α-Synuclein strain homogeneity in multiple system atrophy clinical subtypes

Abstract

Conformationally distinct strains of -synuclein aggregates are believed to contribute to the clinical and pathological diversity observed among synucleinopathies such as multiple system atrophy (MSA) and Parkinsons disease. Cases of MSA can be classified into two distinct clinical subtypes: the cerebellar variant, MSA-C, and the parkinsonian variant, MSA-P. To assess whether distinct -synuclein strains may be present in individuals with MSA-C versus MSA-P, we characterized the conformational and seeding properties of -synuclein aggregates in various brain regions from MSA-C and MSA-P patients and performed propagation studies in M83 transgenic mice. Biochemical fingerprinting of -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 -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 -synuclein deposition in M83 mice inoculated with either MSA-C or MSA-P, regardless of the brain region from which the injected -synuclein aggregates were derived. These results suggest that MSA clinical subtypes are unlikely to arise due to distinct -synuclein strains. Instead, our findings support a model in which the same -synuclein strain initially forms in different brain regions, leading to differences in disease manifestation.