{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:05:05Z","timestamp":1790553905553,"version":"4.1.0"},"reference-count":125,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:00:00Z","timestamp":1621555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010146","name":"Alzheimer Forschung Initiative","doi-asserted-by":"publisher","award":["16004"],"award-info":[{"award-number":["16004"]}],"id":[{"id":"10.13039\/100010146","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Deutsche Forschungsgemeinschaft","award":["RO 2226\/13-1"],"award-info":[{"award-number":["RO 2226\/13-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In Parkinson\u2019s disease, aggregates of \u03b1-synuclein within Lewy bodies and Lewy neurites represent neuropathological hallmarks. However, the cellular and molecular mechanisms triggering oligomeric and fibrillary \u03b1-synuclein aggregation are not fully understood. Recent evidence indicates that oxidative stress induced by metal ions and post-translational modifications such as phosphorylation, ubiquitination, nitration, glycation, and SUMOylation affect \u03b1-synuclein conformation along with its aggregation propensity and neurotoxic profiles. In addition, proteolytic cleavage of \u03b1-synuclein by specific proteases results in the formation of a broad spectrum of fragments with consecutively altered and not fully understood physiological and\/or pathological properties. In the present review, we summarize the current knowledge on proteolytical \u03b1-synuclein cleavage by neurosin, calpain-1, cathepsin D, and matrix metalloproteinase-3 in health and disease. We also shed light on the contribution of the same enzymes to proteolytical processing of pathogenic proteins in Alzheimer\u2019s disease and report potential cross-disease mechanisms of pathogenic protein aggregation.<\/jats:p>","DOI":"10.3390\/ijms22115450","type":"journal-article","created":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T13:15:15Z","timestamp":1621602915000},"page":"5450","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Proteolytic \u03b1-Synuclein Cleavage in Health and Disease"],"prefix":"10.3390","volume":"22","author":[{"given":"Alexandra","family":"Bluhm","sequence":"first","affiliation":[{"name":"Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Schrempel","sequence":"additional","affiliation":[{"name":"Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6409-0664","authenticated-orcid":false,"given":"Stephan von","family":"von H\u00f6rsten","sequence":"additional","affiliation":[{"name":"Department for Experimental Therapy, University Clinics Erlangen and Preclinical Experimental Center, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3358-8299","authenticated-orcid":false,"given":"Anja","family":"Schulze","sequence":"additional","affiliation":[{"name":"Department of Molecular Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, 06120 Halle\/Saale, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Ro\u00dfner","sequence":"additional","affiliation":[{"name":"Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bloem, B.R., Okun, M.S., and Klein, C. 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