{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:49:38Z","timestamp":1787010578933,"version":"build-2736575974"},"posted":{"date-parts":[[2024,6,21]]},"group-title":"Neuroscience","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T00:00:00Z","timestamp":1718928000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Aligning Science Across Parkinson\u2019s","award":["ASAP-020616"],"award-info":[{"award-number":["ASAP-020616"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\u03b1-Synuclein aggregates characterize \u03b1-synucleinopathies, including Parkinson\u2019s disease and Dementia with Lewy bodies. A majority of people with these disorders experience cognitive decline, and its extent correlates with cortical \u03b1-synuclein pathology. Mechanisms by which pathology targets cortical circuits remain to be understood so that the debilitating non-motor impairments can be addressed. Overt neuronal loss is not a major feature of cortical pathology, but a reduction of presynaptic sites has been reported at late stages of PD. We here define excitatory synapses as neuronal loci affected by \u03b1-synuclein aggregation, showing that they are progressively lost, and identify temporal and spatial patterns of synaptic vulnerability. Results were obtained in a mouse model using intrastriatal injection of pre-formed \u03b1-synuclein fibrils to template the aggregation of endogenous \u03b1-synuclein in cortical neurons. Lewy neurite-like aggregates were predominantly observed in axons. Super-resolved imaging showed \u03b1-synuclein aggregation within cortical synapses and revealed that synaptic aggregation is most severe proximal to Lewy neurite-like structures and linked to the earliest detectable loss of excitatory synapses. Excitatory synapses also exhibited ultrastructural aberrations, including a redistribution of pre- and post-synaptic protein clusters away from contact sites and reduced synaptic vesicle size. As pathology advanced, VGLUT1-positive intracortical synapses, enriched in \u03b1-synuclein, were progressively vulnerable in this striatal seeding model, while VGLUT2-positive long-range synapses with minimal \u03b1-synuclein were spared. Inhibitory synapses were not affected. In agreement with a disruptive role of synaptic \u03b1-synuclein aggregation, super-resolved mesoscale imaging determined that synaptic but not non-synaptic \u03b1-synuclein pathology is correlated with excitatory synapse loss. Physiological recordings confirmed impaired excitatory neurotransmission. Pathology propagation tracked cortical connectivity, with intra-column synapse loss correlated between interconnected layers V and II\/III. Contralateral areas receiving projections from pathologic layer V also exhibited synapse loss. These findings reveal synapses as principal cellular loci of \u03b1-synuclein pathology and define how molecular and circuit-based mechanisms underlie the cortical progression of synaptic pathology in \u03b1-synucleinopathies.<\/jats:p>","DOI":"10.1101\/2024.06.20.599774","type":"posted-content","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T07:10:13Z","timestamp":1718953813000},"source":"Crossref","is-referenced-by-count":7,"title":["Progressive Vulnerability of Cortical Synapses in \u03b1-Synucleinopathy"],"prefix":"10.64898","author":[{"given":"Saroj","family":"Sah","sequence":"first","affiliation":[{"name":"Department of Neurology, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Sauerbeck","sequence":"additional","affiliation":[{"name":"Department of Neurology, 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