Alpha synuclein (asyn) is expressed in neurons and is associated with the pathogenesis of synucleinopathies like Parkinson's Disease. Asyn aggregates are associated with phosphorylation at serine position 129 (pS129), which can be induced by environmental triggers, including viral infection, and the risk increases with aging. We show that brain tissue from West Nile Virus (WNV) infected patients exhibit increased expression of pS129 asyn in neurons of brain tissue. We found that WNV infection, Poly I:C treatment, and type 1 interferon (T1 IFN) treatment elicit the acute induction, followed by rapid degradation of pS129 asyn in olfactory pathways and primary cortical neurons. Induction of pS129 asyn was induced at these early time points independent of asyn aggregates. In IFN receptor knockout neurons, virus infection and Poly I:C stimulation do not induce pS129 asyn, implying that pS129 asyn is dependent on the type 1 interferon receptor. Our findings suggest that infections with DNA and RNA viruses and subsequent antiviral immunity can trigger the acute formation of pS129 asyn, and T1 IFN stimulation in neurons can trigger post-translational modifications in asyn. Further studies evaluating the interactions between pS129 asyn and interferon signaling may provide a common trigger for the formation of pathogenic asyn species.
Heiden et al. (2026) studied this question.