Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
Acta Neuropathol. 2022 Jun;143(6):663-685. doi: 10.1007/s00401-022-02425-4. Epub 2022 Apr 30.
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）是一种无规则结构的蛋白质，可发生结构转变，形成稳定、不溶性的纤维。αSyn 淀粉样纤维的成核可被错误折叠的“种子”诱导，这些“种子”充当构象模板，类似于朊病毒样机制。Lewy 体痴呆（DLB）和多系统萎缩（MSA）的关键特征是αSyn 包涵体的积累，并且在阿尔茨海默病（AD）中如具有杏仁核优势Lewy 体的 AD（AD/ALB）中也发现了额外的病理学。尽管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存在异质性；然而，这种变异性背后的机制仍然难以捉摸。来自人体尸检研究、动物接种模型和体外特征实验的累积数据为以下假设提供了可信度，即 αSyn 淀粉样纤维结构的构象多态性导致具有分类感染特征的不同“菌株”。在此，我们直接比较了这些疾病的人脑匀浆、以及通过转染过表达人野生型 αSyn 或具有家族性 A53T 突变的人 αSyn 的转基因小鼠脑内接种的重组预形成人 αSyn 纤维的接种能力和结果。我们的研究表明，起始接种物严重决定了疾病的表型和病理过程。有趣的是，我们还在传播模式方面建立了相关的宿主依赖性差异，包括神经轴内包涵体病理学的负担和传播以及神经症状的严重程度。这些发现为多样性朊病毒样构象可能解释突触核蛋白病中所见的变异性的假设提供了有力证据。
