Human- and Rodent-derived Extracellular Vesicles Mediate the Spread of Pathology in MSA-like Models

Multiple system atrophy (MSA) is characterized by the presence of protein-rich inclusions mainly within oligodendrocytes, comprised primarily by the neuronal protein αSynuclein and the oligodendroglial-specific phosphoprotein TPPP/p25α. Μature oligodendrocytes do not normally express detectable αSynuclein levels, suggesting that its oligodendroglial accumulation may arise from intercellular transfer, potentially via extracellular vesicles (EVs); however the precise role of oligodendroglial-derived EVs in MSA progression remains relatively understudied.

Herein, we characterized the cargo/features and pathogenic potential of EVs released by oligodendrocytes treated with human αSynuclein fibrils amplified from MSA or Parkinson’s disease patient brains (or human recombinant αSynuclein fibrils) and EVs isolated from murine and human MSA (or respective control) brains. Our findings reveal that both oligodendroglial cell- and brain-derived EVs harbor pathological αSynuclein and TPPP/p25α conformations, similar to those accumulating in human MSA brains. These EVs are readily taken up by both neurons and oligodendrocytes, driving αSynuclein propagation in vitro .

Importantly, inoculation of these MSA-like EVs in animal models induce robust pSer129-αSynuclein accumulation along the nigrostriatal axis, colocalizing with markers of mature oligodendrocytes and dopaminergic neurons. These findings underscore the pivotal role of oligodendroglial-derived EVs in pathology progression and neuronal-oligodendroglial communication, positioning them as promising targets for therapeutic strategies aimed at combating alpha-Synucleinopathies.