小柯机器人

近日，美国约翰霍普金斯大学Gabsang Lee等研究人员合作揭示ALS中脂质代谢的改变。相关论文于2021年11月15日在线发表在《自然—神经科学》杂志上。

研究人员利用人类诱导多能干细胞衍生的脊髓运动神经元（sMN）和眼部运动神经元的比较多组学分析，来确定了遗传性和散发性肌萎缩性脊髓侧索硬化症（ALS）sMNs的共同代谢紊乱，从而揭示了脂质代谢及其相关基因的失调。靶向代谢组学研究证实了17个ALS（SOD1、C9ORF72、TDP43（TARDBP）和散发的）人类诱导多能干细胞系sMN中的这种发现，并确定了花生四烯酸水平的升高。通过药物降低花生四烯酸水平足以逆转人类sMN和果蝇及SOD1^G93A小鼠模型中与ALS相关的表型。总的来说，这些发现将脂质代谢的一个催化步骤确定为ALS的潜在治疗靶标。

据介绍，ALS是一种毁灭性的疾病，其中运动神经元变性，原因仍不清楚。特别是，ALS中sMN的选择性脆弱和眼部运动神经元对退化的抵抗力的基础还没有被阐明。

附：英文原文

Title: Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS

Author: Lee, Hojae, Lee, Jae Jin, Park, Na Young, Dubey, Sandeep Kumar, Kim, Taeyong, Ruan, Kai, Lim, Su Bin, Park, Seong-Hyun, Ha, Shinwon, Kovlyagina, Irina, Kim, Kyung-tai, Kim, Seongjun, Oh, Yohan, Kim, Hyesoo, Kang, Sung-Ung, Song, Mi-Ryoung, Lloyd, Thomas E., Maragakis, Nicholas J., Hong, Young Bin, Eoh, Hyungjin, Lee, Gabsang

Issue&Volume: 2021-11-15

Abstract: 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 SOD1G93A mouse models. Collectively, these findings pinpoint a catalytic step of lipid metabolism as a potential therapeutic target for ALS. By comparing human induced pluripotent stem cell-derived spinal and ocular motor neurons, the authors identify low levels of a natural 5-lipoxygenase inhibitor in amyotrophic lateral sclerosis (ALS) spinal motor neurons. Functional analogs of 5-lipoxygenase inhibitors can ameliorate in vitro and in vivo ALS phenotypes.

DOI: 10.1038/s41593-021-00944-z

Source: https://www.nature.com/articles/s41593-021-00944-z

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex