Rutherford Nicola J, Brooks Mieu, Riffe Cara J, Gorion Kimberly-Marie M, Howard Jasie K, Dhillon Jess-Karan S, Giasson Benoit I
Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA; 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; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Neurosci Lett. 2017 Nov 20;661:114-120. doi: 10.1016/j.neulet.2017.09.054. Epub 2017 Sep 28.
Neurofilaments are a major component of the axonal cytoskeleton in neurons and have been implicated in a number of neurodegenerative diseases due to their presence within characteristic pathological inclusions. Their contributions to these diseases are not yet fully understood, but previous studies investigated the effects of ablating the obligate subunit of neurofilaments, low molecular mass neurofilament subunit (NFL), on disease phenotypes in transgenic mouse models of Alzheimer's disease and tauopathy. Here, we tested the effects of ablating NFL in α-synuclein M83 transgenic mice expressing the human pathogenic A53T mutation, by breeding them onto an NFL null background. The induction and spread of α-synuclein inclusion pathology was triggered by the injection of preformed α-synuclein fibrils into the gastrocnemius muscle or hippocampus in M83 versus M83/NFL null mice. We observed no difference in the post-injection time to motor-impairment and paralysis endpoint or amount and distribution of α-synuclein inclusion pathology in the muscle injected M83 and M83/NFL null mice. Hippocampal injected M83/NFL null mice displayed subtle region-specific differences in the amount of α-synuclein inclusions however, pathology was observed in the same regions as the M83 mice. Overall, we observed only minor differences in the induction and transmission of α-synuclein pathology in these induced models of synucleinopathy in the presence or absence of NFL. This suggests that NFL and neurofilaments do not play a major role in influencing the induction and transmission of α-synuclein aggregation.
神经丝是神经元轴突细胞骨架的主要组成部分，由于其存在于特征性病理包涵体中，已被认为与多种神经退行性疾病有关。它们对这些疾病的作用尚未完全了解，但先前的研究调查了去除神经丝的必需亚基，即低分子量神经丝亚基（NFL），对阿尔茨海默病和tau蛋白病转基因小鼠模型疾病表型的影响。在此，我们通过将表达人类致病性A53T突变的α-突触核蛋白M83转基因小鼠与NFL基因敲除背景小鼠杂交，测试了去除NFL对α-突触核蛋白M83转基因小鼠的影响。在M83小鼠与M83/NFL基因敲除小鼠中，通过向腓肠肌或海马体注射预先形成的α-突触核蛋白纤维来触发α-突触核蛋白包涵体病理的诱导和扩散。我们观察到，在注射后出现运动障碍和瘫痪终点的时间、以及在注射肌肉的M83和M83/NFL基因敲除小鼠中α-突触核蛋白包涵体病理的数量和分布方面，没有差异。然而，海马体注射的M83/NFL基因敲除小鼠在α-突触核蛋白包涵体数量上表现出细微的区域特异性差异，不过，在与M83小鼠相同的区域观察到了病理变化。总体而言，在这些α-突触核蛋白病诱导模型中，无论有无NFL，我们仅观察到α-突触核蛋白病理诱导和传播方面的微小差异。这表明NFL和神经丝在影响α-突触核蛋白聚集的诱导和传播方面不发挥主要作用。
