Involvement of 75NTR extracellular domain in rotenone-induced Parkinson's disease cell models.

IF 1.7 4区医学 Q4 NEUROSCIENCES

Neuroreport Pub Date : 2026-04-01 Epub Date: 2026-03-10 DOI:10.1097/WNR.0000000000002258

Yifei You, Anyan Ren, Nan Wang, Fang Chen, Xianzhi Wang, Chen Li, Hongcai Wang

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引用次数: 0

Abstract

Objective: While the p75 neurotrophin receptor (p75NTR) is critically implicated in the aggregation of α-synuclein (α-syn), a defining pathological hallmark of Parkinson's disease, the distinct functional contributions of its structural domains remain largely unresolved.

Methods: To investigate this, we employed a rotenone-induced cellular Parkinson's disease model utilizing SH-SY5Y neuroblastoma cells transfected with plasmids encoding specific p75NTR truncation mutants.

Results: Overexpression of a mutant representing the p75NTR extracellular domain (HA-p75Δ151, lacking residues 277-427) significantly exacerbated both α-syn expression levels and its aggregation phenotype. This effect is potentially attributable to the aberrant activation of caspase-1. Conversely, unlike full-length p75NTR which enhanced α-syn ubiquitination, the HA-p75Δ151 truncation failed to modulate ubiquitination dynamics. Furthermore, expression of this extracellular domain fragment induced cell cycle dysregulation and promoted cell death.

Conclusion: These findings delineate the p75NTR extracellular domain-induced α-syn proteotoxic stress. This domain-specific mechanism advances our understanding of Parkinson's disease pathogenesis and highlights the therapeutic potential of targeting specific p75NTR domains.

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75NTR细胞外结构域参与鱼藤酮诱导的帕金森病细胞模型。

目的：虽然p75神经营养因子受体（p75NTR）与α-突触核蛋白（α-syn）的聚集密切相关，α-突触核蛋白是帕金森病的一个决定性病理标志，但其结构域的独特功能贡献在很大程度上仍未得到解决。方法：为了研究这一点，我们采用鱼素诱导的细胞帕金森病模型，利用SH-SY5Y神经母细胞瘤细胞转染编码特异性p75NTR截断突变体的质粒。结果：一个代表p75NTR细胞外结构域的突变体（HA-p75Δ151，缺失残基277-427）的过表达显著加剧了α-syn的表达水平及其聚集表型。这种效应可能归因于caspase-1的异常激活。相反，与全长p75NTR增强α-syn泛素化不同，HA-p75Δ151截断未能调节泛素化动力学。此外，这种细胞外结构域片段的表达诱导细胞周期失调并促进细胞死亡。结论：这些发现揭示了p75NTR胞外结构域诱导的α-syn蛋白毒性应激。这种结构域特异性机制促进了我们对帕金森病发病机制的理解，并突出了靶向特定p75NTR结构域的治疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuroreport 医学-神经科学

CiteScore

3.20

自引率

0.00%

发文量

150

审稿时长

1 months

期刊介绍： NeuroReport is a channel for rapid communication of new findings in neuroscience. It is a forum for the publication of short but complete reports of important studies that require very fast publication. Papers are accepted on the basis of the novelty of their finding, on their significance for neuroscience and on a clear need for rapid publication. Preliminary communications are not suitable for the Journal. Submitted articles undergo a preliminary review by the editor. Some articles may be returned to authors without further consideration. Those being considered for publication will undergo further assessment and peer-review by the editors and those invited to do so from a reviewer pool. The core interest of the Journal is on studies that cast light on how the brain (and the whole of the nervous system) works. We aim to give authors a decision on their submission within 2-5 weeks, and all accepted articles appear in the next issue to press.