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.

α-突触核蛋白 (αSyn) 是一种本质上无序的蛋白质，可以进行结构转变，从而形成稳定的、不溶性原纤维。αSyn 淀粉样蛋白型成核可由错误折叠的“种子”作为构象模板诱导，相当于朊病毒样机制。αSyn 包涵体的积累是路易体痴呆 (DLB) 和多系统萎缩 (MSA) 的一个关键特征，并且被发现是阿尔茨海默病 (AD) 的附加病理学，例如以杏仁核为主的路易体 (AD/ALB) AD。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，这种可变性背后的机制仍然难以捉摸。从人体解剖研究、动物接种模型中收集数据，和体外表征实验，证实了 αSyn 淀粉样蛋白型原纤维结构的构象多态性导致具有分类感染性特征的不同“菌株”的假设。在此，我们通过脑内接种过表达人类野生型 αSyn 或具有家族性 A53T 突变的人类 αSyn 的转基因小鼠，直接比较了来自这些疾病的人脑裂解物以及重组预制人类 αSyn 原纤维的接种能力和结果。我们的研究表明，起始接种物在很大程度上决定了疾病的表型和病理过程。有趣的是，我们还在传播概况之间建立了相关的宿主依赖性区别，包括包涵体病理学在整个神经轴的负担和传播，以及神经系统症状的严重程度。这些发现提供了令人信服的证据，支持不同的朊病毒型构象异构体可以解释突触核蛋白病中的变异性这一假设。