■散发性和家族性肌萎缩性侧索硬化症(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,在一些患者中,与额颞叶痴呆(FTD)相关。除了蛋白质沉积物的积累,新出现的文献表明,异常的线粒体生物能学可能有助于ALS/FTD的发生和发展。在这里,我们试图研究与ALS/FTD相关的线粒体功能障碍的病理生理特征。
■通过无标记质谱(MS)和mRNA测序(mRNA-seq),我们报道了TDP-43和FUS突变小鼠模型皮层的症状前变化.使用线粒体疾病转基因小鼠模型的组织作为参考,我们进行了比较分析,并提取了独特和常见的线粒体特征,这些特征揭示了响应早期损伤的神经保护性代偿机制.
■在这方面,酰基辅酶A合成酶长链家族成员3(ACSL3)和线粒体酪氨酰tRNA合成酶2(YARS2)的上调是症状前ALS/FTD组织中最具代表性的变化,提示脂肪酸β-氧化和线粒体蛋白翻译是响应ALS/FTD病理的适应机制。
■一起,我们的无偏整合分析揭示了在ALS早期阶段可能影响线粒体稳态的新型分子组分.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.