Evidence of a novel α-synuclein strain isolated from a Parkinson’s disease with dementia patient sample
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, wherea...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-08-01
|
| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-025-02093-x |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | 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. |
|---|---|
| ISSN: | 2051-5960 |