Connexin 50 mediates disease-relevant alpha-synuclein oligomer propagation and neuroinflammation in neurodegenerative disease.

Connexins, fundamental components of gap junctions and hemichannels, regulate intercellular communication and are emerging neurodegeneration regulators. Primary synucleinopathies and co-morbid synuclein pathologies feature pathological α-synuclein (α-Syn) aggregation, yet mechanisms driving pathogenic α-Syn propagation remain unclear. We identify that connexin 50 (Cx50) interacts with α-Syn aggregates in synucleinopathy-affected human brain tissue. Ex vivo dye uptake assays show markedly elevated hemichannel activity in synucleinopathy mouse brain tissue versus wild-type controls, suppressed by selective Cx50 inhibition. Cx50-expressing cell models exhibit strain-dependent brain-derived α-Syn oligomers (BDSOs) uptake, confirmed pharmacologically. In primary neuron-astrocyte co-cultures from mice expressing human wild-type α-Syn, Cx50 knockdown markedly reduced BDSO uptake and α-Syn aggregation. Cx50 knockdown differentially modulates pro-inflammatory cytokines in BDSO-treated conditions, indicating strain-dependent effects and Cx50-mediated neuron-astrocyte crosstalk in regulating neuroinflammation. This identifies Cx50 as a plausible target for modulating initiation and early spread of α-Syn pathology, supporting Cx50-directed interventions for early-stage disease modification.