Synaptic enrichment of pSer129 alpha-synuclein correlates with dopaminergic denervation in early-stage Parkinson’s disease
Abstract 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—includin...
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2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61052-1 |
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| author | Irene Frigerio Martino L. Morella Amber B. Winkelaar Danai T. Vorgia John JP Brevé Walter A. Boiten Bram L. van der Gaag Ismael L. Calandri Allert J. Jonker Henk W. Berendse Daniel Mona Markus Britschgi Laura E. Jonkman Wilma DJ van de Berg |
| author_facet | Irene Frigerio Martino L. Morella Amber B. Winkelaar Danai T. Vorgia John JP Brevé Walter A. Boiten Bram L. van der Gaag Ismael L. Calandri Allert J. Jonker Henk W. Berendse Daniel Mona Markus Britschgi Laura E. Jonkman Wilma DJ van de Berg |
| author_sort | Irene Frigerio |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-a7fa43f9248c4bdf8c1eedcde2c1ef8a |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a7fa43f9248c4bdf8c1eedcde2c1ef8a2025-08-20T03:05:06ZengNature PortfolioNature Communications2041-17232025-07-0116111910.1038/s41467-025-61052-1Synaptic enrichment of pSer129 alpha-synuclein correlates with dopaminergic denervation in early-stage Parkinson’s diseaseIrene Frigerio0Martino L. Morella1Amber B. Winkelaar2Danai T. Vorgia3John JP Brevé4Walter A. Boiten5Bram L. van der Gaag6Ismael L. Calandri7Allert J. Jonker8Henk W. Berendse9Daniel Mona10Markus Britschgi11Laura E. Jonkman12Wilma DJ van de Berg13Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam UMC, Vrije Universiteit AmsterdamDepartment of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam UMC, Vrije Universiteit AmsterdamDepartment of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam UMC, Vrije Universiteit AmsterdamDepartment of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam UMC, Vrije Universiteit AmsterdamDepartment of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam UMC, Vrije Universiteit AmsterdamDepartment of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam UMC, Vrije Universiteit AmsterdamDepartment of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam UMC, Vrije Universiteit AmsterdamDepartment of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam UMC, Vrije Universiteit AmsterdamDepartment of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam UMC, Vrije Universiteit AmsterdamAmsterdam Neuroscience, NeurodegenerationRoche Pharma Research and Early Development; Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center BaselRoche Pharma Research and Early Development; Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center BaselDepartment of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam UMC, Vrije Universiteit AmsterdamDepartment of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam UMC, Vrije Universiteit AmsterdamAbstract 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.https://doi.org/10.1038/s41467-025-61052-1 |
| spellingShingle | Irene Frigerio Martino L. Morella Amber B. Winkelaar Danai T. Vorgia John JP Brevé Walter A. Boiten Bram L. van der Gaag Ismael L. Calandri Allert J. Jonker Henk W. Berendse Daniel Mona Markus Britschgi Laura E. Jonkman Wilma DJ van de Berg Synaptic enrichment of pSer129 alpha-synuclein correlates with dopaminergic denervation in early-stage Parkinson’s disease Nature Communications |
| title | Synaptic enrichment of pSer129 alpha-synuclein correlates with dopaminergic denervation in early-stage Parkinson’s disease |
| title_full | Synaptic enrichment of pSer129 alpha-synuclein correlates with dopaminergic denervation in early-stage Parkinson’s disease |
| title_fullStr | Synaptic enrichment of pSer129 alpha-synuclein correlates with dopaminergic denervation in early-stage Parkinson’s disease |
| title_full_unstemmed | Synaptic enrichment of pSer129 alpha-synuclein correlates with dopaminergic denervation in early-stage Parkinson’s disease |
| title_short | Synaptic enrichment of pSer129 alpha-synuclein correlates with dopaminergic denervation in early-stage Parkinson’s disease |
| title_sort | synaptic enrichment of pser129 alpha synuclein correlates with dopaminergic denervation in early stage parkinson s disease |
| url | https://doi.org/10.1038/s41467-025-61052-1 |
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