{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:51:15Z","timestamp":1790711475687,"version":"4.1.0"},"reference-count":266,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006292","name":"Infectious Disease Society of America","doi-asserted-by":"crossref","award":["ALZ-ID-0000000016"],"award-info":[{"award-number":["ALZ-ID-0000000016"]}],"id":[{"id":"10.13039\/100006292","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100020360","name":"IDSA Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100020360","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"crossref","award":["#2034292"],"award-info":[{"award-number":["#2034292"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alpha-synuclein (\u03b1Syn) is one of the most abundant proteins in the nervous system and is currently associated with devastating synucleinopathies, yet its biology extends far beyond this. In this review, we suggest that \u03b1Syn-driven disease emerges within specific neural circuits through the combined effects of cell-type-specific roles, subcellular environments, post-translational modifications (PTMs), and co-pathology. These interacting and additive dimensions, rather than \u03b1Syn alone, generate the pathological diversity, shaping whether pathology manifests as Parkinson\u2019s disease (PD), Parkinson\u2019s disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), or mixed dementia phenotypes. We integrate recent advances on the physiological roles of \u03b1Syn in neurons and glia (astrocytes, oligodendrocytes, and microglia), its compartment-dependent (e.g., synaptic and nuclear) functions, and the molecular transitions (e.g., mediated by pS129) that convert functional assemblies into pathogenic conformers. Building on this foundation, we outline mechanisms through which these factors contribute to disease-specific vulnerability, progression, and clinical heterogeneity. Finally, we highlight how this multidimensional perspective on \u03b1Syn biology can inform the development of next-generation biomarkers that support precision therapies across distinct disorders.<\/jats:p>","DOI":"10.3390\/cells15050451","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T14:42:47Z","timestamp":1772548967000},"page":"451","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Alpha-Synuclein in Neurodegeneration: From Shared Biology to Disease-Specific Phenotypes"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0680-5159","authenticated-orcid":false,"given":"Feifei","family":"Su","sequence":"first","affiliation":[{"name":"Brain and Mind Centre & Faculty of Medicine and Health School of Medical Sciences, The University of Sydney, Camperdown, NSW 2050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4707-933X","authenticated-orcid":false,"given":"Woojin S.","family":"Kim","sequence":"additional","affiliation":[{"name":"Brain and Mind Centre & Faculty of Medicine and Health School of Medical Sciences, The University of Sydney, Camperdown, NSW 2050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0422-8398","authenticated-orcid":false,"given":"Glenda M.","family":"Halliday","sequence":"additional","affiliation":[{"name":"Brain and Mind Centre & Faculty of Medicine and Health School of Medical Sciences, The University of Sydney, Camperdown, NSW 2050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4539-2039","authenticated-orcid":false,"given":"YuHong","family":"Fu","sequence":"additional","affiliation":[{"name":"Brain and Mind Centre & Faculty of Medicine and Health School of Medical Sciences, The University of Sydney, Camperdown, NSW 2050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41582-024-01043-w","article-title":"\u03b1-Synuclein pathology as a target in neurodegenerative diseases","volume":"21","author":"Park","year":"2025","journal-title":"Nat. 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