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

Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People's Republic of China.Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People's Republic of China. · pubmed

Paper

Abstract

Parkinson's disease (PD) is an age-related neurodegenerative disorder. The pathological feature of PD is abnormal α-synuclein (α-syn) formation and transmission. Recent evidence demonstrates that α-syn preformed fibrils (α-syn PFFs) can be detected in the serum of patients with PD. The peripheral blood α-syn PFF can cross the blood-brain barrier (BBB) and aggravate neuronal damage, but the mechanism remains to be elucidated. 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. 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. 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.

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper claims that targeting endothelial Lag3 can prevent the transmission of peripheral blood α-synuclein fibrils to the brain, potentially modifying the progression of early-stage Parkinson's disease. This research is relevant as it addresses mechanisms that could influence the underlying pathology of an age-related neurodegenerative disorder, contributing to our understanding of disease modification in the context of aging.

Author of this paper? Send a correction.