Localized Induction of Wild-Type and Mutant Alpha-Synuclein Aggregation Reveals Propagation along Neuroanatomical Tracts
Localized Induction of Wild-Type and Mutant Alpha-Synuclein Aggregation Reveals Propagation along Neuroanatomical Tracts
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DOI：
10.1128/jvi.00586-18
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发表时间：
2018-09-01
影响因子：
5.4
通讯作者：
Giasson, Benoit I.
中科院分区：
文献类型：
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作者：
Ayers, Jacob I.;Riffe, Cara J.;Giasson, Benoit I.
错误折叠的α-突触核蛋白(α-S)可能会表现出许多类似于普恩蛋白的特征，包括明显的沿着神经解剖连接传播的能力。对这一传播机制的论证很大程度上是基于小鼠脑内注射预聚集的α-S种子，其中不能排除弥漫、手术扰动和血源性传播也有助于病理的传播。为此，我们利用坐骨神经作为注射途径，迫使接种物进入腰髓，并诱导出一个局部的α-S包涵体病理。我们的结果表明，单侧向坐骨神经注射小鼠α-S纤维(FIB)能有效地诱导M83和M20转基因小鼠的病理和麻痹症状的出现。此外，对这些注射的时空研究揭示了可预见的病理扩散到脑区，其轴突直接与脊髓腹侧运动神经元突触，强烈支持轴突运输是α-S诱导或播种因子扩散的机制。我们还发现，含有E46K突变的人αS纤维通过这种注射范例诱发疾病的效率相对降低，这支持了最近的研究，该研究表明这种突变的αS经历聚集诱导的能力减弱。这些结果进一步证明了α-S具有类病毒的性质，即α-S包涵体病理能够沿着神经解剖连接进展和扩散。提示α-突触核蛋白(α-S)包涵体的堆积是帕金森病(PD)和帕金森病相关疾病的一个显著特征。最近，许多研究已经证明了普恩蛋白和阿尔法S之间的相似之处，包括它沿着中枢神经系统(CNS)的神经解剖束传播的能力。然而，这些研究中的每一项研究都有警告，在这些研究中，所使用的注射途径有可能导致含有α-S的接种疫苗的广泛传播，使得准确定义传播机制变得困难。在这项研究中，我们评估了在单侧坐骨神经注射后，腰椎脊髓局部诱导α-S包涵体后的病理扩散。使用这一范式，我们展示了在两个α-S过度表达的小鼠模型中，α-S包涵体沿着神经解剖束传播和/或诱导的能力。
Misfolded alpha-synuclein (alpha S) 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 alpha S 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 alpha S inclusion pathology. Our results demonstrate that mouse alpha S 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 alpha S 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 alpha S inducing, or seeding, factor. We also revealed a relatively decreased efficiency for human alpha S fibs containing the E46K mutation to induce disease via this injection paradigm, supportive of recent studies demonstrating a diminished ability of this mutant alpha S to undergo aggregate induction. These results further demonstrate prion-like properties for alpha S by the ability for a progression and spread of alpha S inclusion pathology along neuroanatomical connections.IMPORTANCE The accumulation of alpha-synuclein (alpha S) 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 alpha S, 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 alpha S-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 alpha S inclusions in the lumbar spinal cord following a unilateral injection in the sciatic nerve. Using this paradigm, we demonstrated the ability for alpha S inclusion spread and/or induction along neuroanatomical tracts within the CNS of two alpha S-overexpressing mouse models.