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Sequential Extraction of Soluble and Insoluble Alpha-Synuclein from Parkinsonian Brains
Published on: January 5, 2016
α-Synuclein strain homogeneity in multiple system atrophy subtypes
Heather H C Lau1,2, Nicholas R G Silver1,2, Surabhi Mehra1
1Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
Abstract:
Conformationally distinct "strains" of α-synuclein aggregates are believed to contribute to the clinical and pathological diversity observed among synucleinopathies such as multiple system atrophy (MSA) and Parkinson's disease. Cases of MSA can be classified into two distinct subtypes: the cerebellar variant, MSA-C, and the parkinsonian variant, MSA-P, as determined by differences in their clinical and/or neuropathological presentations. To assess whether distinct α-synuclein strains may be present in individuals with MSA-C versus MSA-P, we characterized the conformational and seeding properties of α-synuclein aggregates in various brain regions from MSA-C and MSA-P patients and performed propagation studies in M83 transgenic mice. Biochemical fingerprinting of α-synuclein aggregates using limited proteolysis and a conformational stability assay failed to reveal differences between MSA-C and MSA-P either before or after propagation in mice. Similarly, using brain extracts from either MSA patients or MSA-inoculated mice, MSA-C and MSA-P α-synuclein aggregates exhibited indistinguishable seeding attributes in a seed amplification assay. Finally, no differences were observed in either the kinetics of disease progression or the extent of cerebral α-synuclein deposition in M83 mice inoculated with either MSA-C or MSA-P, regardless of the brain region from which the injected α-synuclein aggregates were derived. These results suggest that MSA subtypes are unlikely to arise because of distinct α-synuclein strains. Instead, our findings support a model in which the same α-synuclein strain initially forms in different brain regions, leading to differences in disease manifestation.
Insights
Distinct alpha-synuclein strains do not explain multiple system atrophy (MSA) subtypes. Instead, the same alpha-synuclein strain forming in different brain regions likely causes varied disease presentations in MSA-C and MSA-P.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Synucleinopathies, including multiple system atrophy (MSA), exhibit clinical and pathological diversity.
- This diversity is hypothesized to stem from conformationally distinct alpha-synuclein aggregate strains.
- MSA presents as two subtypes: MSA-C (cerebellar) and MSA-P (parkinsonian), differing in clinical and neuropathological features.
Purpose of the Study:
- To investigate whether distinct alpha-synuclein strains are present in MSA-C versus MSA-P.
- To compare the conformational and seeding properties of alpha-synuclein aggregates from MSA subtypes.
- To assess the impact of MSA-C and MSA-P derived aggregates on disease progression in a mouse model.
Main Methods:
- Biochemical fingerprinting (limited proteolysis, conformational stability assays) of alpha-synuclein aggregates from human MSA-C and MSA-P brain tissue.
- Propagation studies in M83 transgenic mice inoculated with aggregates from MSA subtypes.
- Seed amplification assays to evaluate the seeding properties of aggregates.
- Monitoring disease kinetics and alpha-synuclein deposition in inoculated mice.
Main Results:
- Biochemical analyses revealed no conformational differences between alpha-synuclein aggregates from MSA-C and MSA-P, even after in vivo propagation.
- Seed amplification assays showed indistinguishable seeding attributes for aggregates from both MSA subtypes.
- M83 mice inoculated with MSA-C or MSA-P aggregates exhibited similar disease progression rates and levels of alpha-synuclein deposition.
Conclusions:
- The findings suggest that distinct alpha-synuclein strains are unlikely to be the cause of MSA subtypes (MSA-C and MSA-P).
- A revised model proposes that the same alpha-synuclein strain initiates aggregation in different brain regions, leading to varied disease manifestations.
- This challenges the strain-based hypothesis for MSA heterogeneity and points towards regional seeding as a key factor.
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