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Transmission of \u03b1syn necessitates the release of misfolded \u03b1syn from one cell and the uptake of that \u03b1syn by another, in which it can template the misfolding of endogenous \u03b1syn upon cell internalization. 14-3-3 proteins are a family of highly expressed brain proteins that are neuroprotective in multiple PD models. We have previously shown that 14-3-3\u03b8 acts as a chaperone to reduce \u03b1syn aggregation, cell-to-cell transmission, and neurotoxicity in the in vitro pre-formed fibril (PFF) model. In this study, we expanded our studies to test the impact of 14-3-3s on \u03b1syn toxicity in the in vivo \u03b1syn PFF model. We used both transgenic expression models and adenovirus associated virus (AAV)-mediated expression to examine whether 14-3-3 manipulation impacts behavioral deficits, \u03b1syn aggregation, and neuronal counts in the PFF model. 14-3-3\u03b8 transgene overexpression in cortical and amygdala regions rescued social dominance deficits induced by PFFs at 6\u00a0months post injection, whereas 14-3-3 inhibition by transgene expression of the competitive 14-3-3 peptide inhibitor difopein in the cortex and amygdala accelerated social dominance deficits. The behavioral rescue by 14-3-3\u03b8 overexpression was associated with delayed \u03b1syn aggregation induced by PFFs in these brain regions. Conversely, 14-3-3 inhibition by difopein in the cortex and amygdala accelerated \u03b1syn aggregation and reduction in NECAB1-positive neuron counts induced by PFFs. 14-3-3\u03b8 overexpression by AAV in the substantia nigra (SN) also delayed \u03b1syn aggregation in the SN and partially rescued PFF-induced reduction in tyrosine hydroxylase (TH)-positive dopaminergic cells in the SN. 14-3-3 inhibition in the SN accelerated nigral \u03b1syn aggregation and enhanced PFF-induced reduction in TH-positive dopaminergic cells. These data indicate a neuroprotective role for 14-3-3\u03b8 against \u03b1syn toxicity in vivo.<\/jats:p>","DOI":"10.1186\/s40478-020-01110-5","type":"journal-article","created":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T18:04:01Z","timestamp":1610042641000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["14-3-3 mitigates alpha-synuclein aggregation and toxicity in the in vivo preformed fibril model"],"prefix":"10.1186","volume":"9","author":[{"given":"Rachel","family":"Underwood","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Gannon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneesh","family":"Pathak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navya","family":"Kapa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidhanth","family":"Chandra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Klop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2227-7310","authenticated-orcid":false,"given":"Talene A.","family":"Yacoubian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,7]]},"reference":[{"key":"1110_CR1","doi-asserted-by":"publisher","first-page":"8797","DOI":"10.1523\/JNEUROSCI.22-20-08797.2002","volume":"22","author":"DE Cabin","year":"2002","unstructured":"Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking \u03b1-synuclein. 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