To test the hypothesis that the cerebrospinal fluid (CSF) could provide a spreading route for pathogenesis of amyotrophic lateral sclerosis (ALS), we have examined the effects of intraventricular infusion during 2 weeks of pooled CSF samples from sporadic ALS patients or control CSF samples into transgenic mice expressing human TDP43WT which do not develop pathological phenotypes. Infusion of ALS-CSF, but not of control CSF, triggered motor and cognitive dysfunction, as well as ALS-like pathological changes including TDP43 proteinopathy, neurofilament disorganization and neuroinflammation. In addition, the neuron-specific translational profiles from peptide analyses of immunoprecipitated ribosomes revealed dysregulation of multiple protein networks in response to ALS-CSF altering cytoskeletal organization, vesicle trafficking, mitochondrial function, and cell metabolism. With normal mice, similar ALS-CSF infusion induced mild motor dysfunction but without significant TDP43 pathology in spinal neurons. We conclude that the CSF from sporadic ALS contains factors that can transmit and disseminate disease including TDP43 proteinopathy into appropriate recipient animal model expressing human TDP43. These findings open new research avenues for the discovery of etiogenic factors for sporadic ALS and for the testing of drugs aiming to neutralize the ALS-CSF toxicity.

中文翻译：

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脑脊髓液传播ALS发病机理。

为了检验假说脑脊髓液（CSF）可以为肌萎缩性侧索硬化（ALS）的发病机理提供传播途径的假设，我们检查了从散发性ALS患者或对照CSF样品中混合入CSF样品2周内脑室内输注的影响表达人类TDP43WT的转基因小鼠，其不会出现病理表型。输注ALS-CSF而不输注对照CSF会引发运动和认知功能障碍，以及类似ALS的病理变化，包括TDP43蛋白病，神经丝紊乱和神经炎症。此外，免疫沉淀核糖体肽段分析得出的神经元特异性翻译谱显示，响应ALS-CSF改变细胞骨架组织，囊泡运输，线粒体功能和细胞代谢。对于正常小鼠，类似的ALS-CSF输注可引起轻度运动功能障碍，但脊髓神经元无明显的TDP43病理。我们得出结论，来自散发性ALS的CSF包含可以将包括TDP43蛋白病在内的疾病传播和传播到表达人TDP43的适当受体动物模型中的因子。这些发现为发现散发性ALS的病因和为中和ALS-CSF毒性的药物测试开辟了新的研究途径。我们得出结论，来自散发性ALS的CSF包含可以将包括TDP43蛋白病在内的疾病传播和传播到表达人TDP43的适当受体动物模型中的因子。这些发现为发现散发性ALS的病因和为中和ALS-CSF毒性的药物测试开辟了新的研究途径。我们得出结论，来自散发性ALS的CSF包含可以将包括TDP43蛋白病在内的疾病传播和传播到表达人TDP43的适当受体动物模型中的因子。这些发现为发现散发性ALS的病因和为中和ALS-CSF毒性的药物测试开辟了新的研究途径。