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 (10): 5000-5012.doi: 10.4103/NRR.NRR-D-25-00648

• 原著:退行性病与再生 • 上一篇    下一篇

神经毒性、α突触核蛋白病理学和线粒体功能障碍：不同帕金森病小鼠模型的比较

  

  • 出版日期:2026-10-15 发布日期:2026-06-15
  • 基金资助:
    国家自然科学基金面上项目（No.32271003）和克服递药屏障高端制剂全国重点实验室开放课题（No.2025-KFA-007）

Neurotoxicity, α-synuclein pathology, and mitochondrial dysfunction: A comparative study of different mouse models of Parkinson’s disease

Xiwen Tang1, #, Yifei He1, #, Min Liang2, Penggang Ning1, Jiayin Zhao1, Yunhe Zhang1, Xin Yan1, Ruilin Sun3, Gang Wei4, Ruling Shen2, *, Fang Huang1, *, Mei Yu1, *    

  1. 1Department of Translational Neuroscience, Jing’an District Center Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China; 
    2Shanghai Laboratory Animal Research Center, Shanghai, China; 
    3Shanghai Engineering Research Center for Model Organisms, Shanghai Model Organisms Center, Inc., Shanghai, China; 
    4State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers, Fudan University, Shanghai, China
  • Online:2026-10-15 Published:2026-06-15
  • Contact: Ruling Shen, PhD, shenruling@slarc.org.cn; Fang Huang, PhD, huangf@shmu.edu.cn; Mei Yu, MD, PhD, yumei@fudan.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 32271003 (to FH); and The Open Fund of State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers, No. 2025-KFA-007 (to MY).

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摘要：

帕金森病（PD）的病因十分复杂，单个动物模型很难完全模拟其病理特征。此次研究拟对不同的帕金森病小鼠模型（MPTP诱导模型、α-Syn A53T转基因模型和MitoPark模型）的行为、帕金森病样病理以及基因和蛋白质表达谱进行全面分析。可见3种帕金森病小鼠模型都表现出运动障碍，尤其是MitoPark小鼠呈年龄相关性恶化。在病理学方面，所有小鼠模型均可见黑质纹状体通路损伤，但神经胶质细胞活化模式却不同。其中，16个月龄α-Syn A53T小鼠黑质存在pS129-α-Syn阳性信号，但所有模型中均未见α-Syn聚集体。在分子机制方面，RNA测序和蛋白质组学揭示了帕金森病小鼠模型中基因和蛋白质表达的显著变化，显示不同模型存在独特和共同的特征。鉴定出5种常见的差异表达基因（Ifi27l2a、Ifitm3、Oasl2、Rtp4和Ankk1）和2种常见的差异表达蛋白（Timm8a1和Sephs1）。功能富集分析表明，免疫反应、细胞因子和神经递质转运在帕金森病发病机制中至关重要。值得注意的是，在不同模型中可见多种与铁相关的细胞损伤（铁死亡）相关的差异表达基因，且MitoPark小鼠存在IL17通路激活变化。上述发现从多维度阐明不同帕金森病模型病理模拟能力和常见机制的共性和特异性，这将提供了对帕金森病多方面特征的洞察，并为疾病机制探索模型选择的提供参考。


https://orcid.org/0000-0003-3824-6367 (Mei Yu)

关键词: 铁死亡通路, 胶质细胞活化, 白细胞介素17通路, 线粒体功能障碍, MitoPark模型, MPTP诱导模型, 神经变性, 黑质纹状体通路, pS129-α-Syn, α-Syn A53T转基因模型

Abstract: The causes of Parkinson’s disease are complex, and it is difficult for a single animal model to fully mimic its pathological characteristics. In this study, a comprehensive analysis of behaviors, Parkinson’s disease–like pathologies, and gene and protein expression profiles was carried out in three mouse models of disease: 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced, α-synuclein (α-syn) A53T transgenic, and MitoPark, revealing both shared and model-specific pathogenic pathways to guide model selection and identify potential therapeutic targets. All three Parkinson’s disease models exhibited motor impairments, with particularly pronounced age-related decline observed in MitoPark mice. Pathologically, nigrostriatal pathway damage was observed in all models, yet with distinct patterns of glial cell activation. Sixteen-month-old α-syn A53T mice displayed a few pS129- α-syn-positive signals in the substantia nigra, while no α-syn aggregates were observed in any of the models. RNA sequencing and proteomics analysis revealed significant changes in gene and protein expression, with both unique and common features among the three models. Five common differentially expressed genes (Ifi27l2a, Ifitm3, Oasl2, Rtp4, and Ankk1) and two common differentially expressed proteins (Timm8a1 and Sephs1) were identified. Functional enrichment analysis indicated that immune responses, cytokines, and neurotransmitter transport were crucial in Parkinson’s disease pathogenesis. Notably, multiple iron-related cell damage (ferroptosis)-related differentially expressed genes were identified across all three models, while interleukin 17 pathway activation was altered in MitoPark mice. In summary, we analyzed the commonalities and specificities of pathological simulation capabilities and common disease mechanisms in different mouse models of Parkinson’s disease from multiple perspectives. Our findings offer valuable insights into the multifaceted characteristics of Parkinson’s disease and will assist in model selection for mechanistic exploration in the future. 

Key words: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced model, ferroptosis pathway, glial cell activation, interleukin 17 pathway, mitochondrial dysfunction, MitoPark model, nerve regeneration, neurodegeneration, nigrostriatal pathway, pS129-α-syn, α-syn A53T transgenic model