Astrocyte-derived aberrant protein secretion contributes to neurodegeneration in α-synucleinopathies

초록

α-synucleinopathies (ASPs), including Parkinson’s disease and dementia with Lewy bodies, characterized by the accumulation of insoluble α-synuclein fibrils in neurons and glia. Astrocytes may play a crucial role in ASPs, as they exhibit cytoplasmic α-synuclein inclusions and a proinflammatory phenotype. However, the pathological role of α-synuclein in astrocytes remains largely unknown. Here, we show that α-synuclein preformed fibrils (PFFs) induce a pathogenic activation of astrocytes, leading to neuroinflammation and non-cell autonomous neuronal toxicity. To elucidate key mediators of this process, we performed a secretome analysis of conditioned media from PFF-treated astrocytes and identified seven candidates whose knockdown significantly attenuated neuronal toxicity. Among these, Candidate A was shown to mediate astrocyte-induced neurotoxicity via activation of the NF-κB signaling pathway. Furthermore, Candidate A was found to be elevated not only in conditioned media from PFF-treated astrocytes but also in the CSF of patients with Parkinson’s disease. These findings suggest that pathogenic alterations in astrocyte-secreted proteins contribute to neurodegeneration in ASPs.