{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:26:40Z","timestamp":1785432400213,"version":"3.56.0"},"posted":{"date-parts":[[2025,12,22]]},"group-title":"Neuroscience","reference-count":58,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["RF1NS115767"],"award-info":[{"award-number":["RF1NS115767"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P50 NS108675"],"award-info":[{"award-number":["P50 NS108675"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["5T32NS095775"],"award-info":[{"award-number":["5T32NS095775"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1F31NS135928-01A1"],"award-info":[{"award-number":["1F31NS135928-01A1"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["5T32GM135028"],"award-info":[{"award-number":["5T32GM135028"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04sedwh45","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Parkinson\u2019s Disease (PD) and other synucleinopathies are characterized by the formation of inclusions comprised of alpha-synuclein (\u03b1syn) among other proteins, but the mechanisms by which these inclusions form and cause toxicity are not well understood. We have previously reported that the small GTPase Rab27b modulates autophagic-lysosomal function in neurons and supports lysosomal degradation of \u03b1syn across multiple \u03b1syn cellular models. Knockout (KO) and knockdown of Rab27b damage lysosomal degradative capacity and exacerbate \u03b1syn pathology, while Rab27b overexpression is conversely protective in cellular \u03b1syn models. Elevations of Rab27b seen in human synucleinopathies suggest a compensatory role for Rab27b in these disorders. Here, we examined the role Rab27b plays\n                  <jats:italic>in vivo<\/jats:italic>\n                  in the context of both A53T genetic \u03b1syn overexpression and viral AAV \u03b1syn overexpression mouse models. Rab27b knockout in A53T\n                  <jats:sup>+<\/jats:sup>\n                  mice did not alter motor behavior or survival. However, Rab27b knockout increased proteinase-K resistant \u03b1syn in the cortex, striatum, and substantia nigra of A53T mice starting as early as six months of age. Additionally, Rab27b KO increased phosphorylated S129 \u03b1syn in the cortex and nigra. Astrocyte and microglial activation were also observed upon Rab27b KO in the A53T model. In the AAV \u03b1syn model, Rab27b KO resulted in accelerated dopaminergic cell loss in the nigra. Collectively, we report that loss of Rab27b results in elevated neuropathology in PD-relevant brain regions, validating its role as a therapeutic target in synucleinopathies.\n                <\/jats:p>","DOI":"10.64898\/2025.12.19.695485","type":"posted-content","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T01:55:22Z","timestamp":1766454922000},"source":"Crossref","is-referenced-by-count":0,"title":["Knockout of Rab27b exacerbates neuropathology in alpha-synuclein mouse models"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8724-5454","authenticated-orcid":false,"given":"Kasandra","family":"Scholz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary 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