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Experimental and pathological studies support the notion that \u03b1Syn aggregates contribute to cellular demise and dysfunction with disease progression associated with a prion-like spread of \u03b1Syn aggregates via conformational templating. The initiating event(s) and factors that contribute to diverse forms of synucleinopathies remain poorly understood. A major post-translational modification of \u03b1Syn associated with pathological inclusions is a diverse array of specific truncations within the carboxy terminal region. While these modifications have been shown experimentally to induce and promote \u03b1Syn aggregation, little is known about their disease-, region- and cell type specific distribution. To this end, we generated a series of monoclonal antibodies specific to neo-epitopes in \u03b1Syn truncated after residues 103, 115, 119, 122, 125, and 129. Immunocytochemical investigations using these new tools revealed striking differences in the \u03b1Syn truncation pattern between different synucleinopathies, brain regions and specific cellular populations. In LBD, neuronal inclusions in the\u00a0substantia nigra and amygdala were positive for \u03b1Syn cleaved after residues 103, 119, 122, and 125, but not 115. In contrast, in the same patients' brain \u03b1Syn cleaved at residue 115, as well as 103, 119 and 122 were abundant in the dorsal motor nucleus of the vagus. In patients with AD\/ALB, these modifications were only weakly or not detected in amygdala \u03b1Syn inclusions. \u03b1Syn truncated at residues 103, 115, 119, and 125 was readily present in MSA glial cytoplasmic inclusions, but 122 cleaved \u03b1Syn was only weakly or not present. Conversely, MSA neuronal pathology in the pontine nuclei was strongly reactive to the \u03b1Syn x-122 neo-epitope but did not display any reactivity for \u03b1Syn 103 cleavage. These studies demonstrate significant disease-, region- and cell type specific differences in carboxy terminal \u03b1Syn processing associated with pathological inclusions that likely contributes to their distinct strain-like prion properties and promotes the diversity displayed in the degrees of these insidious diseases.<\/jats:p>","DOI":"10.1186\/s40478-021-01242-2","type":"journal-article","created":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T16:02:35Z","timestamp":1630166555000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Disease-, region- and cell type specific diversity of \u03b1-synuclein carboxy terminal truncations in synucleinopathies"],"prefix":"10.1186","volume":"9","author":[{"given":"Ethan W.","family":"Hass","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary A.","family":"Sorrentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxing","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace M.","family":"Lloyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Q.","family":"Trojanowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Prokop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2992-4234","authenticated-orcid":false,"given":"Benoit I.","family":"Giasson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,28]]},"reference":[{"key":"1242_CR1","doi-asserted-by":"publisher","first-page":"29739","DOI":"10.1074\/jbc.M600933200","volume":"281","author":"JP Anderson","year":"2006","unstructured":"Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang J, Kling K, Lee M et al (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. 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