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However, most mouse models expressing single-mutant \u03b1S transgenes develop neuronal aggregates very slowly, and few have dopaminergic cell loss, both key characteristics of PD. To accelerate neurotoxic aggregation, we previously generated fPD \u03b1S E46K mutant mice with rationally designed triple mutations based on the \u03b1-helical repeat motif structure of \u03b1S (fPD E46K\u21923\u2009K). The 3\u2009K variant increased \u03b1S membrane association and decreased the physiological tetramer:monomer ratio, causing lipid- and vesicle-rich inclusions and robust tremor-predominant, L-DOPA responsive PD-like phenotypes. Here, we applied an analogous approach to the G51D fPD mutation and its rational amplification (G51D \u2192 3D) to generate mutant mice. In contrast to 3\u2009K mice, G51D and 3D mice accumulate monomers almost exclusively in the cytosol while also showing decreased \u03b1S tetramer:monomer ratios. Both 1D and 3D mutant mice gradually accumulate insoluble, higher-molecular weight \u03b1S oligomers. Round \u03b1S neuronal deposits at 12 mos immunolabel for ubiquitin and pSer129 \u03b1S, with limited proteinase K resistance. Both 1D and 3D mice undergo loss of striatal TH+ fibers and midbrain dopaminergic neurons by 12 mos and a bradykinesia responsive to L-DOPA. The 3D \u03b1S mice have decreased tetramer:monomer equilibria and recapitulate major features of PD. These fPD G51D and 3D mutant mice should be useful models to study neuronal \u03b1S-toxicity associated with bradykinetic motor phenotypes.<\/jats:p>","DOI":"10.1038\/s41531-024-00662-w","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T19:03:49Z","timestamp":1709233429000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Generation of G51D and 3D mice reveals decreased \u03b1-synuclein tetramer-monomer ratios promote Parkinson\u2019s disease phenotypes"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2124-6865","authenticated-orcid":false,"given":"Silke","family":"Nuber","sequence":"first","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"}]},{"given":"Thomas D.","family":"McCaffery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2223-9947","authenticated-orcid":false,"given":"Tim E.","family":"Moors","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Alexandre","family":"Adom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1154-9281","authenticated-orcid":false,"given":"Wolf N.","family":"Hahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9205-6930","authenticated-orcid":false,"given":"Dylan","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4563-3683","authenticated-orcid":false,"given":"Maria","family":"Ericsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arati","family":"Tripathi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6676-0107","authenticated-orcid":false,"given":"Ulf","family":"Dettmer","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8846-9767","authenticated-orcid":false,"given":"Dennis J.","family":"Selkoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,29]]},"reference":[{"key":"662_CR1","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1007\/s00401-013-1096-7","volume":"125","author":"AP Kiely","year":"2013","unstructured":"Kiely, A. 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