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Proteolysis of \u03b1-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-\u03b1-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-\u03b1-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of \u03b1-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-\u03b1-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-\u03b1-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-\u03b1-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and \u03b1-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of \u03b1-synuclein, pGlu79-\u03b1-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human \u03b1-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-\u03b1-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-\u03b1-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-\u03b1-synuclein in human synucleinopathies, which may\u2014in analogy to pGlu-A\u03b2 peptides in Alzheimer\u2019s disease\u2014act as a seed for pathogenic protein aggregation.<\/jats:p>","DOI":"10.1007\/s00401-021-02349-5","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T08:02:52Z","timestamp":1627286572000},"page":"399-421","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["A glutaminyl cyclase-catalyzed \u03b1-synuclein modification identified in human synucleinopathies"],"prefix":"10.1007","volume":"142","author":[{"given":"Maike","family":"Hartlage-R\u00fcbsamen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Bluhm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Moceri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Machner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janett","family":"K\u00f6ppen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Schenk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Hilbrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Holzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Weidenfeller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Richter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Coras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geidy E.","family":"Serrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Beach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Schilling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"von H\u00f6rsten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Schulze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9959-283X","authenticated-orcid":false,"given":"Steffen","family":"Ro\u00dfner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,26]]},"reference":[{"key":"2349_CR1","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.1002\/acn3.50944","volume":"6","author":"S Abd Elhadi","year":"2019","unstructured":"Abd Elhadi S, Grigoletto J, Poli M, Arosio P, Arkadir D, Sharon R (2019) alpha-Synuclein in blood cells differentiates Parkinson\u2019s disease from healthy controls. 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All experiments carried out were in agreement with European regulations on the protection of animals used for scientific purposes (Directive 2010\/63\/EU), and they were also approved by the Ethical Committee for Animal Research of Landesdirektion Sachsen, license numbers T28\/16 and the local ethical board of the District Government of Middle Franconia, Bavaria, Germany; approval # 55.2-DMS 2532-2-218.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All the authors have approved publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}