Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA
Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.
J Virol. 2018 Aug 29;92(18). doi: 10.1128/JVI.00586-18. Print 2018 Sep 15.
Misfolded alpha-synuclein (αS) may exhibit a number of characteristics similar to those of the prion protein, including the apparent ability to spread along neuroanatomical connections. The demonstration for this mechanism of spread is largely based on the intracerebral injections of preaggregated αS seeds in mice, in which it cannot be excluded that diffuse, surgical perturbations and hematogenous spread also contribute to the propagation of pathology. For this reason, we have utilized the sciatic nerve as a route of injection to force the inoculum into the lumbar spinal cord and induce a localized site for the onset of αS inclusion pathology. Our results demonstrate that mouse αS fibrils (fibs) injected unilaterally in the sciatic nerve are efficient in inducing pathology and the onset of paralytic symptoms in both the M83 and M20 lines of αS transgenic mice. In addition, a spatiotemporal study of these injections revealed a predictable spread of pathology to brain regions whose axons synapse directly on ventral motor neurons in the spinal cord, strongly supporting axonal transport as a mechanism of spread of the αS inducing, or seeding, factor. We also revealed a relatively decreased efficiency for human αS fibs containing the E46K mutation to induce disease via this injection paradigm, supportive of recent studies demonstrating a diminished ability of this mutant αS to undergo aggregate induction. These results further demonstrate prion-like properties for αS by the ability for a progression and spread of αS inclusion pathology along neuroanatomical connections. The accumulation of alpha-synuclein (αS) inclusions is a hallmark feature of Parkinson's disease (PD) and PD-related diseases. Recently, a number of studies have demonstrated similarities between the prion protein and αS, including its ability to spread along neuroanatomical tracts throughout the central nervous system (CNS). However, there are caveats in each of these studies in which the injection routes used had the potential to result in a widespread dissemination of the αS-containing inocula, making it difficult to precisely define the mechanisms of spread. In this study, we assessed the spread of pathology following a localized induction of αS inclusions in the lumbar spinal cord following a unilateral injection in the sciatic nerve. Using this paradigm, we demonstrated the ability for αS inclusion spread and/or induction along neuroanatomical tracts within the CNS of two αS-overexpressing mouse models.
错误折叠的α-突触核蛋白（αS）可能表现出许多类似于朊病毒蛋白的特征，包括明显的沿神经解剖连接传播的能力。这种传播机制的证明在很大程度上基于在小鼠中进行的预聚集αS 种子的脑内注射，其中不能排除弥漫性、手术干扰和血源性传播也有助于病理学的传播。出于这个原因，我们利用坐骨神经作为注射途径，将接种物强行注入腰椎脊髓，以诱导αS 包含物病理学的局部起始点。我们的结果表明，单侧注射到坐骨神经中的小鼠αS 原纤维（fibs）能够有效地诱导 M83 和 M20 两条αS 转基因小鼠的病理学和瘫痪症状的发生。此外，对这些注射的时空研究表明，病理学向大脑区域的可预测传播，这些大脑区域的轴突直接与脊髓中的腹运动神经元突触，强烈支持轴突运输作为αS 诱导或播种因子传播的机制。我们还发现，含有 E46K 突变的人αS fibs 通过这种注射范式诱导疾病的效率相对较低，这支持了最近的研究表明这种突变αS 进行聚集诱导的能力降低。这些结果通过αS 包含物病理学沿神经解剖连接的进展和传播的能力进一步证明了αS 的类朊病毒特性。α-突触核蛋白（αS）的积累是帕金森病（PD）和 PD 相关疾病的一个标志特征。最近，许多研究表明朊病毒蛋白和αS 之间存在相似性，包括其在整个中枢神经系统（CNS）中沿神经解剖途径传播的能力。然而，这些研究中的每一项都存在一些限制，其中使用的注射途径有可能导致含有αS 的接种物广泛传播，从而难以精确定义传播机制。在这项研究中，我们评估了在坐骨神经单侧注射后，在腰椎脊髓中局部诱导αS 包含物后，病理学的传播情况。使用这种范式，我们在两种αS 过表达小鼠模型的中枢神经系统内，证明了αS 包含物的传播和/或诱导能力沿着神经解剖途径。
