Extracellular vesicle α-synuclein seeds drive divergent phenoconversion from iRBD to Parkinsonism

Idiopathic rapid eye movement (REM) sleep behaviour disorder (iRBD) is a prodromal ɑ-synucleinopathy that often precedes Parkinson’s disease (PD) or multiple system atrophy (MSA), but the determinants of divergent conversion are unknown. We isolated neuronal extracellular vesicles (NEV) from PD plasma and oligodendroglial extracellular vesicles (OEV) from MSA plasma and found that they harbour disease-specific ɑ-synuclein seeds with mutually exclusive seeding activity. These seeds amplify into distinct fibril strains, with MSA-OEV-amplified fibrils displaying greater cytotoxicity. To model conversion, we primed the sublaterodorsal tegmental nucleus, a key REM-atonia hub, with neuronal or oligodendroglial ɑ-synuclein expression and delivered matched patient EV. Either cellular priming alone produced only mild REM sleep without atonia, whereas EV seeding triggered robust iRBD-like phenotypes and progressive neurodegeneration. PD-NEV drove early nigrostriatal pathology with prominent hyposmia, while MSA-OEV preferentially produced severe autonomic dysfunction. Together, our data identify a seed-milieu matching principle that links a shared prodrome to distinct ɑ-synucleinopathies, provide complementary iRBD-to-parkinsonism mouse models, and support blood EV seeding signatures as minimally invasive biomarkers to forecast conversion and guide early intervention.