-7171
Popis: BackgroundThe development of therapeutics for Parkinson’s disease (PD) requires the establishment of biomarker assays to enable stratifying patients, monitoring disease progression and assessing target engagement. Attempts to develop diagnostic assays based on detecting levels of the α-synuclein (αSYN) protein, a central player in the pathogenesis of PD, have yielded inconsistent results.ObjectiveTo determine whether the three commercial kits that have been extensively used for total αSYN quantification in human biological fluids (from Euroimmun, MSD, and Biolegend) are capable of capturing the diversity and complexity of relevant αSYN proteoforms.MethodsWe investigated and compared the ability of the different assays to detect the diversity of αSYN proteoform using a library of αSYN proteins that compromise the majority of disease-relevant αSYN variants and post-translational modification.ResultsOur findings showed that none of the three tested immunoassays accurately capture the totality of relevant αSYN species and are unable to recognize most disease-associated C-terminally truncated variants of αSYN. Moreover, several N-terminal truncations and phosphorylation/nitration differentially modify the level of αSYN detection and recovery by different immunoassays, and a CSF matrix effect was observed for most of the αSYN proteoforms analyzed by the three immunoassays.ConclusionsOur results showed that these immunoassays do not capture the totality of the relevant αSYN species and therefore may not be appropriate tools to provide an accurate measure of total αSYN levels in samples containing modified forms of the protein. This highlights the need for next-generation αSYN immunoassays that capture the diversity of αSYN proteoforms.
Databáze: OpenAIRE
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