The misfolding of the small, intrinsically disordered protein alpha synuclein into toxic oligomers and fibers is implicated in the pathology of Parkinson’s disease (PD). Through semi-synthesis we have shown that the endogenous protein post-translational modification O-GlcNAcylation generally inhibits the aggregation of α-synuclein, but with site-specific differences. Interestingly, serine 87 O-GlcNAcylated (gS87) α-synuclein forms aggregates when assembled <i>in vitro </i>at physiological concentration. Gross morphological characterization of these aggregates through limited proteolysis with Proteinase K reveals that a distinct structure results from the modification compared to wild-type fibers. The gS87 aggregates also demonstrate the ability to act as seeds that template their core structure onto unmodified monomers, propagating a gS87-type strain through multiple iterations of seeding reactions. Through solid state NMR, we show that gS87-templated aggregates resemble “ribbons” that have altered structure, and that have previously been shown to elicit lower toxicity. Treatment of gS87 fibers onto mouse primary neuronal cells similarly showed reduced pathology. Importantly, this study supports competitive seeding of endogenous α-synuclein to a less toxic fiber strain (i.e. through gS87 pre-formed fibers) as a potential PD therapeutic strategy.

O-GlcNAcylation of α-synuclein forms ribbons that seed monomers into less pathological aggregates

2019 Fall National Meeting

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