Integrated analysis of transcriptomic and proteomic alterations in mouse models of ALS/FTD identify early metabolic adaptions with similarities to mitochondrial dysfunction disorders

Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD. By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage. In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology. Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.

散发性及家族性肌萎缩侧索硬化症（amyotrophic lateral sclerosis, ALS）是一种致命的进行性神经退行性疾病，可导致运动神经元丢失，且在部分患者中与额颞叶痴呆（frontotemporal dementia, FTD）相关。除蛋白质沉积物蓄积外，新兴研究表明线粒体生物能量学异常可能参与ALS/FTD的发生与进展过程。本研究旨在探究与ALS/FTD相关的线粒体功能障碍的病理生理学特征谱。本研究借助无标记质谱（label-free mass spectrometry, MS）与mRNA测序（mRNA sequencing, mRNA-seq）技术，报道了TDP-43与FUS突变小鼠模型皮层的症状前变化。以线粒体疾病转基因小鼠模型的组织作为参照，本研究开展了比较分析，筛选出了独特且共有的线粒体特征谱，这些特征谱揭示了机体针对早期损伤的神经保护性代偿机制。在此方面，症状前ALS/FTD组织中最具代表性的变化为酰基辅酶A合成酶长链家族成员3（Acyl-CoA Synthetase Long-Chain Family Member 3, ACSL3）与线粒体酪氨酰-tRNA合成酶2（mitochondrial tyrosyl-tRNA synthetase 2, YARS2）的表达上调，这提示脂肪酸β氧化与线粒体蛋白质翻译是机体应对ALS/FTD病理状态的适应性机制。综上，本研究通过无偏倚整合分析，揭示了可能在ALS最早期阶段影响线粒体稳态的新型分子组分。