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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1673-1685
Number of pages13
JournalNature neuroscience
Volume24
Issue number12
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • General Neuroscience

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