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Lewy pathology, containing \u03b1-synuclein, is often associated with regional tau pathology burden in LBD. Similarly, granulovacuolar degeneration bodies (GVBs) have been associated with tau pathology in Alzheimer\u2019s disease. Interestingly, GVBs have been detected in a broad range of neurodegenerative conditions including both \u03b1-synucleinopathies and tauopathies. Despite the frequent co-occurrence, little is known about the relationship between \u03b1-synuclein, tau, and granulovacuolar degeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed a mouse model of limbic-predominant \u03b1-synucleinopathy by stereotactic injection of mouse \u03b1-synuclein pre-formed fibrils (PFFs) into the basal forebrain. This model was used to investigate the relationship of \u03b1-synuclein pathology with tau and GVB formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our model displayed widespread \u03b1-synuclein pathology with a limbic-predominant distribution. Aberrantly phosphorylated tau accumulated in a subset of \u03b1-synuclein inclusion-bearing neurons, often colocalized with lysosomes. Many of these same neurons also contained CHMP2b- and CK1\u03b4-positive granules, established markers of GVBs, which suggests a link between tau accumulation and GVB formation. Despite this observation, GVBs were also detected in tau-deficient mice following PFF injection, suggesting that pathological \u03b1-synuclein alone is sufficient to elicit GVB formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings support that \u03b1-synuclein pathology can independently elicit granulovacuolar degeneration. The frequent co-accumulation of tau and GVBs suggests a parallel mechanism of cellular dysfunction. The ability of \u03b1-synuclein pathology to drive GVB formation in the absence of tau highlights the broader relevance of this process to neurodegeneration with relevance to the pathobiology of LBD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-025-00494-5","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:11:39Z","timestamp":1750291899000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pathological \u03b1-synuclein elicits granulovacuolar degeneration independent of tau"],"prefix":"10.1186","volume":"14","author":[{"given":"Dylan J.","family":"Dues","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalynn L.","family":"Erb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alysa","family":"Kasen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naman","family":"Vatsa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin T.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An Phu Tran","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael X.","family":"Henderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2359-5679","authenticated-orcid":false,"given":"Darren J.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"494_CR1","doi-asserted-by":"publisher","first-page":"2197","DOI":"10.1212\/01.wnl.0000271090.28148.24","volume":"69","author":"JA Schneider","year":"2007","unstructured":"Schneider JA, Arvanitakis Z, Bang W, Bennett DA. 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