Evidence of a novel α-synuclein strain isolated from a Parkinson's disease with dementia patient sample
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Multiple system atrophy (MSA) and the Lewy body diseases (LBDs) are caused by α-synuclein misfolding into distinct conformations, or strains, with unique biological properties. 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 α-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 α-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 α-syn140–YFP 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 α-synuclein strain.
Date Issued
2025-08-18
Date Acceptance
2025-08-01
Citation
Acta Neuropathologica Communications, 2025, 13
ISSN
2051-5960
Publisher
BMC
Journal / Book Title
Acta Neuropathologica Communications
Volume
13
Copyright Statement
© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40826134
PII: 10.1186/s40478-025-02093-x
Subjects
ALZHEIMERS-DISEASE
CONFORMATIONS
CREUTZFELDT-JAKOB-DISEASE
GLIAL CYTOPLASMIC INCLUSIONS
LEWY BODIES
Lewy body diseases
Life Sciences & Biomedicine
MULTIPLE SYSTEM ATROPHY
MUTATION
Neurodegenerative disease
Neurosciences
Neurosciences & Neurology
PATHOLOGY
PRION PROTEIN
Science & Technology
Strain interactions
Synucleinopathies
TAU
Publication Status
Published
Coverage Spatial
England
Article Number
177
Date Publish Online
2025-08-18