α-Synuclein Promotes Atherosclerosis by Impairing Macrophage Autophagic Flux

Atherosclerosis, recognized as a prototypical age-associated vascular disease, is driven by macrophage foam cell formation. Individuals with Parkinson's disease (PD) exhibit an elevated risk for stroke. While α-synuclein (α-Syn) is known for its neuronal role in PD, its presence in the circulation and potential vascular effects remain unexplored. Here, we identify α-Syn as a previously unrecognized circulating factor that promotes atherosclerosis. α-Syn was detected in human atherosclerotic plaques. Genetic deletion of α-Syn reduced atherosclerotic lesion size and macrophage lipid accumulation in a mouse model of atherosclerosis induced by overexpression of proprotein convertase subtilisin/kexin type 9 (PCSK9). On the contrary, administration of exogenous α-Syn accelerated atherosclerosis in Apolipoprotein E knockout (Apoe^-/-) mice. Mechanistically, α-Syn promoted macrophage foam cell formation by impairing autophagic flux, accompanied by activation of PI3K-mTOR signaling. Proteomic analysis identified the membrane raft protein flotillin-1 (FLOT1) as a candidate upstream mediator. Flot1 knockdown reduced α-Syn internalization, PI3K phosphorylation, autophagy impairment, and lipid accumulation, while pharmacological inhibition of PI3K or mTOR attenuated the effects of α-Syn. Together, these findings identify a FLOT1-associated pathway through which extracellular α-Syn disrupts macrophage autophagy and promotes atherosclerosis.