a-Synuclein strains influence multiple system atrophy via central and peripheral mechanisms

Multiple system atrophy (MSA) is a progressive neurodegenerative disease with prominent autonomic and motor features. Different disease subtypes are distinguished by their predominant parkinsonian or cerebellar signs. The pathognomonic feature of MSA is the presence of [a]-synuclein ([a]Syn) protein deposits in glial cells of the central and peripheral nervous system. It is unclear why MSA, that invariably presents with [a]Syn pathology, is clinically so heterogeneous, why it progresses at varying rates and how neuroinflammation affects disease progression. Recently, it was shown that different strains of [a]Syn can assemble in unique disease environments but also that a variety of strains might exist in the brain of MSA patients. We therefore investigated if different [a]Syn strains might influence MSA disease progression. To this aim, we injected two recombinant strains of [a]Syn in MSA transgenic mice and found that they significantly impact MSA disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of [a]Syn strains both in vitro and in vivo. By injecting [a]Syn strains in MSA mice we could more closely mimic a comprehensive MSA phenotype in an experimental setting. This study therefore shows that i) MSA phenotype is governed by both the [a]Syn strain nature and the host environment and ii) [a]Syn strains can directly trigger a detrimental immune response related to disease progression in MSA.