{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T21:56:12Z","timestamp":1784584572769,"version":"3.55.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T00:00:00Z","timestamp":1716249600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T00:00:00Z","timestamp":1716249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000065","name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["K08 NS110876"],"award-info":[{"award-number":["K08 NS110876"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS122880"],"award-info":[{"award-number":["NS122880"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS133979"],"award-info":[{"award-number":["NS133979"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS122880"],"award-info":[{"award-number":["NS122880"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS133979"],"award-info":[{"award-number":["NS133979"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["RF1 NS083845"],"award-info":[{"award-number":["RF1 NS083845"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006309","name":"American Parkinson Disease Association","doi-asserted-by":"publisher","award":["Cotzias Fellowship"],"award-info":[{"award-number":["Cotzias Fellowship"]}],"id":[{"id":"10.13039\/100006309","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke"},{"name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke"},{"name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke"},{"name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke"},{"name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["npj Parkinsons Dis."],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alpha-synuclein (\u03b1S)-rich Lewy bodies and neurites in the cerebral cortex correlate with the presence of dementia in Parkinson disease (PD) and Dementia with Lewy bodies (DLB), but whether \u03b1S influences synaptic vesicle dynamics in human cortical neurons is unknown. Using a new iPSC-based assay platform for measuring synaptic vesicle cycling, we found that in human cortical glutamatergic neurons, increased \u03b1S from either transgenic expression or triplication of the endogenous locus in patient-derived neurons reduced synaptic vesicle cycling under both stimulated and spontaneous conditions. Thus, using a robust, easily adopted assay platform, we show for the first time \u03b1S-induced synaptic dysfunction in human cortical neurons, a key cellular substrate for PD dementia and DLB.<\/jats:p>","DOI":"10.1038\/s41531-024-00725-y","type":"journal-article","created":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T19:01:47Z","timestamp":1716318107000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A stem cell-based assay platform demonstrates alpha-synuclein dependent synaptic dysfunction in patient-derived cortical neurons"],"prefix":"10.1038","volume":"10","author":[{"given":"Andrew J.","family":"White","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karis A.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kellianne D.","family":"Alexander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9459-3593","authenticated-orcid":false,"given":"Nagendran","family":"Ramalingam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy L.","family":"Young-Pearse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6676-0107","authenticated-orcid":false,"given":"Ulf","family":"Dettmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8846-9767","authenticated-orcid":false,"given":"Dennis J.","family":"Selkoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7004-8630","authenticated-orcid":false,"given":"Gary P. H.","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,21]]},"reference":[{"key":"725_CR1","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s13024-019-0306-8","volume":"14","author":"TF Outeiro","year":"2019","unstructured":"Outeiro, T. F. et al. Dementia with Lewy bodies: an update and outlook. Mol. Neurodegener. 14, 5 (2019).","journal-title":"Mol. Neurodegener."},{"key":"725_CR2","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/42166","volume":"388","author":"MG Spillantini","year":"1997","unstructured":"Spillantini, M. G. et al. Alpha-synuclein in Lewy bodies. Nature 388, 839\u2013840 (1997).","journal-title":"Nature"},{"key":"725_CR3","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1111\/jnc.14810","volume":"150","author":"D Sulzer","year":"2019","unstructured":"Sulzer, D. & Edwards, R. H. The physiological role of \u03b1\u2010synuclein and its relationship to Parkinson\u2019s Disease. J. Neurochem. 150, 475\u2013486 (2019).","journal-title":"J. Neurochem."},{"key":"725_CR4","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1016\/S0140-6736(04)17103-1","volume":"364","author":"M-C Chartier-Harlin","year":"2004","unstructured":"Chartier-Harlin, M.-C. et al. \u03b1-synuclein locus duplication as a cause of familial Parkinson\u2019s disease. Lancet 364, 1167\u20131169 (2004).","journal-title":"Lancet"},{"key":"725_CR5","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1126\/science.1090278","volume":"302","author":"AB Singleton","year":"2003","unstructured":"Singleton, A. B. et al. alpha-Synuclein locus triplication causes Parkinson\u2019s disease. Science 302, 841\u2013841 (2003).","journal-title":"Science"},{"key":"725_CR6","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.neuron.2009.12.023","volume":"65","author":"VM Nemani","year":"2010","unstructured":"Nemani, V. M. et al. Increased Expression of \u03b1-Synuclein Reduces Neurotransmitter Release by Inhibiting Synaptic Vesicle Reclustering after Endocytosis. Neuron 65, 66\u201379 (2010).","journal-title":"Neuron"},{"key":"725_CR7","doi-asserted-by":"publisher","first-page":"2319","DOI":"10.1016\/j.cub.2014.08.027","volume":"24","author":"L Wang","year":"2014","unstructured":"Wang, L. et al. \u03b1-Synuclein Multimers Cluster Synaptic Vesicles and Attenuate Recycling. Curr. Biol. 24, 2319\u20132326 (2014).","journal-title":"Curr. Biol."},{"key":"725_CR8","doi-asserted-by":"publisher","first-page":"10129","DOI":"10.1523\/JNEUROSCI.0535-12.2012","volume":"32","author":"D Scott","year":"2012","unstructured":"Scott, D. & Roy, S. \u03b1-Synuclein Inhibits Intersynaptic Vesicle Mobility and Maintains Recycling-Pool Homeostasis. J. Neurosci. 32, 10129\u201310135 (2012).","journal-title":"J. Neurosci."},{"key":"725_CR9","doi-asserted-by":"publisher","first-page":"11915","DOI":"10.1523\/JNEUROSCI.3821-06.2006","volume":"26","author":"KE Larsen","year":"2006","unstructured":"Larsen, K. E. et al. \u03b1-Synuclein Overexpression in PC12 and Chromaffin Cells Impairs Catecholamine Release by Interfering with a Late Step in Exocytosis. J. Neurosci. 26, 11915\u201311922 (2006).","journal-title":"J. Neurosci."},{"key":"725_CR10","doi-asserted-by":"publisher","first-page":"11116","DOI":"10.1073\/pnas.1903054116","volume":"116","author":"M Atias","year":"2019","unstructured":"Atias, M. et al. Synapsins regulate \u03b1-synuclein functions. Proc. Natl Acad. Sci. 116, 11116\u201311118 (2019).","journal-title":"Proc. Natl Acad. Sci."},{"key":"725_CR11","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1126\/science.276.5321.2045","volume":"276","author":"MH Polymeropoulos","year":"1997","unstructured":"Polymeropoulos, M. H. et al. Mutation in the \u03b1-Synuclein Gene Identified in Families with Parkinson\u2019s Disease. Science 276, 2045\u20132047 (1997).","journal-title":"Science"},{"key":"725_CR12","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1038\/nn.4529","volume":"20","author":"T Logan","year":"2017","unstructured":"Logan, T., Bendor, J., Toupin, C., Thorn, K. & Edwards, R. H. \u03b1-Synuclein promotes dilation of the exocytotic fusion pore. Nat. Neurosci. 20, 681\u2013689 (2017).","journal-title":"Nat. Neurosci."},{"key":"725_CR13","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/s40478-021-01203-9","volume":"9","author":"M Lin","year":"2021","unstructured":"Lin, M. et al. In Parkinson\u2019s patient-derived dopamine neurons, the triplication of \u03b1-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition. Acta Neuropathol. Commun. 9, 107 (2021).","journal-title":"Acta Neuropathol. Commun."},{"key":"725_CR14","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/s41531-022-00366-z","volume":"8","author":"S Stern","year":"2022","unstructured":"Stern, S. et al. Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson\u2019s disease patients. npj Parkinsons Dis. 8, 103 (2022).","journal-title":"npj Parkinsons Dis."},{"key":"725_CR15","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1212\/WNL.0000000000004058","volume":"89","author":"IG McKeith","year":"2017","unstructured":"McKeith, I. G. et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 89, 88\u2013100 (2017).","journal-title":"Neurology"},{"key":"725_CR16","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1016\/j.neuron.2013.05.029","volume":"78","author":"Y Zhang","year":"2013","unstructured":"Zhang, Y. et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 78, 785\u2013798 (2013).","journal-title":"Neuron"},{"key":"725_CR17","doi-asserted-by":"publisher","first-page":"3402","DOI":"10.1016\/j.neuron.2021.08.003","volume":"109","author":"VN Lagomarsino","year":"2021","unstructured":"Lagomarsino, V. N. et al. Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors. Neuron 109, 3402\u20133420.e9 (2021).","journal-title":"Neuron"},{"key":"725_CR18","doi-asserted-by":"publisher","first-page":"5867","DOI":"10.1523\/JNEUROSCI.1508-12.2013","volume":"33","author":"W Xu","year":"2013","unstructured":"Xu, W. et al. Simultaneous Monitoring of Presynaptic Transmitter Release and Postsynaptic Receptor Trafficking Reveals an Enhancement of Presynaptic Activity in Metabotropic Glutamate Receptor-Mediated Long-Term Depression. J. Neurosci. 33, 5867\u20135877 (2013).","journal-title":"J. Neurosci."},{"key":"725_CR19","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.stemcr.2020.05.015","volume":"15","author":"F Rosa","year":"2020","unstructured":"Rosa, F. et al. In Vitro Differentiated Human Stem Cell-Derived Neurons Reproduce Synaptic Synchronicity Arising during Neurodevelopment. Stem. Cell Rep. 15, 22\u201337 (2020).","journal-title":"Cell Rep."},{"key":"725_CR20","doi-asserted-by":"publisher","first-page":"2970","DOI":"10.1038\/nprot.2006.449","volume":"1","author":"J Burrone","year":"2006","unstructured":"Burrone, J., Li, Z. & Murthy, V. N. Studying vesicle cycling in presynaptic terminals using the genetically encoded probe synaptopHluorin. Nat. Protoc. 1, 2970\u20132978 (2006).","journal-title":"Nat. Protoc."},{"key":"725_CR21","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/j.neuron.2016.07.005","volume":"91","author":"SSH Wang","year":"2016","unstructured":"Wang, S. S. H. et al. Fusion Competent Synaptic Vesicles Persist upon Active Zone Disruption and Loss of Vesicle Docking. Neuron 91, 777\u2013791 (2016).","journal-title":"Neuron"},{"key":"725_CR22","doi-asserted-by":"publisher","first-page":"100271","DOI":"10.1016\/j.jbc.2021.100271","volume":"296","author":"N Ramalingam","year":"2021","unstructured":"Ramalingam, N. & Dettmer, U. Temperature is a key determinant of alpha- and beta-synuclein membrane interactions in neurons. J. Biol. Chem. 296, 100271 (2021).","journal-title":"J. Biol. Chem."},{"key":"725_CR23","doi-asserted-by":"publisher","first-page":"4328","DOI":"10.1523\/JNEUROSCI.15-06-04328.1995","volume":"15","author":"K Kraszewski","year":"1995","unstructured":"Kraszewski, K. et al. Synaptic vesicle dynamics in living cultured hippocampal neurons visualized with CY3-conjugated antibodies directed against the lumenal domain of synaptotagmin. J. Neurosci. 15, 4328\u20134342 (1995).","journal-title":"J. Neurosci."},{"key":"725_CR24","doi-asserted-by":"publisher","first-page":"9754","DOI":"10.1523\/JNEUROSCI.0344-18.2018","volume":"38","author":"PJ Teravskis","year":"2018","unstructured":"Teravskis, P. J. et al. A53T Mutant Alpha-Synuclein Induces Tau-Dependent Postsynaptic Impairment Independently of Neurodegenerative Changes. J. Neurosci. 38, 9754\u20139767 (2018).","journal-title":"J. Neurosci."},{"key":"725_CR25","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/s41531-023-00444-w","volume":"9","author":"N Ramalingam","year":"2023","unstructured":"Ramalingam, N. et al. Dynamic physiological \u03b1-synuclein S129 phosphorylation is driven by neuronal activity. Npj Park Dis. 9, 4 (2023).","journal-title":"Npj Park Dis."},{"key":"725_CR26","doi-asserted-by":"publisher","first-page":"2509","DOI":"10.1016\/j.celrep.2018.04.066","volume":"23","author":"R Nehme","year":"2018","unstructured":"Nehme, R. et al. Combining NGN2 Programming with Developmental Patterning Generates Human Excitatory Neurons with NMDAR-Mediated Synaptic Transmission. Cell Rep. 23, 2509\u20132523 (2018).","journal-title":"Cell Rep."},{"key":"725_CR27","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1111\/tra.12119","volume":"14","author":"A McCluskey","year":"2013","unstructured":"McCluskey, A. et al. Building a Better Dynasore: The Dyngo Compounds Potently Inhibit Dynamin and Endocytosis. Traffic 14, 1272\u20131289 (2013).","journal-title":"Traffic"},{"key":"725_CR28","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1002\/mds.28346","volume":"36","author":"GPH Ho","year":"2021","unstructured":"Ho, G. P. H. et al. Upregulation of Cellular Palmitoylation Mitigates \u03b1\u2010Synuclein Accumulation and Neurotoxicity. Mov. Disord. 36, 348\u2013359 (2021).","journal-title":"Mov. Disord."},{"key":"725_CR29","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1002\/ana.410430612","volume":"43","author":"MD Muenter","year":"1998","unstructured":"Muenter, M. D. et al. Hereditary form of parkinsonism\u2014dementia. Ann. Neurol. 43, 768\u2013781 (1998).","journal-title":"Ann. Neurol."},{"key":"725_CR30","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.1073\/pnas.1520335113","volume":"113","author":"JR Mazzulli","year":"2016","unstructured":"Mazzulli, J. R., Zunke, F., Isacson, O., Studer, L. & Krainc, D. \u03b1-Synuclein\u2013induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proc. Natl Acad. Sci. 113, 1931\u20131936 (2016).","journal-title":"Proc. Natl Acad. Sci."},{"key":"725_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1453","volume":"2","author":"MJ Devine","year":"2011","unstructured":"Devine, M. J. et al. Parkinson\u2019s disease induced pluripotent stem cells with triplication of the \u03b1-synuclein locus. Nat. Commun. 2, 440 (2011).","journal-title":"Nat. Commun."},{"key":"725_CR32","doi-asserted-by":"publisher","first-page":"1970","DOI":"10.1038\/s41380-022-01454-5","volume":"27","author":"C-I Wu","year":"2022","unstructured":"Wu, C.-I. et al. APP and DYRK1A regulate axonal and synaptic vesicle protein networks and mediate Alzheimer\u2019s pathology in trisomy 21 neurons. Mol. Psychiatr. 27, 1970\u20131989 (2022).","journal-title":"Mol. Psychiatr."}],"container-title":["npj Parkinson's Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41531-024-00725-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41531-024-00725-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41531-024-00725-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T19:06:11Z","timestamp":1716318371000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41531-024-00725-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,21]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["725"],"URL":"https:\/\/doi.org\/10.1038\/s41531-024-00725-y","relation":{},"ISSN":["2373-8057"],"issn-type":[{"value":"2373-8057","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,21]]},"assertion":[{"value":"19 December 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 May 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 May 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"D.J.S. is a director and consultant to Prothena Biosciences. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"107"}}