α-Synuclein, the protein central to Parkinson's pathology, was detected in human atherosclerotic plaques and shown to drive lesion growth in mouse models. It enters macrophages via the membrane raft protein flotillin-1, activates PI3K-mTOR signaling, and blocks autophagosome-lysosome fusion, preventing cells from breaking down accumulated lipid and accelerating foam cell formation. Genetic deletion of α-synuclein, flotillin-1 knockdown, or PI3K/mTOR inhibition each reduced lipid accumulation and plaque burden.
Key Points
- α-Synuclein found circulating and embedded in human atherosclerotic plaques
- FLOT1-PI3K-mTOR activation blocks macrophage lipophagy, driving foam cells
- Blocking FLOT1 or mTOR reversed lipid accumulation in mice
Longevity Analysis
Atherosclerosis emerges here as a failure of cellular waste clearance rather than lipid excess alone — macrophages loaded with cholesterol cannot complete the autophagic digestion that would normally recycle it. The same mTOR signaling that suppresses this clearance is the pathway modulated by caloric restriction, fasting, and rapamycin, placing vascular plaque within the broader biology of impaired cellular renewal. The link between a neurodegenerative protein and arterial disease also reinforces that the immune cells patrolling vessel walls and the neurons of the brain share vulnerability to the same clearance defect, which argues for tracking neurological and cardiovascular risk as one continuum rather than separate specialties.
Original published by Wiley Aging Cell, by Mengting Qin, Xuying Xiang, Xiaoqing Guo, Shengnan Wang, Jiaojiao Chen, Dailiang Jiang, Yuhang Feng, Jiangnan Yu, Ling Mao .