Transmission of Peripheral-blood α-Synuclein Fibrils Exacerbates Synucleinopathy and Neurodegeneration in Parkinson's Disease by Endothelial Lag3 Endocytosis.
Qingrui Duan, Qingxi Zhang, ShuoLin Jiang, Kun Nie, Shujun Feng, Yihui Qiu, Peikun He, Yuxuan Xing, Jiaxuan Liu, Guixian Ma, Yuhu Zhang, Yuyuan Gao, Lijuan Wang
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引用次数: 0
Abstract
Background: Parkinson's disease (PD) is an age-related neurodegenerative disorder. The pathological feature of PD is abnormal alpha-synuclein (α-syn) formation and transmission. Recent evidence demonstrates that α-syn preformed fibrils (α-syn PFF) can be detected in the serum of PD patients. The peripheral-blood α-syn PFF can cross the blood-brain barrier and aggravate neuronal damage, but the mechanism remains to be elucidated. Methods: We constructed the PD mouse models of different severity: the mild pathology (A53T ONLY) and the severe pathology (A53T+Brain FIB); this was followed by α-syn PFFs intravenous injection. Then, we used endothelium-specific Lag3 knockout mice (Lag3-ECs-CKO) to decrease the blood α-syn PFFs spreading. Results: We observed that intravenous transmission of α-syn PFFs significantly aggravated motor deficits, dopaminergic neuron loss, neuroinflammation and pathologic α-syn deposition in A53T ONLY, but not in A53T+Brain FIB. Blocking endothelial Lag3 endocytosis by Lag3-ECs-CKO decreased the blood α-syn PFFs spreading and improved the symptoms and pathogenesis of PD mice. Conclusions: Our findings reveal the role of peripheral-blood α-syn PFFs transmission in the mild pathology or early-stage PD and the mechanism of endothelial Lag3 endocytosis in the pathology of α-syn transmission. Targeting endothelial Lag3 to prevent α-syn from spreading from the blood to the brain may be a disease-modifying therapy in early-stage PD.
期刊介绍:
The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.