{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:57:07Z","timestamp":1793041027284,"version":"4.5.0"},"reference-count":363,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease and related synucleinopathies, including dementia with Lewy bodies and multiple system atrophy, are characterised by the pathological aggregation of the \u03b1-synuclein (aSyn) protein in neuronal and glial cells, leading to cellular dysfunction and neurodegeneration. This review synthesizes knowledge of aSyn biology, including its structure, aggregation mechanisms, cellular interactions, and systemic influences. We highlight the structural diversity of aSyn aggregates, ranging from oligomers to fibrils, their strain-like properties, and their prion-like propagation. While the role of prion-like mechanisms in disease progression remains a topic of ongoing debate, these processes may contribute to the clinical heterogeneity of synucleinopathies. Dysregulation of protein clearance pathways, including chaperone-mediated autophagy and the ubiquitin\u2013proteasome system, exacerbates aSyn accumulation, while post-translational modifications influence its toxicity and aggregation propensity. Emerging evidence suggests that immune responses and alterations in the gut microbiome are key modulators of aSyn pathology, linking peripheral processes\u2014particularly those of intestinal origin\u2014to central neurodegeneration. Advances in biomarker development, such as cerebrospinal fluid assays, post-translationally modified aSyn, and real-time quaking-induced conversion technology, hold promise for early diagnosis and disease monitoring. Furthermore, positron emission tomography imaging and conformation-specific antibodies offer innovative tools for visualising and targeting aSyn pathology in vivo. Despite significant progress, challenges remain in accurately modelling human synucleinopathies, as existing animal and cellular models capture only specific aspects of the disease. This review underscores the need for more reliable aSyn biomarkers to facilitate the development of effective treatments. Achieving this goal requires an interdisciplinary approach integrating genetic, epigenetic, and environmental insights.<\/jats:p>","DOI":"10.3390\/ijms26115405","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T11:14:12Z","timestamp":1749035652000},"page":"5405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["\u03b1-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9982-7571","authenticated-orcid":false,"given":"Oscar","family":"Arias-Carri\u00f3n","sequence":"first","affiliation":[{"name":"Experimental Neurology, Instituto Nacional de Rehabilitaci\u00f3n Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico"},{"name":"Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City 14380, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Guerra-Crespo","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Department of Physiology, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Padilla-God\u00ednez","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Department of Physiology, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04360, Mexico"},{"name":"Department of Mathematics and Physics, Western Institute of Technology and Higher Education, San Pedro Tlaquepaque 45604, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5013-3608","authenticated-orcid":false,"given":"Luis O.","family":"Soto-Rojas","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathogenesis, Building A4, Medical Surgeon Career, Faculty of Higher Studies Iztacala, National Autonomous University of Mexico, Mexico City 54090, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3277-0101","authenticated-orcid":false,"given":"El\u00edas","family":"Manjarrez","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla, 14 Sur 6301, Col. 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