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The toxic properties of \u03b1-synuclein are conserved from yeast to man, but the precise underpinnings of the cellular pathologies associated are still elusive, complicating the development of effective therapeutic strategies. Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced \u03b1-synuclein toxicity in vitro and in vivo, in Drosophila and in mice. Glycation affected primarily the N-terminal region of \u03b1-synuclein, reducing membrane binding, impaired the clearance of \u03b1-synuclein, and promoted the accumulation of toxic oligomers that impaired neuronal synaptic transmission. Strikingly, using glycation inhibitors, we demonstrated that normal clearance of \u03b1-synuclein was re-established, aggregation was reduced, and motor phenotypes in Drosophila were alleviated. Altogether, our study demonstrates glycation constitutes a novel drug target that can be explored in synucleinopathies as well as in other neurodegenerative conditions.<\/jats:p>","DOI":"10.1093\/brain\/awx056","type":"journal-article","created":{"date-parts":[[2017,2,23]],"date-time":"2017-02-23T07:11:55Z","timestamp":1487833915000},"page":"1399-1419","source":"Crossref","is-referenced-by-count":215,"title":["Glycation potentiates \u03b1-synuclein-associated neurodegeneration in synucleinopathies"],"prefix":"10.1093","volume":"140","author":[{"given":"Hugo","family":"Vicente Miranda","sequence":"first","affiliation":[{"name":"1 CEDOC, Chronic Diseases Research Centre, NOVA Medical School | Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"2 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal"}]},{"given":"\u00c9va M.","family":"Szeg\u0151","sequence":"additional","affiliation":[{"name":"3 Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Center for Biostructural Imaging of Neurodegeneration (BIN), University Medical Center G\u00f6ttingen, Waldweg 33, 37073 G\u00f6ttingen, Germany"}]},{"given":"Lu\u00eds M. 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