An Elongator mouse model of ALS spotlights TDP-43 in the motor neuron nucleolus

Dysfunction of the Elongator complex is associated with amyotrophic lateral sclerosis (ALS). To investigate the potential mechanisms via which Elongator contributes to ALS, we generated conditional knockout mouse models in which either Elp1 or Elp3 is selectively ablated in cholinergic neurons including alpha motor neurons of the spinal cord. These mice exhibit numerous ALS phenotypes including a progressive loss of motor strength, motor neuron degeneration, and denervation of the neuromuscular junction. To interrogate the molecular mechanisms that contribute to motor neuron cell death in this model, we examined multiple disease pathways including the expression of TDP-43, a protein whose mislocalization and aggregation are associated with both familial and sporadic forms of ALS. Surprisingly, we see robust expression of TDP-43 in the nucleolus of motor neurons from control mice and clearing of TDP-43 from nucleoli in the conditional knockout. Further analysis of the nucleolar mark..., Mice
All experiments with animals were performed according to the National Institutes of Health Guide for Care and Use of Laboratory Animals and were approved by the Montana State University Institutional Animal Care and Use Committee.  Additionally, all experiments involving live mice were conducted according to ARRIVE guidelines 2.0 where applicable.   Sample sizes were based on pilot studies and sample sizes were calculated using a statistical power of 80%.  Ikbkaptm1a(KOMP)Wtsi− ‘knockout first’ mice containing a frt-flanked LacZ Elp1 (previously known as Ikbkap) reporter that disrupts Elp1 expression before the LoxP flanked 4th exon were obtained from the International Knockout Mouse Consortium.  This strain was generated on a C57Bl/6j background and has been previously described 26. Elp1 CKO mice (Chat-Cre; Elp1LoxP/LoxP) were generated by crosses between Chat-Cre; Elp1+/LoxP X Elp1LoxP/LoxP; Chat-GFP/GFP mice.  A humane endpoint for Elp1 CKO males wa..., , # Data from: An Elongator mouse model of ALS spotlights TDP-43 in the motor neuron nucleolus

Dataset DOI: [10.5061/dryad.x0k6djhvb](10.5061/dryad.x0k6djhvb)

## Description of the data and file structure

Dysfunction of Elongator is associated with amyotrophic lateral sclerosis (ALS).  To investigate this relationship, we generated mouse models in which *Elp1* or* Elp3* is selectively ablated in alpha motor neurons of the spinal cord. These mice exhibit a progressive loss of motor strength and motor neuron degeneration. To interrogate the molecular mechanisms that contribute to motor neuron cell death in this model, we examined multiple disease pathways including the expression of TDP-43 whose aggregation is associated with the human disease.  Importantly, we document TDP-43’s robust presence in the nucleolus of wild-type motor neurons and its clearance from both the nucleus and the nucleolus of motor neurons in *Elp* conditional knockout mice.  Thus, this study directly links dysfunct...,

延伸体复合物（Elongator complex）功能异常与肌萎缩侧索硬化症（amyotrophic lateral sclerosis, ALS）密切相关。为探究延伸体参与ALS发病的潜在机制，我们构建了条件性基因敲除小鼠模型，在包括脊髓α运动神经元在内的胆碱能神经元中选择性敲除Elp1或Elp3基因。此类小鼠呈现出多种ALS相关表型，包括运动能力进行性减退、运动神经元变性以及神经肌肉接头去神经支配。为解析该模型中运动神经元死亡的分子机制，我们检测了多条疾病相关通路，其中包括TDP-43（Transactive response DNA-binding protein 43）的表达情况——该蛋白的异常定位与聚集与家族性和散发性ALS均存在关联。令人意外的是，我们在对照组小鼠的运动神经元核仁中检测到了TDP-43的高表达，而在条件性敲除小鼠的核仁中，TDP-43则出现了清除现象。后续针对核仁标记物的分析……[原文截断：nucleolar mark..., Mice]

所有动物实验均遵循美国国立卫生研究院《实验动物护理与使用指南》开展，并经蒙大拿州立大学实验动物护理与使用委员会批准。此外，所有涉及活小鼠的实验均符合ARRIVE指南2.0的相关要求。样本量基于预实验结果确定，并以80%的统计效力进行计算。来自国际基因敲除小鼠联盟的Ikbkaptm1a(KOMP)Wtsi"先敲除"小鼠，其携带了frt位点侧翼的LacZ-Elp1（此前被称为Ikbkap）报告基因，该基因在LoxP位点侧翼的第4外显子之前即可破坏Elp1的表达。该品系构建于C57Bl/6J背景之上，此前已有相关文献报道26。Elp1条件性敲除小鼠（Chat-Cre; Elp1LoxP/LoxP）通过将Chat-Cre; Elp1+/LoxP与Elp1LoxP/LoxP; Chat-GFP/GFP小鼠杂交获得。Elp1条件性敲除雄性小鼠的人道终点……[原文截断]

# 数据来自：基于延伸体的ALS小鼠模型揭示运动神经元核仁中的TDP-43

数据集DOI：10.5061/dryad.x0k6djhvb

## 数据与文件结构描述

延伸体功能异常与肌萎缩侧索硬化症（ALS）相关。为探究二者的关联，我们构建了在脊髓α运动神经元中选择性敲除Elp1或Elp3基因的小鼠模型。此类小鼠表现为运动能力进行性丧失以及运动神经元变性。为解析该模型中运动神经元细胞死亡的分子机制，我们检测了多条疾病相关通路，包括与人类疾病发病相关的TDP-43聚集情况。值得注意的是，我们证实了野生型小鼠运动神经元核仁中存在丰富的TDP-43，而在Elp条件性敲除小鼠的运动神经元细胞核及核仁中，TDP-43均被清除。因此，本研究直接将功能异常……[原文截断]