Synaptic enrichment of pSer129 alpha-synuclein correlates with dopaminergic denervation in early-stage Parkinson's disease

In Parkinson's disease (PD), α-synuclein aggregation in striatal synapses is hypothesised to trigger a cascade of events leading to synaptic loss and cortical Lewy body (LB) pathology. Using multiplex immunofluorescence and confocal microscopy on 69 brains spanning Braak stages 0-6-including controls, incidental LB disease (iLBD), and PD-we show that phosphorylated (pSer129) α-synuclein is enriched in putaminal dopaminergic synapses already in early disease stages, and associates with dopaminergic terminal loss. C-terminally truncated (CTT122) α-synuclein shows a similar trend in later stages. Enrichment of pSer129 and CTT122 α-synuclein in cortical glutamatergic synapses in the putamen occurs prior to LB appearance in cortical regions, supporting the theory of α-synuclein retrograde transport from synapse to cell body. Using AlphaLISA, we confirm that isolated PD putaminal synaptosomes contain higher pSer129 α-synuclein protein levels compared to controls. These findings suggest that synaptic enrichment of pSer129 α-synuclein occurs in early PD, possibly contributing to dopaminergic denervation and cortical LB pathology.