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

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Title: Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS.
Authors: Lee, Hojae (AUTHOR), Lee, Jae Jin (AUTHOR), Park, Na Young (AUTHOR), Dubey, Sandeep Kumar (AUTHOR), Kim, Taeyong (AUTHOR), Ruan, Kai (AUTHOR), Lim, Su Bin (AUTHOR), Park, Seong-Hyun (AUTHOR), Ha, Shinwon (AUTHOR), Kovlyagina, Irina (AUTHOR), Kim, Kyung-tai (AUTHOR), Kim, Seongjun (AUTHOR), Oh, Yohan (AUTHOR), Kim, Hyesoo (AUTHOR), Kang, Sung-Ung (AUTHOR), Song, Mi-Ryoung (AUTHOR), Lloyd, Thomas E. (AUTHOR), Maragakis, Nicholas J. (AUTHOR), Hong, Young Bin (AUTHOR), Eoh, Hyungjin (AUTHOR)
Source: Nature Neuroscience. Dec2021, Vol. 24 Issue 12, p1673-1685. 13p.
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. [ABSTRACT FROM AUTHOR]
Copyright of Nature Neuroscience is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS.
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  Data: 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Nature Neuroscience is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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