人类α -突触核蛋白的非侵入性全身病毒递送模拟了啮齿类动物大脑帕金森病的选择性和进行性神经病理学。

IF 14.9 1区 医学 Q1 NEUROSCIENCES
Morgan Bérard, Laura Martínez-Drudis, Razan Sheta, Omar M A El-Agnaf, Abid Oueslati
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引用次数: 0

摘要

背景:α-突触核蛋白(α-syn)聚集在被称为路易体(LBs)的蛋白质神经元内包涵体中,是帕金森病(PD)和相关突触核蛋白病的神经病理学标志。然而,α-syn包涵体在PD发病机制中的确切作用尚不清楚。这种知识的缺乏主要是由于缺乏基于α-syn的最佳动物模型来概括神经变性的不同阶段。方法:在这里,我们描述了一种新的方法,用于系统递送携带人类α-syn的病毒颗粒,允许在小鼠大脑中大规模过表达这种蛋白质。这种方法是基于使用新一代腺相关病毒(AAV), AAV- php。eB具有更强的穿越血脑屏障的能力,因此为在中枢神经系统中进行非侵入性和大规模的基因传递提供了一种可行的工具。结果:通过该模型,我们报道了人类α-syn的广泛过度表达诱导多巴胺能(DA)神经元的选择性变性,黑质神经炎症反应加剧,pd样运动障碍的进行性表现。有趣的是,生化分析显示在中脑中存在不溶性α-syn低聚物。总之,我们的数据表明,单次非侵入性的系统传递过表达α-syn的病毒颗粒会导致类似PD早期的选择性和进行性神经病理。结论:我们的新体内模型为研究α-syn在PD发病机制和黑质DA神经元选择性易感性中的作用提供了有价值的工具;并提供了测试针对α-syn毒性的新策略的机会,以开发PD和相关疾病的疾病改善疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson's disease in rodent brains.

Background: Alpha-synuclein (α-syn) aggregation into proteinaceous intraneuronal inclusions, called Lewy bodies (LBs), is the neuropathological hallmark of Parkinson's disease (PD) and related synucleinopathies. However, the exact role of α-syn inclusions in PD pathogenesis remains elusive. This lack of knowledge is mainly due to the absence of optimal α-syn-based animal models that recapitulate the different stages of neurodegeneration.

Methods: Here we describe a novel approach for a systemic delivery of viral particles carrying human α-syn allowing for a large-scale overexpression of this protein in the mouse brain. This approach is based on the use of a new generation of adeno-associated virus (AAV), AAV-PHP.eB, with an increased capacity to cross the blood-brain barrier, thus offering a viable tool for a non-invasive and large-scale gene delivery in the central nervous system.

Results: Using this model, we report that widespread overexpression of human α-syn induced selective degeneration of dopaminergic (DA) neurons, an exacerbated neuroinflammatory response in the substantia nigra and a progressive manifestation of PD-like motor impairments. Interestingly, biochemical analysis revealed the presence of insoluble α-syn oligomers in the midbrain. Together, our data demonstrate that a single non-invasive systemic delivery of viral particles overexpressing α-syn prompted selective and progressive neuropathology resembling the early stages of PD.

Conclusions: Our new in vivo model represents a valuable tool to study the role of α-syn in PD pathogenesis and in the selective vulnerability of nigral DA neurons; and offers the opportunity to test new strategies targeting α-syn toxicity for the development of disease-modifying therapies for PD and related disorders.

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来源期刊
Molecular Neurodegeneration
Molecular Neurodegeneration 医学-神经科学
CiteScore
23.00
自引率
4.60%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Molecular Neurodegeneration, an open-access, peer-reviewed journal, comprehensively covers neurodegeneration research at the molecular and cellular levels. Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and prion diseases, fall under its purview. These disorders, often linked to advanced aging and characterized by varying degrees of dementia, pose a significant public health concern with the growing aging population. Recent strides in understanding the molecular and cellular mechanisms of these neurodegenerative disorders offer valuable insights into their pathogenesis.
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