中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (4): 1595-1606.doi: 10.4103/NRR.NRR-D-23-01965

• 原著:退行性病与再生 • 上一篇    下一篇

低密度脂蛋白受体相关蛋白1介导帕金森病α-突触核蛋白从纹状体向黑质的传递

  

  • 出版日期:2026-04-15 发布日期:2025-07-28
  • 基金资助:
    广西自然科学基金重点项目（2019GXNSFDA245015）广西自然科学基金青年基金项目（2022GXNSFBA035654）等。

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).

PDF

9

摘要：

α-突触核蛋白的积累和传递在帕金森病的发病机制中至关重要，但错误折叠的α-突触核蛋白积累和传递的机制尚未完全明确。低密度脂蛋白受体相关蛋白1可在神经元中大量表达，被认为是一种多功能的内吞受体，在帕金森病神经元中高表达。然而，低密度脂蛋白受体相关蛋白1与帕金森病中α-突触核蛋白的聚集和传递之间是否存在直接联系尚不清楚。此次实验以α-突触核蛋白预成型纤维诱导帕金森病模型猴和小鼠，发现两者纹状体和黑质中低密度脂蛋白受体相关蛋白1水平升高，并伴有多巴胺能神经元损失和α-突触核蛋白水平升高。而敲低低密度脂蛋白受体相关蛋白1可有效地减轻多巴胺能神经退行性变，并抑制黑质纹状体系统中α-突触核蛋白水平的上调。进一步观察片段化α-突触核蛋白质粒过表达HEK293A细胞发现，只有当α-突触核蛋白的N端存在时，低密度脂蛋白受体相关蛋白1水平才会上调，而N端缺失的α-突触核蛋白不能引起低密度脂蛋白受体相关蛋白1水平的上调。而后在α-突触核蛋白预成型纤维诱导PC12细胞中发现α-突触核蛋白的N端富含赖氨酸，而阻断赖氨酸可有效降低低密度脂蛋白受体相关蛋白1和α-突触核蛋白水平的升高。上述发现表明，低密度脂蛋白受体相关蛋白1可通过与α-突触核蛋白 N端赖氨酸残基作用，介导了α-突触核蛋白在帕金森病黑质纹状体系统中从纹状体到黑质的病理传递。

https://orcid.org/0000-0002-2308-9031 (Min Chen)

关键词: α-突触核蛋白, 低密度脂蛋白受体相关蛋白1, 黑质纹状体系统, 内化, 传递, 帕金森病, 赖氨酸, 预成型纤维, 多巴胺能神经变性, 运动障碍

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