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However, it is unclear which cellular factors render certain neuronal populations vulnerable, while others stay devoid of LP throughout the course of disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study aimed to identify and compare the cellular architecture of vulnerable and non-vulnerable neurons exposed to \u03b1Syn pathology by using a projection-based retro-AAV approach in combination with an in vivo \u03b1-synucleinopathy mouse model. To do so, a set of viral genetic, immunohistochemical, and optical tools was used in combination with the preformed \u03b1Syn fibril (PFF) model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\u03b1Syn pathology propagated robustly into the input connectome of the pedunculopontine nucleus (PPN). However, we observed a marked mismatch between the anatomically expected and the actual distribution of pathology. While anatomically connected neurons in the bed nucleus of the stria terminalis (BST) and the central amygdala (CEA) accumulated substantial \u03b1Syn pathology, equally strong connected neurons of the substantia nigra pars reticulata (SNr), and the dentate nucleus (DN) were devoid of pathology. Second, cellular vulnerability and resilience were consistent and reproducible features. When PFFs were injected into alternative major output projection sites of BST, CEA, SNr, and DN, we observed similar patterns of \u03b1Syn accumulation. Third, projection-specific axonal mapping revealed that the \u03b1Syn-accumulating BST and CEA neurons possessed larger axonal arbors than the more resilient neurons in SNr and DN. Correspondingly, neurons in BST and CEA exhibited higher basal mitochondrial oxidation levels, indicating an increased bioenergetic burden. Finally, the site of initial seeding significantly influenced the extent of developing brain-wide pathology, suggesting that certain brain regions may function as \"super-seeders\", promoting widespread propagation of pathology, while others contribute relatively little to the global LP burden.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\u03b1Syn pathology propagates along anatomical pathways, but cell-autonomous factors determine if a neuron exposed to misfolded \u03b1Syn will develop Lewy-like pathology or not.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-026-00535-7","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T13:00:01Z","timestamp":1769778001000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mapping cellular vulnerability in Parkinson\u2019s disease using retro-AAVs and preformed \u03b1-synuclein fibrils"],"prefix":"10.1186","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5480-0463","authenticated-orcid":false,"given":"Fanni F.","family":"Geibl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A. 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