Journal Article

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

Vorgia, Danai T., Frigerio, Irene, Jonker, Allert J., Jonkman, Laura E., Calandri, Ismael L., Mona, Daniel, Morella, Martino L., van der Gaag, Bram L., Boiten, Walter A., Brevé, John JP, van de Berg, Wilma DJ, Winkelaar, Amber B., Berendse, Henk W., Britschgi, Markus

2025

Overview

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. α-Synuclein accumulation in putaminal synapses is hypothesised to drive Parkinson’s disease progression. This study demonstrates synaptic pSer129 α-synuclein enrichment in early-stage Parkinson’s disease, and its link with dopaminergic denervation and cortical Lewy body pathology.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/51 / 14/19 / 14/34 / 14/63 / 631/378/1689/1718 / 631/378/340 / 631/80/458/1733 / Aged / Aged, 80 and over / alpha-Synuclein - metabolism / Biomarkers / Brain / Cell body / Confocal microscopy / Denervation / Disease control / Dopamine - metabolism / Dopamine receptors / Dopaminergic Neurons - metabolism / Dopaminergic Neurons - pathology / Enrichment / Female / Females / Glutamatergic transmission / Humanities and Social Sciences / Humans / Immunofluorescence / Lewy bodies / Lewy Bodies - metabolism / Lewy Bodies - pathology / Male / Middle Aged / Movement disorders / multidisciplinary / Neostriatum / Neurodegenerative diseases / Parkinson Disease - metabolism / Parkinson Disease - pathology / Parkinson's disease / Pathology / Phosphorylation / Putamen / Putamen - metabolism / Putamen - pathology / Retrograde transport / Science / Science (multidisciplinary) / Synapses / Synapses - metabolism / Synapses - pathology / Synaptosomes / Synaptosomes - metabolism / Synuclein