Host oligodendrogliopathy and -synuclein strains dictate disease severity in multiple system atrophy

Multiple system atrophy is a progressive neurodegenerative disease with prominent autonomic and motor features. During early stages, different subtypes of the disease are distinguished by their predominant parkinsonian or cerebellar symptoms, reflecting its heterogeneous nature. The pathognomonic feature of multiple system atrophy is the presence of alpha-synuclein (alpha Syn) protein deposits in oligodendroglial cells. alpha Syn can assemble in specific cellular or disease environments and form alpha Syn strains with unique structural features, but the ability of alpha Syn strains to propagate in oligodendrocytes remains elusive. Recently, it was shown that alpha Syn strains with related conformations exist in the brains of patients. Here, we investigated whether different alpha Syn strains can influence multiple system atrophy progression in a strain-dependent manner. To this aim, we injected two recombinant alpha Syn strains (fibrils and ribbons) in multiple system atrophy transgenic mice and found that they determined disease severity in multiple system atrophy via host-restricted and cell-specific pathology in vivo. alpha Syn strains significantly impact 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 alpha Syn strains both in vitro and in vivo. Spectral analysis showed that ribbons propagated oligodendroglial inclusions that were structurally distinct from those of fibrils, with resemblance to oligodendroglial inclusions, in the brains of patients with multiple system atrophy. This study, therefore, shows that the multiple system atrophy phenotype is governed by both the nature of the alpha Syn strain and the host environment and that by injecting alpha Syn strains into an animal model of the disease, a more comprehensive phenotype can be established.