选择性易损运动神经元亚型的多组学分析提示 ALS 中脂质代谢改变。
Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS.
机构信息
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
出版信息
Nat Neurosci. 2021 Dec;24(12):1673-1685. doi: 10.1038/s41593-021-00944-z. Epub 2021 Nov 15.
Amyotrophic lateral sclerosis (ALS) is a devastating disorder in which motor neurons degenerate, the causes of which remain unclear. In particular, the basis for selective vulnerability of spinal motor neurons (sMNs) and resistance of ocular motor neurons to degeneration in ALS has yet to be elucidated. Here, we applied comparative multi-omics analysis of human induced pluripotent stem cell-derived sMNs and ocular motor neurons to identify shared metabolic perturbations in inherited and sporadic ALS sMNs, revealing dysregulation in lipid metabolism and its related genes. Targeted metabolomics studies confirmed such findings in sMNs of 17 ALS (SOD1, C9ORF72, TDP43 (TARDBP) and sporadic) human induced pluripotent stem cell lines, identifying elevated levels of arachidonic acid. Pharmacological reduction of arachidonic acid levels was sufficient to reverse ALS-related phenotypes in both human sMNs and in vivo in Drosophila and SOD1 mouse models. Collectively, these findings pinpoint a catalytic step of lipid metabolism as a potential therapeutic target for ALS.
肌萎缩侧索硬化症（ALS）是一种破坏性疾病，其中运动神经元退化，其原因仍不清楚。特别是，ALS 中脊髓运动神经元（sMNs）的选择性易损性和眼动神经元对退化的抗性的基础尚未阐明。在这里，我们应用人类诱导多能干细胞衍生的 sMNs 和眼动神经元的比较多组学分析，来确定遗传性和散发性 ALS sMNs 中共同的代谢扰动，揭示脂质代谢及其相关基因的失调。靶向代谢组学研究在 17 个人类诱导多能干细胞系（SOD1、C9ORF72、TDP43（TARDBP）和散发性）的 sMNs 中证实了这些发现，发现花生四烯酸水平升高。花生四烯酸水平的药理学降低足以在人类 sMNs 以及果蝇和 SOD1 小鼠模型中逆转与 ALS 相关的表型。总的来说，这些发现指出脂质代谢的催化步骤是 ALS 的一个潜在治疗靶点。
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