Characterizing a mouse model of Multiple System Atrophy based on alpha-synuclein aggregation

Synucleinopathies are a group of neurodegenerative diseases characterized by the presence of αSynuclein (αSyn) aggregates. These aggregates can be mainly found in neurons, in Parkinson’s disease (PD), or in oligodendrocytes in multiple system atrophy (MSA). In both pathologies, patients present cell loss of specific neuronal populations. These diseases don’t have any disease modifying treatment available yet and the pathological mechanisms are not completely elucidated. Thus, several in vivo and in vitro models have emerged in this research field. In this work, we aimed to develop two novel MSA seeding mouse models combining adenoassociated viral vectors (AAV) driving expression of αSyn in oligodendrocytes with αSyn fibrils in mice with different genetic backgrounds (wild type-C57BL/6J and αSynuclein humanized PAC-Tg(SNCAWT);Snca-/- mice). In this work, we studied different markers of neurodegeneration in two combination MSA mouse models. We developed and validated a new AI model using a commercially available platform to automate the analysis. We discovered that upon (h)αSyn preformed fibril (hPFFs) injection, humanized mice experienced tyrosine hydroxylase positive (TH+) terminal loss in the caudoputamen and dopaminergic loss in the substantia nigra. Meanwhile, αSyn overexpression and the combination of mPFFs injection and αSyn overexpression in wild-type mice caused neuronal loss in the caudoputamen and the globus pallidus. Altogether, our work shows that these two models can replicate some MSA neurodegenerative features observed in patients.