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 Eoh; Gabsang Lee

doi:10.1038/s41593-021-00944-z

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

Nat Neurosci. 2021 Dec;24(12):1673-1685. doi: 10.1038/s41593-021-00944-z. Epub 2021 Nov 15.

Authors

Hojae Lee^{1

2

3}, Jae Jin Lee⁴, Na Young Park^{5

6}, Sandeep Kumar Dubey^{2

7}, Taeyong Kim⁸, Kai Ruan², Su Bin Lim⁹, Seong-Hyun Park^{1

2}, Shinwon Ha^{1

2}, Irina Kovlyagina^{1

10}, Kyung-Tai Kim^{11

12}, Seongjun Kim¹, Yohan Oh^{1

13}, Hyesoo Kim^{1

2}, Sung-Ung Kang^{1

2}, Mi-Ryoung Song¹¹, Thomas E Lloyd^{2

7

14}, Nicholas J Maragakis², Young Bin Hong^{15

16}, Hyungjin Eoh¹⁷, Gabsang Lee^{18

19

20

21}

Affiliations

¹ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ The Robert Packard Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Biochemistry, College of Medicine, Dong-A University, Busan, Korea.
⁶ Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, Korea.
⁷ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Department of Biology, San Diego State University, San Diego, CA, USA.
⁹ Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea.
¹⁰ Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
¹¹ School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
¹² Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeongeup, Republic of Korea.
¹³ Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
¹⁴ Cellular and Molecular Medicine Program, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁵ Department of Biochemistry, College of Medicine, Dong-A University, Busan, Korea. ybhong@dau.ac.kr.
¹⁶ Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan, Korea. ybhong@dau.ac.kr.
¹⁷ Department of Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA, USA. heoh@usc.edu.
¹⁸ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. glee48@jhmi.edu.
¹⁹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. glee48@jhmi.edu.
²⁰ The Robert Packard Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. glee48@jhmi.edu.
²¹ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. glee48@jhmi.edu.

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 SOD1^G93A mouse models. Collectively, these findings pinpoint a catalytic step of lipid metabolism as a potential therapeutic target for ALS.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Animals
Disease Models, Animal
Humans
Induced Pluripotent Stem Cells* / metabolism
Lipid Metabolism / genetics
Mice
Mice, Transgenic
Motor Neurons / physiology
Superoxide Dismutase / genetics
Superoxide Dismutase / metabolism
Superoxide Dismutase-1 / genetics

Substances

Superoxide Dismutase
Superoxide Dismutase-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding