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neurodegenerative diseases defined by the misfolding and aggregation of \u03b1-synuclein (\u03b1-syn). Abnormal accumulation and spreading of \u03b1-syn aggregates lead to synapse dysfunction and neuronal cell death. Yet, little is known about the synaptic mechanisms underlying the \u03b1-syn pathology. Here we identified \u03b2-isoforms of neurexins (\u03b2-NRXs) as presynaptic organizing proteins that interact with \u03b1-syn preformed fibrils (\u03b1-syn PFFs), toxic \u03b1-syn aggregates, but not \u03b1-syn monomers. Our cell surface protein binding assays and surface plasmon resonance assays reveal that \u03b1-syn PFFs bind directly to \u03b2-NRXs through their N-terminal histidine-rich domain (HRD) at the nanomolar range (KD: ~500 nM monomer equivalent). Furthermore, our artificial synapse formation assays show that \u03b1-syn PFFs diminish excitatory and inhibitory presynaptic organization induced by a specific isoform of neuroligin 1 that binds only \u03b2-NRXs, but not \u03b1-isoforms of neurexins. Thus, our data suggest that \u03b1-syn PFFs interact with \u03b2-NRXs to inhibit \u03b2-NRX-mediated presynaptic organization, providing novel molecular insight into how \u03b1-syn PFFs induce synaptic pathology in synucleinopathies such as Parkinson\u2019s disease and dementia with Lewy bodies.<\/jats:p>","DOI":"10.3390\/cells12071083","type":"journal-article","created":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T01:39:26Z","timestamp":1680658766000},"page":"1083","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["\u03b1-Synuclein Preformed Fibrils Bind to \u03b2-Neurexins and Impair \u03b2-Neurexin-Mediated Presynaptic Organization"],"prefix":"10.3390","volume":"12","author":[{"given":"Benjamin","family":"Feller","sequence":"first","affiliation":[{"name":"Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4938-6480","authenticated-orcid":false,"given":"Aur\u00e9lie","family":"Fallon","sequence":"additional","affiliation":[{"name":"Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Luo","sequence":"additional","affiliation":[{"name":"The Neuro\u2019s Early Drug Discovery Unit (EDDU), Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC H3A 2B4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuong Trang","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, Universit\u00e9 du Qu\u00e9bec \u00e0 Montr\u00e9al, Montreal, QC H3C 3P8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Shlaifer","sequence":"additional","affiliation":[{"name":"The Neuro\u2019s Early Drug Discovery Unit (EDDU), Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC H3A 2B4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred Kihoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"},{"name":"Integrated Program in Neuroscience, McGill University, Montreal, QC H3A 2B2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Chofflet","sequence":"additional","affiliation":[{"name":"Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"},{"name":"Integrated Program in Neuroscience, McGill University, Montreal, QC H3A 2B2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayoung","family":"Yi","sequence":"additional","affiliation":[{"name":"Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Husam","family":"Khaled","sequence":"additional","affiliation":[{"name":"Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samer","family":"Karkout","sequence":"additional","affiliation":[{"name":"Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5563-8787","authenticated-orcid":false,"given":"Steve","family":"Bourgault","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, Universit\u00e9 du Qu\u00e9bec \u00e0 Montr\u00e9al, Montreal, QC H3C 3P8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3942-1956","authenticated-orcid":false,"given":"Thomas 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