在帕金森病动物模型中,低密度脂蛋白受体相关蛋白1介导α-突触核蛋白从纹状体向黑质的传递。

IF 5.9 2区 医学 Q2 CELL BIOLOGY
Neural Regeneration Research Pub Date : 2026-04-01 Epub Date: 2024-07-29 DOI:10.4103/NRR.NRR-D-23-01965
Hanjiang Luo, Caixia Peng, Chengli Wu, Chengwei Liu, Qinghua Li, Shun Yu, Jia Liu, Min Chen
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引用次数: 0

摘要

α-突触核蛋白的积聚和传播对帕金森病的发病机制至关重要,但错误折叠的α-突触核蛋白积聚和传播的机制尚未最终确定。低密度脂蛋白受体相关蛋白 1 在神经元中大量表达,被认为是一种多功能内细胞受体。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播之间是否存在直接联系仍不清楚。在这里,我们通过给猴子和小鼠接种α-突触核蛋白预成纤维建立了帕金森病动物模型,并观察到纹状体和黑质中低密度脂蛋白受体相关蛋白1水平升高,同时伴有多巴胺能神经元缺失和α-突触核蛋白水平升高。然而,敲除低密度脂蛋白受体相关蛋白1能有效地挽救多巴胺能神经变性,并抑制黑质系统中α-突触核蛋白水平的增加。在过表达α-突触核蛋白片段的HEK293A细胞中,只有当α-突触核蛋白的N末端存在时,低密度脂蛋白受体相关蛋白1的水平才会上调,而缺乏N末端的α-突触核蛋白片段不会导致低密度脂蛋白受体相关蛋白1的上调。此外,研究还发现α-突触核蛋白的N末端富含赖氨酸残基,用α-突触核蛋白预成纤维处理PC12细胞后,阻断赖氨酸残基可有效降低升高的低密度脂蛋白受体相关蛋白1和α-突触核蛋白水平。这些研究结果表明,低密度脂蛋白受体相关蛋白1通过α-突触核蛋白N端赖氨酸残基调节α-突触核蛋白从纹状体向黑质的病理传递。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

JOURNAL/nrgr/04.03/01300535-202604000-00040/figure1/v/2025-06-30T060627Z/r/image-tiff 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.

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来源期刊
Neural Regeneration Research
Neural Regeneration Research CELL BIOLOGY-NEUROSCIENCES
CiteScore
8.00
自引率
9.80%
发文量
515
审稿时长
1.0 months
期刊介绍: Neural Regeneration Research (NRR) is the Open Access journal specializing in neural regeneration and indexed by SCI-E and PubMed. The journal is committed to publishing articles on basic pathobiology of injury, repair and protection to the nervous system, while considering preclinical and clinical trials targeted at improving traumatically injuried patients and patients with neurodegenerative diseases.
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