Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS
Summary
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. © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
| Authors | Lee H, Lee JJ, Park NY, Dubey SK, Kim T, Ruan K, Lim SB, Park SH, Ha S, Kovlyagina I, Kim KT, Kim S, Oh Y, Kim H, Kang SU, Song MR, Lloyd TE, Maragakis NJ, Hong YB, Eoh H, Lee G |
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| Journal | Nature neuroscience |
| Publication Date | 2021 Dec;24(12):1673-1685 |
| PubMed | 34782793 |
| PubMed Central | PMC8639773 |
| DOI | 10.1038/s41593-021-00944-z |