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O-GlcNAcylation, an abundant post-translational modification throughout the brain, is regulated by the enzymatic activity of the cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and has been implicated in altering \u03b1-syn toxicity. Nevertheless, the interplay between modulating O-GlcNAc cycling and \u03b1-syn aggregation and the propagation of amyloid pathology is not well elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To this end, we delivered conformational strains of \u03b1-syn in the striatum of mice or neuronal and microglial co-cultured cells following pharmacologically or genetically inhibited OGT and OGA. The substantia nigra was injected with an adeno-associated viral vector coding for \u03b1-syn combined with \u03b1-syn preformed fibrils to examine \u03b1-syn-induced dopaminergic cytotoxicity. The \u03b1-syn pathology and spreading, protein O-GlcNAcylation, OGT and OGA levels, microglial inflammation, and behavioral impairments were evaluated. Furthermore, the O-GlcNAc modification and proteolysis status of \u03b1-syn under O-GlcNAc cycling modification were also assessed using a combination of approaches, including Click-iT\u2122 O-GlcNAc enzyme labeling, sWGA pulldown, HPLC-MS\/MS, and immunohistochemical analysis following proteasome and autophagy-lysosome inhibition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that modulation of O-GlcNAc cycling, governed by the two enzymes OGT and OGA, significantly affected \u03b1-syn aggregation, propagation, dopaminergic neuronal degeneration, and microglial inflammation. Pathological \u03b1-syn transmission to adjacent cells and anatomically connected brain regions was found to suppress recipient cellular O-GlcNAc levels, concomitant with reduced OGT expression. Pharmacological inhibition or genetic knockdown of OGT exacerbated \u03b1-syn aggregation, enhanced its intercellular transmission, and intensified NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)-mediated microglial inflammation. Conversely, increasing O-GlcNAcylation via OGA inhibition ameliorated these pathological processes. Furthermore, we demonstrate that enzymatic O-GlcNAcylation significantly regulates the aggregation of fibril-induced initial dimer formation and facilitates the clearance of \u03b1-syn aggregates through autophagosome-lysosome flux.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings highlight the critical regulatory role of O-GlcNAc modification in \u03b1-syn pathology and conformational strain formation, and provide mechanical evidence that enhancing O-GlcNAc modifications alleviates pathological \u03b1-syn proteolysis by restoring autophagosome-lysosome flux.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13024-025-00904-2","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T13:14:44Z","timestamp":1761570884000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Modulation of O-GlcNAc cycling influences \u03b1-synuclein amplification, degradation, and associated neuroinflammatory pathology"],"prefix":"10.1186","volume":"20","author":[{"given":"Yongzhen","family":"Miao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoya","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanhuan","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qipei","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengni","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangping","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Feng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongrui","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"key":"904_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cger.2019.08.002","volume":"36","author":"DK Simon","year":"2020","unstructured":"Simon DK, Tanner CM, Brundin P. 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