Spreading α-synuclein rewires organelle communication and impairs neuron–astrocyte mitochondrial quality control

Progressive intercellular spreading of α-synuclein (αS) is implicated in pathology initiation and propagation of synucleinopathies. However, how recipient neurons respond to incoming αS and whether these responses contribute to disease-associated early metabolic events, remains unknown. Here, using extracellular monomeric αS to model the earliest cellular response to spreading, we found that internalized αS accumulates at tri-organelle contact sites linking mitochondria, endoplasmic reticulum, and endo/lysosomal compartments. At these interfaces, αS stabilizes generally dynamic contacts and constrains their remodeling, thereby rewiring organelle communication. These effects require the acidic αS C-terminus and are not recapitulated by intracellular αS overexpression. Proteomic profiling of αS-associated mitochondria identified a contact site-enriched but quality-control-deficient state. Functionally, spreading αS impairs neuron-astrocyte mitochondrial quality control (MQC) by reducing neuronal mitochondria transfer to astrocytes, while enhancing mitochondrial import. Our findings establish organelle contact sites as critical target of spreading αS, through which rewired organelle communication impairs MQC and neuron-astrocyte crosstalk.