한빛사 논문
Hojae Lee1,2,3, Jae Jin Lee 4, Na Young Park5,6, Sandeep Kumar Dubey2,7, Taeyong Kim 8, Kai Ruan2, Su Bin Lim9, Seong-Hyun Park1,2, Shinwon Ha1,2, Irina Kovlyagina1,12, Kyung-tai Kim10,13, Seongjun Kim1, Yohan Oh 1,14, Hyesoo Kim1,2, Sung-Ung Kang1,2, Mi-Ryoung Song10, Thomas E. Lloyd2,7,11, Nicholas J. Maragakis 2, Young Bin Hong 5,6,*, Hyungjin Eoh4,* and Gabsang Lee1,2,3,7,*
1Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 3The Robert Packard Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 4Department of Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA, USA. 5Department of Biochemistry, College of Medicine, Dong-A University, Busan, Korea. 6Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, Korea. 7The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 8Department of Biology, San Diego State University, San Diego, CA, USA. 9Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea. 10School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. 11Cellular and Molecular Medicine Program, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. 12Present address: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 13Present address: Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeongeup, Republic of Korea. 14Present address: Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
*Correspondence to Young Bin Hong, Hyungjin Eoh or Gabsang Lee.
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.
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