Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA.
Institute of Systems Biology, Seattle, WA 98109, USA.
Neurobiol Dis. 2018 Dec;120:98-106. doi: 10.1016/j.nbd.2018.09.005. Epub 2018 Sep 6.
Mechanisms underlying α-synuclein (αSyn) mediated neurodegeneration are poorly understood. Intramuscular (IM) injection of αSyn fibrils in human A53T transgenic M83 mice produce a rapid model of α-synucleinopathy with highly predictable onset of motor impairment. Using varying doses of αSyn seeds, we show that αSyn-induced phenotype is largely dose-independent. We utilized the synchrony of this IM model to explore the temporal sequence of αSyn pathology, neurodegeneration and neuroinflammation. Longitudinal tracking showed that while motor neuron death and αSyn pathology occur within 2 months post IM, astrogliosis appears at a later timepoint, implying neuroinflammation is a consequence, rather than a trigger, in this prionoid model of synucleinopathy. Initiating at 3 months post IM, immune activation dominates the pathologic landscape in terminal IM-seeded M83 mice, as revealed by unbiased transcriptomic analyses. Our findings provide insights into the role of neuroinflammation in αSyn mediated proteostasis and neurodegeneration, which will be key in designing potential therapies.
α-突触核蛋白（αSyn）介导的神经退行性变的机制尚不清楚。将αSyn 纤维内注射到人类 A53T 转基因 M83 小鼠中，可快速产生α-突触核蛋白病模型，其运动障碍的发作具有高度可预测性。我们使用不同剂量的 αSyn 种子，结果表明 αSyn 诱导的表型在很大程度上与剂量无关。我们利用该 IM 模型的同步性来探索 αSyn 病理学、神经退行性变和神经炎症的时间顺序。纵向跟踪显示，虽然运动神经元死亡和 αSyn 病理学发生在 IM 后 2 个月内，但星形胶质细胞增生出现在稍后的时间点，这意味着在这种类朊病毒样的突触核蛋白病模型中，神经炎症是后果而不是触发因素。正如无偏倚转录组分析所揭示的那样，从 IM 后 3 个月开始，免疫激活在终末期 IM 接种的 M83 小鼠中主导病理景观。我们的研究结果为神经炎症在 αSyn 介导的蛋白质稳态和神经退行性变中的作用提供了新的见解，这将是设计潜在治疗方法的关键。
