How can rAAV-α-synuclein and the fibril α-synuclein models advance our understanding of Parkinson's disease?
How can rAAV-α-synuclein and the fibril α-synuclein models advance our understanding of Parkinson's disease?
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RAAV-α-核蛋白和原纤维α-突触核蛋白模型如何提高我们对帕金森氏病的理解？
DOI：
10.1111/jnc.13627
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发表时间：
2016-10
影响因子：
4.7
通讯作者：
Harms AS
中科院分区：
文献类型：
--
作者：
Volpicelli-Daley LA;Kirik D;Stoyka LE;Standaert DG;Harms AS
帕金森氏病(PD)的动物模型对于了解该病的发病机制具有重要意义，有助于开发和验证新的治疗方法。理想情况下，这些模型应该复制帕金森病的基本特征，例如儿茶酚胺能神经元的进行性神经变性和运动缺陷。目前许多PD模型强调α-突触核蛋白的病理形式，其基础是α-突触核蛋白的常染色体显性突变和SNCA基因的复制/三倍体导致PD。此外，主要由α-突触蛋白组成的路易小体和路易神经突起代表了帕金森病的主要病理特征。这些包裹体具有明确的特征，如在非离子洗涤剂中不溶，过度磷酸化，对蛋白酶K敏感，电子显微镜下呈丝状外观，以及β-Sheet结构。此外，路易氏小体和路易氏神经突起广泛存在于周围和中枢神经系统，不仅可以解释运动症状，也可以解释疾病的非运动症状。本综述的目的是描述两种新的基于α-突触核蛋白的模型：重组腺相关病毒载体-α-突触核蛋白模型和α-突触核蛋白原纤维模型。这两种模型的一个优点是，它们不需要将转α-突触核蛋白的啮齿动物与其他转感兴趣基因的啮齿动物进行广泛的杂交，以研究这些基因对帕金森病相关病理和表型的影响。此外，异常的α-突触核蛋白可以在与疾病相关的大脑区域表达。在这里，我们讨论每个模型的特点，每个模型到目前为止如何有助于我们对PD的理解，以及每个模型的优势和潜在的警告。该综述描述了两种基于α-突触核蛋白的帕金森病啮齿动物模型：rAAV-α-突触核蛋白模型和α-突触核蛋白原纤维模型。描述了这些模型的主要特征，以及它们在多大程度上概括了帕金森病的特征，如α-突触核蛋白包涵体的形成，纹状体中多巴胺能突触的丢失，运动缺陷，炎症和多巴胺神经元死亡。
Animal models of Parkinson’s disease (PD) are important for understanding the mechanisms of the disease and can contribute to developing and validating novel therapeutics. Ideally, these models should replicate the cardinal features of PD, such as progressive neurodegeneration of catecholaminergic neurons and motor defects. Many current PD models emphasize pathological forms of α-synuclein, based on findings that autosomal dominant mutations in α-synuclein and duplications/triplications of the SNCA gene cause PD. In addition, Lewy bodies and Lewy neurites, primarily composed of α-synuclein, represent the predominant pathological characteristics of PD. These inclusions have defined features, such as insolubility in non-ionic detergent, hyperphosphorylation, proteinase K sensitivity, a filamentous appearance by electron microscopy, and β-sheet structure. Furthermore, it has become clear that Lewy bodies and Lewy neurites are found throughout the peripheral and central nervous system, and could account not only for motor symptoms, but also for non-motor symptoms of the disease. The goal of this review is to describe two new α-synuclein-based models: the recombinant adeno-associated viral vector-α-synuclein model and the α-synuclein fibril model. An advantage of both models is that they do not require extensive crossbreeding of rodents transgenic for α-synuclein with other rodents transgenic for genes of interest to study the impact of such genes on PD-related pathology and phenotypes. In addition, abnormal α-synuclein can be expressed in brain regions relevant for disease. Here, we discuss the features of each model, how each model has contributed thus far to our understanding of PD, and the advantages and potential caveats of each model. This review describes two α-synuclein-based rodent models of Parkinson’s disease: the rAAV-α-synuclein model and the α-synuclein fibril model. The key features of these models are described, and the extent to which they recapitulate features of PD, such as α-synuclein inclusion formation, loss of dopaminergic synapses in the striatum, motor defects, inflammation, and dopamine neuron death.
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影响因子：
5.3
作者：
Decressac, M.;Mattsson, B.;Bjorklund, A.
通讯作者：
Bjorklund, A.
影响因子：
5.3
作者：
Caudal, D.;Alvarsson, A.;Svenningsson, P.
通讯作者：
Svenningsson, P.
影响因子：
4.8
作者：
Daher, Joao P. L.;Abdelmotilib, Hisham A.;West, Andrew B.
通讯作者：
West, Andrew B.
影响因子：
17.1
作者：
Decressac, Mickael;Kadkhodaei, Banafsheh;Bjorklund, Anders
通讯作者：
Bjorklund, Anders
DOI：
10.1126/science.1245296
发表时间：
2013-11-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chung CY;Khurana V;Auluck PK;Tardiff DF;Mazzulli JR;Soldner F;Baru V;Lou Y;Freyzon Y;Cho S;Mungenast AE;Muffat J;Mitalipova M;Pluth MD;Jui NT;Schüle B;Lippard SJ;Tsai LH;Krainc D;Buchwald SL;Jaenisch R;Lindquist S
通讯作者：
Lindquist S