Parkinson’s Protein Alpha-Synuclein Drives Clogged Arteries by Jamming Cellular Recycling

Alpha-synuclein, the small protein whose misbehavior defines Parkinson’s disease, has long been treated as an exclusively neurological villain. A new study published in Aging Cell argues that its reach extends far beyond the brain, all the way into the fatty plaques that stiffen arteries and trigger heart attacks and strokes. By combining human plaque tissue, genetically engineered mice, and an arsenal of cell-biology assays, the researchers present a mechanistic chain linking this notorious protein to the formation of foam cells, the lipid-engorged macrophages that are the building blocks of atherosclerosis.

The investigation began with a straightforward question: is alpha-synuclein actually present in atherosclerotic lesions? The team collected carotid plaque specimens from three patients undergoing endarterectomy and subjected them to liquid chromatography–tandem mass spectrometry. Peptides corresponding to alpha-synuclein were detected in every specimen, and western blotting confirmed the finding, revealing an immunoreactive band just above 15 kilodaltons, the expected size of the monomeric protein, along with higher-molecular-weight species that may represent modified or protein-associated forms. This protein-level validation established that the Parkinson’s-associated protein genuinely inhabits the vascular disease environment rather than merely circulating in the bloodstream at large.

To test whether the protein matters functionally, the researchers turned to mice lacking the Snca gene, which encodes alpha-synuclein. Using an adeno-associated virus carrying PCSK9 followed by sixteen weeks of high-cholesterol diet, they induced atherosclerosis in both knockout animals and wild-type littermates. The results were striking: mice without alpha-synuclein developed significantly smaller lesions across the whole aorta and aortic arch, with reduced plaque area, smaller necrotic cores, and diminished lipid deposition at the aortic root. The phenotype appeared in both sexes, and immunofluorescence analysis pinpointed the difference to macrophage-derived foam cells, identified as cells positive for both the macrophage marker CD68 and the lipid dye BODIPY. Lipid-laden smooth muscle cells, by contrast, were not detectably altered, suggesting the protein’s influence is concentrated on the macrophage arm of plaque biology.

Because alpha-synuclein circulates in blood, largely as monomers carried by red blood cells, the team next asked whether extracellular exposure to the protein could actively worsen disease. They injected purified recombinant alpha-synuclein into atherosclerosis-prone Apoe-deficient mice twice weekly for twelve weeks while the animals consumed a high-cholesterol diet. Compared with controls receiving vehicle, the treated mice showed markedly increased lipid deposition in the whole aorta and aortic arch, larger plaques, expanded necrotic cores, and a higher density of macrophage foam cells within lesions. Collagen content, a measure of plaque stability, did not increase proportionally, implying that the additional lipid burden came with reduced lesion stability. In cell culture, adding alpha-synuclein to macrophages exposed to oxidized low-density lipoprotein further amplified neutral lipid accumulation, while uptake of labeled ox-LDL remained unchanged.

The critical clue came from cholesterol efflux assays. When macrophages pre-loaded with fluorescent NBD-cholesterol were treated with alpha-synuclein, their ability to export cholesterol to both high-density lipoprotein and apolipoprotein A-1 acceptors dropped significantly. Curiously, the protein levels of the classical lipid-handling machinery, including the uptake receptors CD36, MSR1, and OLR1 and the transporters ABCA1 and ABCG1, were unaffected. This pointed the investigators away from transcriptional regulation of lipid traffic and toward the autophagy-lysosome system, the intracellular recycling network that, through a process called lipophagy, delivers lipid droplets to lysosomes for hydrolysis and frees cholesterol for export.

A series of complementary experiments converged on a specific defect: the fusion of autophagosomes with lysosomes. Alpha-synuclein-treated macrophages accumulated the autophagy markers LC3B-II and SQSTM1, a signature of blocked degradation rather than enhanced autophagic activity, since chloroquine pre-treatment eliminated the further LC3B-II increase. Confocal microscopy showed reduced colocalization between lipid droplets and lysosomes, between lipid droplets and LC3, and, most tellingly, between LC3-labeled autophagosomes and LAMP1-labeled lysosomes. Transmission electron microscopy revealed fewer autolysosomal structures and enlarged lipid droplets. Finally, a macrophage line stably expressing the tandem RFP-EGFP-LC3 reporter, in which red-only puncta mark completed autolysosomes and yellow puncta mark stalled autophagosomes, showed a clear shift toward yellow puncta after alpha-synuclein treatment. The autophagy conveyor belt, in short, jammed at the fusion step.

Having localized the blockage, the researchers traced it upstream to signaling. The SNARE proteins that physically mediate autophagosome-lysosome fusion, STX17, SNAP29, and VAMP8, were not reduced in abundance, distinguishing macrophages from neurons, where alpha-synuclein overexpression was previously shown to degrade SNAP29. Instead, alpha-synuclein treatment increased phosphorylation of PI3K and AKT, which in turn activated mTOR and its downstream effectors S6K and ULK1 at the inhibitory Ser757 site, while AMPK phosphorylation remained unchanged. Pharmacological intervention confirmed the pathway’s relevance: pretreatment with the PI3K inhibitor LY294002 blunted the mTOR phosphorylation response, and either LY294002 or the mTOR inhibitor rapamycin normalized LC3B-II accumulation and significantly reduced alpha-synuclein-induced lipid droplet buildup. Blocking this axis, in other words, partially rescues the foam cell phenotype.

The remaining question was how extracellular alpha-synuclein gains entry and triggers PI3K signaling. Proteomic comparison of treated and untreated macrophages flagged flotillin-1, or FLOT1, a membrane raft-associated protein previously implicated in alpha-synuclein endocytosis in dopaminergic neurons. Alpha-synuclein treatment increased FLOT1 protein levels, and silencing Flot1 with siRNA markedly reduced the protein’s uptake into macrophages. Immunofluorescence showed intracellular colocalization between alpha-synuclein and FLOT1, and co-immunoprecipitation supported a biochemical association, though the authors note these assays do not establish direct binding. Functionally, Flot1 knockdown abolished the alpha-synuclein-induced phosphorylation of PI3K, prevented the accumulation of LC3B-II, partially reduced SQSTM1 upregulation, restored HDL-mediated cholesterol efflux, and attenuated foam cell formation. Consistent with the in vitro data, atherosclerotic mice injected with alpha-synuclein carried a higher density of FLOT1-positive macrophages in their plaques.

The study’s authors emphasize that endogenous alpha-synuclein expression in macrophages is extremely low, which likely explains why Snca-deficient macrophages showed no intrinsic defect in foaming capacity in vitro. The atheroprotective phenotype of the knockout mice may instead reflect reduced exposure to circulating, extracellular alpha-synuclein, a hypothesis their injection experiments directly support. This reframing matters because it positions alpha-synuclein not merely as a neuronal liability but as a circulating factor whose peripheral levels, already known to be elevated in Parkinson’s patients, could plausibly influence vascular risk. Epidemiological observations lend circumstantial weight: Parkinson’s disease has been associated with a higher prevalence of carotid plaques and an increased risk of ischemic stroke, and alpha-synuclein has been detected in HDL and lipoprotein(a) fractions as well as in cerebrovascular walls and endothelial cell secretions.

The implications reach into therapeutics. The identification of FLOT1 as a candidate entry mediator and of the PI3K-AKT-mTOR axis as the signaling conduit suggests at least two pharmacologically tractable nodes, both already targeted by existing drugs such as rapamycin. The authors caution that inhibitor effects were partial, that SQSTM1 accumulation also reflects transcriptional upregulation possibly tied to inflammatory signaling, and that the colocalization and co-immunoprecipitation data do not prove direct molecular binding. Nonetheless, the convergence of human plaque proteomics, genetic mouse models, and mechanistic cell biology builds a coherent case that extracellular alpha-synuclein impairs macrophage autophagic flux, stalls cholesterol export, and accelerates atherosclerosis. For aging populations, in which declining autophagy and rising vascular disease already converge, the prospect that a single protein links neurodegeneration and arterial pathology offers both a unifying biological insight and a fresh set of intervention points.

Subject of Research: The role of alpha-synuclein in macrophage autophagic dysfunction and atherosclerosis progression

Article Title: α‐Synuclein Promotes Atherosclerosis by Impairing Macrophage Autophagic Flux

Article References: Qin, M., Xiang, X., Guo, X., Wang, S., Chen, J., Jiang, D., Feng, Y., Yu, J., & Mao, L. (2026). α‐Synuclein Promotes Atherosclerosis by Impairing Macrophage Autophagic Flux. Aging Cell, 25(10), Article e70713. https://doi.org/10.1111/acel.70713

Image Credits: AI Generated

DOI: 10.1111/acel.70713

Keywords: alpha-synuclein, atherosclerosis, macrophages, autophagy, foam cells, FLOT1, PI3K-AKT-mTOR, cholesterol efflux, Parkinson's disease, lipophagy, vascular aging, Aging Cell