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MSA patient samples readily transmit disease following intracranial (i.c.) inoculation into humanized mice, whereas LBD samples typically do not. Unexpectedly, we identified one LBD patient sample that, following i.c. inoculation, transmitted neurological disease to four out of six mice over an extended incubation period. In light of these unexpected results, we sought to identify the \u03b1-synuclein strain responsible for disease onset. Using immunohistochemistry, we identified both Lewy bodies and oligodendroglial inclusions with a glial cytoplasmic inclusion-like appearance in the substantia nigra of the patient sample. To determine if these glial inclusions were due to the presence of low titer MSA \u03b1-synuclein in the sample, we performed a secondary passage of two terminal mouse brains from the primary passage and found that the humanized mice developed disease with a shortened incubation period. Unexpectedly, using our panel of mutant \u03b1-syn140\u2013YFP cells to analyze the primary and secondary passage samples showed that the strain isolated in the in vivo studies has unique biological properties compared to the MSA and LBD strains. These data suggest that the oligodendroglial pathology in the LBD patient sample was not caused by MSA co-pathology, and provide evidence for the isolation of a novel distinct \u03b1-synuclein strain.<\/jats:p>","DOI":"10.1186\/s40478-025-02093-x","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T11:46:28Z","timestamp":1755517588000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Evidence of a novel \u03b1-synuclein strain isolated from a Parkinson\u2019s disease with dementia patient sample"],"prefix":"10.1186","volume":"13","author":[{"given":"Sara A. 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Tissue from two MSA patient samples (MSA2 and MSA16) were provided by the Massachusetts Alzheimer\u2019s Disease Research Center. Tissue from three MSA patient samples (MSA3, MSA4, and MSA5) were provided by the Sydney Brain Bank. Frozen brain tissue from one PDD (PDD1) patient sample was provided by the UKPD Brain Bank. University of California San Francisco (UCSF) and Colorado State University (CSU) Institutional Review Board approvals were not required for this study. Animals were maintained in AAALAC-accredited facilities in compliance with the\n                      8th Guide for the Care and Use of Laboratory Animals\n                      . All procedures used in this study were approved by the UCSF and CSU Institutional Animal Care and Use Committees.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"177"}}