Snow Magge, Cameron BreAnna, Pond Renzie, Trudell Rachel, Snyder Sara, Torres-Hernandez Lauryn, Deschamps Devyn, Tulimaiau Danara, Hawkinson Kiana, Russell Morgan, Horan Danielle, Walters Joseph, Fox James H, Arlian Britni, Chariot Alain, Nguyen Laurent, George Lynn
Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA.
College of Veterinary Medicine, Washington State University, Pullman, WA, USA.
Commun Biol. 2025 Aug 21;8(1):1259. doi: 10.1038/s42003-025-08701-9.
Dysfunction of Elongator is associated with amyotrophic lateral sclerosis (ALS). Here, we describe mouse models in which either Elongator subunit 1(Elp1) or subunit 3 (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 these mice, we examine multiple disease pathways, including the expression of TDP-43 whose cytoplasmic aggregation is associated with the human disease. Although TDP-43 is a well-characterized nuclear protein functioning in RNA metabolism and gene transcription, here 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 dysfunction of Elongator with nucleolar disruption and TDP-43 clearing, two hallmark cellular pathologies of ALS.
延伸因子功能障碍与肌萎缩侧索硬化症（ALS）相关。在此，我们描述了脊髓α运动神经元中延伸因子亚基1（Elp1）或亚基3（Elp3）被选择性敲除的小鼠模型。这些小鼠表现出运动强度的逐渐丧失和运动神经元变性。为了探究导致这些小鼠运动神经元细胞死亡的分子机制，我们研究了多种疾病途径，包括TDP-43的表达，其在细胞质中的聚集与人类疾病相关。尽管TDP-43是一种在RNA代谢和基因转录中发挥作用的特征明确的核蛋白，但在此我们记录了TDP-43在野生型运动神经元核仁中的大量存在以及其在Elp条件性敲除小鼠运动神经元的细胞核和核仁中的清除。因此，本研究直接将延伸因子功能障碍与核仁破坏和TDP-43清除联系起来，这是ALS的两种标志性细胞病理学特征。
