Nitrated products formed on α-synuclein are preferentially incorporated into oligomers but excluded from fibrils: A mechanism for accumulation of neurotoxic species.

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Post-translational modifications (PTMs) such as nitration of Tyr (Y) residues and di-tyrosine (DT) formation are known to impact the aggregation behavior of α-synuclein (α-syn), a protein closely linked to Parkinson's disease. Using tetranitromethane (TNM) as a model nitrating agent, we systematically investigated the chemical modifications of α-syn and their consequences for aggregation. Mass spectrometry analysis revealed site-selective nitration of all four Tyr residues, with Y39 and Y125 being most susceptible. DT crosslinks were also observed, primarily involving Y39, but were disfavored at higher TNM concentrations, indicating competition between nitration and crosslinking pathways. Higher TNM concentrations favored nitration over crosslinking, consistent with common radical intermediates. Even sub-stoichiometric amounts of TNM-modified α-syn significantly inhibited fibril elongation, suggesting that nitration disrupts the templated addition of monomers into the ordered fibrillar structure. Consistent with this, TNM-modified α-syn was strongly excluded from fibrillar assemblies. In contrast, they were preferentially incorporated into soluble oligomers, underlining the promiscuous ability of oligomers to act as a sink for chemically modified α-syn monomers, with potential implications for neurotoxicity.

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