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Abstract Background At early stages in Parkinson’s disease (PD), α-synuclein aggregation in pre-synaptic terminals in the striatum is hypothesized to set off a cascade of events leading to synaptic loss and widespread cortical Lewy body (LB) pathology. Here, we tested whether α-synuclein proteoforms are enriched in putaminal pre- and post-synaptic terminals in relation to synaptic degeneration and cortical LB pathology in anatomically connected regions across PD stages.Methods We employed multiplex-immunofluorescence in combination with high-resolution confocal microscopy to visualize and quantify total α-synuclein (Syn1), phosphorylated at Serine129 (pSer129), and C-terminal-truncated at residue 122 (CTT122) in dopaminergic (DAT+), cortical glutamatergic (VGLUT1+) pre-synapses and post-synapses (PSD95+), in the putamen of 32 incidental LB disease (iLBD), 27 PD, and 10 control brain donors. LB density was quantified in cingulate and frontal regions. In a subset of the same donors (n = 38), total, pSer129, and CTT122 α-synuclein protein levels were quantified in putaminal synaptosomes using AlphaLISA immunoassays.Results In PD, severe DAT+ terminal loss was observed in the putamen (-86%, p + DAT+ synaptic density (rho = 0.61, p + and PSD95+ synaptic density did not change across disease stages (p > 0.05). pSer129 was highly increased in DAT+ synapses in iLBD cases with Braak stage 3 (+ 2000%, p = 0.007) and in VGLUT1+ and PSD95+ synapses in later stages (Braak stages 4–5; +1296–1613%, p +, VGLUT1+, PSD95+ synapses in late PD stages (Braak stages 4–6; +294–1332%, p + synaptic loss was associated with pSer129 (rho=-0.54, p + synapses. pSer129 and CTT122 were enriched in VGLUT1+ synapses prior to LB pathology in cingulate and frontal regions. Synaptosome fractions showed increased pSer129 protein levels in PD (+ 134%, p = 0.043) but not in iLBD (p = 0.392). We did not detect changes in total or CTT122 protein levels in PD or iLBD (p > 0.05).Conclusions Our results strongly suggest that synaptic enrichment of pSer129 α-synuclein is already increased in early PD stages, possibly contributing to dopaminergic denervation and cortical LB pathology, while CTT122 α-synuclein enrichment in synaptic terminals accompanies pSer129 in later stages.
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