Stansberry Wesley M, Fiur Natalie C, Robins Melissa M, Pierchala Brian A
Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, United States.
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States.
Front Neurol. 2024 Nov 19;15:1491415. doi: 10.3389/fneur.2024.1491415. eCollection 2024.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressively worsening motor symptoms that lead to eventual fatal paralysis. The number of gene mutations associated with ALS have increased dramatically in recent years, suggesting heterogeneity in the etiology of ALS and the need to develop new models of the disease that encompass these pathologies. In 2011, mutations in the gene were identified in families with both ALS and frontotemporal dementia (FTD) and have since been linked to ubiquitinated TDP43 inclusion pathology. The involvement of in ubiquitination and proteasome function suggests an important role in proteostasis, which is reported to be impaired in ALS.
A mouse model was generated for the P497S mutation and recapitulates some of the motor symptoms of ALS. We utilized ribosomal profiling followed by mRNA sequencing of associated transcripts to characterize gene expression changes of motor neurons in the model and evaluated ALS phenotypes in these animals.
At 12 months of age, we observed reduced motor neuron survival and neuromuscular junction denervation in these mice that translated into motor deficits observed in locomotor behavioral trials. The sequencing of motor neuron transcripts revealed that Wnt pathways and muscle-related transcripts were downregulated in mice, while metabolic pathways were upregulated.
Surprisingly, genes often reported to be muscle-specific, such as Desmin and Acta1, were expressed in motor neurons and were dramatically downregulated in symptomatic mice. The expression of muscle transcripts by motor neurons suggests their potentially supportive role in skeletal muscle maintenance.
肌萎缩侧索硬化症（ALS）是一种毁灭性的神经退行性疾病，其特征是运动症状逐渐恶化，最终导致致命性瘫痪。近年来，与ALS相关的基因突变数量急剧增加，这表明ALS病因存在异质性，需要开发包含这些病理情况的新疾病模型。2011年，在患有ALS和额颞叶痴呆（FTD）的家族中发现了该基因的突变，此后这些突变与泛素化TDP43包涵体病理相关联。该基因参与泛素化和蛋白酶体功能，表明其在蛋白质稳态中起重要作用，据报道ALS患者的蛋白质稳态受损。
构建了携带P497S突变的小鼠模型，该模型重现了ALS的一些运动症状。我们利用核糖体分析技术，随后对相关转录本进行mRNA测序，以表征该模型中运动神经元的基因表达变化，并评估这些动物的ALS表型。
在12个月大时，我们观察到这些小鼠的运动神经元存活率降低和神经肌肉接头去神经支配，这转化为在运动行为试验中观察到的运动缺陷。运动神经元转录本测序显示，Wnt信号通路和与肌肉相关的转录本在该小鼠中下调，而代谢通路上调。
令人惊讶的是，通常被报道为肌肉特异性的基因，如结蛋白和α-平滑肌肌动蛋白1，在运动神经元中表达，并且在出现症状的该小鼠中显著下调。运动神经元中肌肉转录本的表达表明它们在骨骼肌维持中可能具有支持作用。
