{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:05:33Z","timestamp":1790348733406,"version":"4.1.0"},"reference-count":92,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T00:00:00Z","timestamp":1616371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"UK Medical Research Council","doi-asserted-by":"crossref","award":["G0701498"],"award-info":[{"award-number":["G0701498"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000265","name":"UK Medical Research Council","doi-asserted-by":"crossref","award":["MR\/L010666\/1"],"award-info":[{"award-number":["MR\/L010666\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000268","name":"UK Biotechnology and Biological Sciences Research Council","doi-asserted-by":"crossref","award":["BB\/N001230\/1"],"award-info":[{"award-number":["BB\/N001230\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alpha-synuclein (\u03b1-syn) mislocalization and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinson\u2019s disease, Parkinson\u2019s disease with dementia and dementia with Lewy bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying \u03b1-syn accumulation and toxicity in a Drosophila model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human \u03b1-syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, cysteine string protein, synapsin, and syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These \u03b1-syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing Drosophila that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of dementia with Lewy bodies. Together, these findings demonstrate that presynaptic accumulation of \u03b1-syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that \u03b1-syn-mediated synaptopathy is an initiating cause of age-related neurodegeneration.<\/jats:p>","DOI":"10.1093\/braincomms\/fcab049","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T16:25:22Z","timestamp":1616171122000},"source":"Crossref","is-referenced-by-count":22,"title":["Presynaptic accumulation of \u03b1-synuclein causes synaptopathy and progressive neurodegeneration in\n                    <i>Drosophila<\/i>"],"prefix":"10.1093","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7692-9866","authenticated-orcid":false,"given":"Jessika C","family":"Bridi","sequence":"first","affiliation":[{"name":"Department of Basic & Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London SE5 9RX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0373-7417","authenticated-orcid":false,"given":"Erika","family":"Bereczki","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Novum, Stockholm 171 77, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0353-4836","authenticated-orcid":false,"given":"Saffron K","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Biology and York Biomedical Research Institute, University of York, York YO1 5DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gon\u00e7alo M","family":"Po\u00e7as","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Lisbon 2780-157, Portugal"},{"name":"School of Biological Sciences, Monash University, Melbourne, VIC 34QP+JV, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4551-5791","authenticated-orcid":false,"given":"Benjamin","family":"Kottler","sequence":"additional","affiliation":[{"name":"Department of Basic & Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London SE5 9RX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro M","family":"Domingos","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Lisbon 2780-157, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J","family":"Elliott","sequence":"additional","affiliation":[{"name":"Department of Biology and York Biomedical Research Institute, University of York, York YO1 5DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dag","family":"Aarsland","sequence":"additional","affiliation":[{"name":"Department of Old Age Psychiatry, Institute of Psychiatry Psychology and Neuroscience, King\u2019s College London, London, UK"},{"name":"Centre for Age-Related Diseases, Stavanger University Hospital, Stavanger 4068, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8581-9450","authenticated-orcid":false,"given":"Frank","family":"Hirth","sequence":"additional","affiliation":[{"name":"Department of Basic & Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London SE5 9RX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"issue":"10004","key":"2021070810503621700_fcab049-B1","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1016\/S0140-6736(15)00462-6","article-title":"Lewy body dementias","volume":"386","author":"Walker","year":"2015","journal-title":"Lancet"},{"issue":"6","key":"2021070810503621700_fcab049-B2","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.neuron.2013.09.004","article-title":"The function of \u03b1-synuclein","volume":"79","author":"Bendor","year":"2013","journal-title":"Neuron"},{"issue":"S1","key":"2021070810503621700_fcab049-B3","first-page":"S53","article-title":"The synucleinopathies: Twenty years on","volume":"7","author":"Goedert","year":"2017","journal-title":"J Parkinsons 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