Journal article
Templating of monomeric alpha-synuclein results in inflammation and SNpc dopamine neuron death in a genetic mouse model of induced synucleinopathy
Scientific reports, Vol.15(1), pp.26537-15
07/22/2025
DOI: 10.1038/s41598-025-10705-8
PMCID: PMC12279996
PMID: 40691198
Abstract
While the etiology of most cases of Parkinson’s disease (PD) are idiopathic, it has been estimated that 5–10% of PD arise from known genetic mutations. The first mutations described that leads to the development of an autosomal dominant form of PD are in the SNCA gene that codes for the protein alpha-synuclein (α-syn). α-syn is an abundant presynaptic protein that is natively disordered and whose function is still unclear. In PD, α-syn misfolds into multimeric b-pleated sheets that aggregate in neurons (Lewy Bodies/neurites) and spread throughout the neuraxis in a pattern that aligns with disease progression. Here, using IHC, HC, HPLC, and cytokine analysis, we examined the sequelae of intraparenchymal brain seeding of pre-formed fibrils (PFFs) and monomeric α-syn in C57BL/6J (WT) and A53T SNCA mutant mice. We found that injection of PFFs, but not monomeric α-syn, into the striatum of C57BL/6J mice induced spread of aggregated α-syn, loss of SNpc DA neurons and increased neuroinflammation. However, in A53T SNCA mice, we found that both PFFs and monomeric α-syn induced this pathology. This suggests that the conformation changes in α-syn seen in the A53T strain can recruit wild-type α-syn to a pathological misfolded conformation which may provide a mechanism for the induction of PD in humans with SNCA duplication/triplication.
Details
- Title: Subtitle
- Templating of monomeric alpha-synuclein results in inflammation and SNpc dopamine neuron death in a genetic mouse model of induced synucleinopathy
- Creators
- Matthew D. Byrne - Thomas Jefferson UniversityPeyman Petramfar - Thomas Jefferson UniversityJae-Kyung Lee - University of GeorgiaRichard Jay Smeyne - Thomas Jefferson University
- Resource Type
- Journal article
- Publication Details
- Scientific reports, Vol.15(1), pp.26537-15
- DOI
- 10.1038/s41598-025-10705-8
- PMID
- 40691198
- PMCID
- PMC12279996
- NLM abbreviation
- Sci Rep
- ISSN
- 2045-2322
- eISSN
- 2045-2322
- Publisher
- Nature Publishing Group UK
- Grant note
- R01NS110084); R01NS110084) / National Institute of Health (USA) Michael J. Fox Foundation for Parkinson’s Research
- Language
- English
- Date published
- 07/22/2025
- Academic Unit
- Neurology
- Record Identifier
- 9985013727002771
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