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ResearchIn-Press PreviewMetabolismNeuroscience Open Access | 10.1172/jci.insight.198842

Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis

Daisuke Ito,1 Madoka Iida,1 Yohei Iguchi,1 Atsushi Hashizume,2 Shinichiro Yamada,1 Yoshiyuki Kishimoto,1 Shota Komori,1 Kazuki Obara,1 Shuto Nishisaki,3 Satoshi Yokoi,3 Teppei Shimamura,4 Yuto Takemoto,5 Masahiro Nakatochi,5 Tomohiro Akashi,4 Kunihiko Hinohara,6 Hyeon-Cheol Lee-Okada,7 Yohei Okada,8 Junichi Niwa,9 Gen Sobue,9 Shinji Tanaka,10 Ken Takashina,10 Takehiko Yokomizo,7 and Masahisa Katsuno1

1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

Find articles by Ito, D. in: PubMed | Google Scholar

1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

3Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

4Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

5Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

6Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

7Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

8Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

9Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Japan

10Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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Published June 11, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.198842.
Copyright © 2026, Ito et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 11, 2026 - Version history
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Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the selective loss of upper and lower motor neurons. There is a considerable variability in the disease progression of sporadic ALS, but the molecular basis for phenotypic heterogeneity remains largely unknown. ALS patients often manifest systemic metabolic abnormalities such as glucose intolerance and hypermetabolic state. We conducted reverse translational research to explore therapeutic targets in ALS based on the systemic metabolic alterations in patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NATs) were correlated with the longitudinal change in the revised ALS functional rating scale and survival. Experiments with ALS cellular models, iPS cells derived from ALS patients and SOD1G93A transgenic mice revealed that PF-04457845, a fatty acid amide hydrolase inhibitor, upregulated the expanded ECS, particularly the levels of NATs and ameliorated motor neuron degeneration through the regulation of microglial environment, synapse plasticity, and neuronal development. These results collectively indicate that dysregulation of NATs is associated with ALS progression and PF-04457845 may represent a potential disease-modifying therapy for ALS.

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