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Although non-motor features such as gastrointestinal and sleep disturbances often precede motor impairments and are critical to PD pathogenesis, the mechanisms underlying their onset and progression remain insufficiently characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To investigate the sequential development of motor and non-motor symptoms in a model of experimental parkinsonism, we injected alpha-synuclein (\u03b1Syn) preformed fibrils (PFFs) into the duodenum and antrum of wild-type mice, establishing a gut-brain axis model of PD. We performed whole-brain anatomical mapping of \u03b1Syn-PFF propagation and assessed behavioral alterations at multiple time points post-injection. Correlations between anatomical spread and behavioral changes, particularly sleep, were further validated through\n                      <jats:italic>SNCA<\/jats:italic>\n                      overexpression or local \u03b1Syn-PFF injections in the substantia nigra, combined with dual-wavelength fiber photometry, behavioral assays, and histological analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Injection of \u03b1Syn-PFFs into the gastrointestinal tract of wild-type mice led to a progressive spread of pathological \u03b1Syn throughout the central nervous system, in temporal association with distinct motor and non-motor phenotypes. These findings provide translational validity of the gut-brain model, mirroring the clinical progression seen in many PD patients. In two established \u03b1Syn-based PD models, dual-wavelength fiber photometry that monitors dopamine and acetylcholine release in the striatum, demonstrated a central role for dopamine dysfunction in modulating sleep architecture, particularly in relation to REM sleep without atonia, consistent with REM sleep behavior disorder (RBD)-like manifestations in PD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This work provides a detailed characterization of the progressive and multisystem nature of experimental parkinsonism, highlighting the interplay between \u03b1Syn pathology, gut-brain signaling, and the onset of non-motor disturbances, with a particular focus on RBD-like alterations in sleep.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-026-00536-6","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T07:20:16Z","timestamp":1773127216000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Gut-initiated alpha synuclein fibrils drive parkinsonism phenotypes: temporal mapping of REM sleep behavior disorder-like and other non-motor symptoms"],"prefix":"10.1186","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1001-5727","authenticated-orcid":false,"given":"Daniel","family":"Dautan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2141-4547","authenticated-orcid":false,"given":"Wojciech","family":"Paslawski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5278-626X","authenticated-orcid":false,"given":"Sergio G.","family":"Montejo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8320-864X","authenticated-orcid":false,"given":"Daniel C.","family":"Doyon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9000-0908","authenticated-orcid":false,"given":"Valentina I.","family":"Brioschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7609-7000","authenticated-orcid":false,"given":"Roberta","family":"Marongiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8979-2459","authenticated-orcid":false,"given":"Michael G.","family":"Kaplitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9291-5539","authenticated-orcid":false,"given":"Rong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2915-3970","authenticated-orcid":false,"given":"Valina L.","family":"Dawson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9461-8682","authenticated-orcid":false,"given":"Xiaoqun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6459-0893","authenticated-orcid":false,"given":"Ted M.","family":"Dawson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6727-3802","authenticated-orcid":false,"given":"Per","family":"Svenningsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"issue":"7","key":"536_CR1","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/nrn.2017.62","volume":"18","author":"AHV Schapira","year":"2017","unstructured":"Schapira AHV, Chaudhuri KR, Jenner P. 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