Unique seeding profiles and prion-like propagation of synucleinopathies are highly dependent on the host in human α-synuclein transgenic mice.
Unique seeding profiles and prion-like propagation of synucleinopathies are highly dependent on the host in human α-synuclein transgenic mice.
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DOI：
10.1007/s00401-022-02425-4
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发表时间：
2022-06
影响因子：
12.7
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中科院分区：
文献类型：
--
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α-突触核蛋白(αSyn)是一种内在的无序蛋白质，它可以进行结构转换，形成稳定的、不溶于水的纤维。错误折叠的‘种子’作为构象模板可以诱导αSyn淀粉样核化，这等同于普里恩机制。α系统内含物的积累是路易体痴呆和多系统萎缩的一个重要特征，也是阿尔茨海默病(AD)的附加病理，如以杏仁核为主的路易体AD(AD/ALB)。虽然这些疾病积累了相同的病理蛋白，但它们在临床和组织学特征上表现出异质性；然而，这种差异背后的机制(S)仍然不清楚。从人类尸检研究、动物接种模型和体外特性实验中获得的数据支持了这样一种假设，即αSyn淀粉型纤维结构的构象多态导致了具有明确传染性特征的不同“菌株”。在这里，我们直接比较了这些疾病的人脑裂解物以及通过脑内接种过表达人野生型α同步蛋白或带有家族性A53T突变的人α同步蛋白的转基因小鼠而获得的重组人α同步纤维的种子能力和结果。我们的研究表明，初始接种在很大程度上决定了疾病的表型和病理过程。有趣的是，我们还在传播特征之间建立了相关的依赖于宿主的区别，包括包涵体病理在神经轴上的负担和扩散，以及神经症状的严重程度。这些发现提供了令人信服的证据，支持这样一种假设，即不同的Prion类型构象可以解释在联核病中看到的可变性。
α-synuclein (αSyn) is an intrinsically disordered protein which can undergo structural transformations, resulting in the formation of stable, insoluble fibrils. αSyn amyloid-type nucleation can be induced by misfolded ‘seeds’ serving as a conformational template, tantamount to the prion-like mechanism. Accumulation of αSyn inclusions is a key feature of dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), and are found as additional pathology in Alzheimer’s disease (AD) such as AD with amygdala predominant Lewy bodies (AD/ALB). While these disorders accumulate the same pathological protein, they exhibit heterogeneity in clinical and histological features; however, the mechanism(s) underlying this variability remains elusive. Accruing data from human autopsy studies, animal inoculation modeling, and in vitro characterization experiments, have lent credence to the hypothesis that conformational polymorphism of the αSyn amyloid-type fibril structure results in distinct “strains” with categorical infectivity traits. Herein, we directly compare the seeding abilities and outcome of human brain lysates from these diseases, as well as recombinant preformed human αSyn fibrils by the intracerebral inoculation of transgenic mice overexpressing either human wild-type αSyn or human αSyn with the familial A53T mutation. Our study has revealed that the initiating inoculum heavily dictates the phenotypic and pathological course of disease. Interestingly, we have also established relevant host-dependent distinctions between propagation profiles, including burden and spread of inclusion pathology throughout the neuroaxis, as well as severity of neurological symptoms. These findings provide compelling evidence supporting the hypothesis that diverse prion-type conformers may explain the variability seen in synucleinopathies.
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影响因子：
82.9
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Conway, KA;Harper, JD;Lansbury, PT
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