TY - RPRT TI - α-Synuclein strains influence multiple system atrophy via central and peripheral mechanisms AU - Torre Murazabal, T. AU - Van der Perren, A. AU - Coens, A. AU - Barber Janer, A. AU - Camacho-Garcia, S. AU - Stefanova, N. AU - Melki, R. AU - Baekelandt, V. AU - Peelaerts, W. AB - Abstract 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 α-synuclein (αSyn) protein deposits in glial cells of the central and peripheral nervous system. It is unclear why MSA, that invariably presents with αSyn 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 αSyn 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 αSyn strains might influence MSA disease progression. To this aim, we injected two recombinant strains of αSyn 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 αSyn strains both in vitro and in vivo . By injecting αSyn 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 αSyn strain nature and the host environment and ii) αSyn strains can directly trigger a detrimental immune response related to disease progression in MSA. DA - 2020/10/16/ PY - 2020 DP - DOI.org (Crossref) LA - en M3 - preprint PB - Neuroscience UR - https://biorxiv.org/lookup/doi/10.1101/2020.10.16.342089 Y2 - 2022/02/17/14:01:24 KW - preprint ER -