Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (4): 1595-1606.doi: 10.4103/NRR.NRR-D-23-01965

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Low-density lipoprotein receptor–related protein 1 mediates α-synuclein transmission from the striatum to the substantia nigra in animal models of Parkinson’s disease

Hanjiang Luo1, 2, 3, #, Caixia Peng1, 2, #, Chengli Wu1, 2, Chengwei Liu1, 2, Qinghua Li1, 2, 3, Shun Yu4 , Jia Liu5 , Min Chen1, 2, 3, *   

  1. 1 Laboratory of Neuroscience, Guangxi Neurological Diseases Clinical Research Center, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, China;  2 Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, China;  3 Guangxi Engineering Research Center of Digital Medicine and Clinical Translation, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, China;  4 Department of Neurobiology, Xuanwu Hospital, Capital Medical University, Beijing, China;  5 Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China
  • Online:2026-04-15 Published:2025-07-28
  • Contact: Min Chen, PhD, chenmin790830@163.com.
  • Supported by:
    This study was supported by the Natural Science Foundation of Guangxi Zhuang Automomous Region, Nos. 2019GXNSFDA245015 (to MC), 2022GXNSFBA035654 (to HL), the National Natural Science Foundation of China, Nos. 82360241 (to MC), 82304876 (to HL), Scientific Research and Technology Development Project of Guilin City, Nos. 20220139-3 (to MC), 20210218-5 (to HL), and Guangxi Medical and Health Key Discipline Construction Project (to QL).

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Abstract: α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson’s disease, although the mechanisms underlying misfolded α-synuclein accumulation and propagation have not been conclusively determined. The expression of low-density lipoprotein receptor–related protein 1, which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor, is elevated in the neurons of patients with Parkinson’s disease. However, whether there is a direct link between low-density lipoprotein receptor–related protein 1 and α-synuclein aggregation and propagation in Parkinson’s disease remains unclear. Here, we established animal models of Parkinson’s disease by inoculating monkeys and mice with α-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra, accompanied by dopaminergic neuron loss and increased α-synuclein levels. However, low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase in α-synuclein levels in the nigrostriatal system. In HEK293A cells overexpressing α-synuclein fragments, low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus of α-synuclein was present, whereas an α-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation. Furthermore, the N-terminus of α-synuclein was found to be rich in lysine residues, and blocking lysine residues in PC12 cells treated with α-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 and α-synuclein levels. These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission of α-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in the α-synuclein N-terminus.

Key words: α-synuclein, dopaminergic neurodegeneration, internalization, low-density lipoprotein receptor-related protein 1, lysine, pre-formed fibril, movement disorder, nigrostriatal system, Parkinson’s disease, transmission