{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:49:18Z","timestamp":1791946158731,"version":"4.3.4"},"reference-count":333,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Abnormal accumulation of aggregated \u03b1-synuclein (\u03b1-Syn) is seen in a variety of neurodegenerative diseases, including Parkinson\u2019s disease (PD), multiple system atrophy (MSA), dementia with Lewy body (DLB), Parkinson\u2019s disease dementia (PDD), and even subsets of Alzheimer\u2019s disease (AD) showing Lewy-body-like pathology. These synucleinopathies exhibit differences in their clinical and pathological representations, reminiscent of prion disorders. Emerging evidence suggests that \u03b1-Syn self-assembles and polymerizes into conformationally diverse polymorphs in vitro and in vivo, similar to prions. These \u03b1-Syn polymorphs arising from the same precursor protein may exhibit strain-specific biochemical properties and the ability to induce distinct pathological phenotypes upon their inoculation in animal models. In this review, we discuss clinical and pathological variability in synucleinopathies and several aspects of \u03b1-Syn fibril polymorphism, including the existence of high-resolution molecular structures and brain-derived strains. The current review sheds light on the recent advances in delineating the structure\u2013pathogenic relationship of \u03b1-Syn and how diverse \u03b1-Syn molecular polymorphs contribute to the existing clinical heterogeneity in synucleinopathies.<\/jats:p>","DOI":"10.3390\/biom11101419","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T12:29:14Z","timestamp":1632832154000},"page":"1419","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":116,"title":["Structural and Functional Insights into \u03b1-Synuclein Fibril Polymorphism"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1777-673X","authenticated-orcid":false,"given":"Surabhi","family":"Mehra","sequence":"first","affiliation":[{"name":"Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3157-2998","authenticated-orcid":false,"given":"Laxmikant","family":"Gadhe","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1651-1097","authenticated-orcid":false,"given":"Riya","family":"Bera","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay Singh","family":"Sawner","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9110-1565","authenticated-orcid":false,"given":"Samir K.","family":"Maji","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/j.1749-6632.2000.tb06900.x","article-title":"The alpha-synucleinopathies: Parkinson\u2019s disease, dementia with Lewy bodies, and multiple system atrophy","volume":"920","author":"Spillantini","year":"2000","journal-title":"Ann. 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