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Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis.

Overview

Authors: Daisuke Ito1,2, Madoka Iida1, Yohei Iguchi1, Atsushi Hashizume2, Shinichiro Yamada1, Yoshiyuki Kishimoto1, Shota Komori1, Kazuki Obara1, Shuto Nishisaki3, Satoshi Yokoi1,3, Teppei Shimamura4, Yuto Takemoto5, Masahiro Nakatochi5, Tomohiro Akashi4, Kunihiko Hinohara6,7, Hyeon-Cheol Lee-Okada8, Yohei Okada9, Junichi Niwa10, Gen Sobue11, Shinji Tanaka12, Ken Takashina12, Takehiko Yokomizo8, Masahisa Katsuno1
ORCID iDs: Kazuki Obara, Teppei Shimamura, Yohei Okada, Takehiko Yokomizo
  1. Department of Neurology
  2. Department of Clinical Research Education
  3. Department of Pathophysiological Laboratory Sciences
  4. Division of Systems Biology
  5. Public Health Informatics Unit, Department of Integrated Health Sciences, and
  6. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
  7. Institute for Advanced Research, Nagoya University, Nagoya, Aichi, Japan
  8. Department of Biochemistry, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
  9. Department of Neural iPSC Research Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Aichi, Japan
  10. Department of Neurology and
  11. Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
  12. Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
Institutions: Nagoya University (Japan); Juntendo University (Japan); Aichi Medical University (Japan); Tanabe Pharma Corporation (Japan) (Japan)
Journal: JCI insight, volume 11, issue 15, article e198842
Dates: received 11 August 2025; accepted 5 June 2026; published online 11 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1172/jci.insight.198842 · PMID 42275159 · PMCID PMC13463617 · OpenAlex W7164336734
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), other condition (population)
Methods: Statistics, Smoothing, state filtering, decompositions, Machine learning, Connectivity
Keywords: Metabolism, Neuroscience, ALS, Biomarkers, Drug therapy
MeSH: Amidohydrolases*, Amyotrophic Lateral Sclerosis*, Animals, Disease Models, Animal, Disease Progression, Endocannabinoids, Fatty Acid Amide Hydrolases, Female, Humans, Induced Pluripotent Stem Cells, Male, Mice, Mice, Transgenic, Motor Neurons, Superoxide Dismutase-1 (* major topic)
Topic: Amyotrophic Lateral Sclerosis Research (Neurology, Medicine), according to OpenAlex
Funding: Japan Agency for Medical Research and Development (JP24wm0625301, 22nk0101575h0002, JP21wm0425008, JP22am0401007, JP21wm0425008,JP21wm0425013,JP22nk0101575,JP22am0401007,JP23bm1423006,JP24wm0625301, JP21wm0425013); Mitsubishi Tanabe Pharma Corporation; Japan Society for the Promotion of Science (JP22am0401007, 20H00527, 21K15677, 23H00420, 23K14773, JP22nk0101575)
Citations: not cited yet (Europe PMC); 75 references in the paper

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. Patients with ALS 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 and induced pluripotent stem (iPS) cells derived from patients with ALS 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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

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Data

Datasets cited

Data availability

The metabolomics source data were deposited into Mendeley (doi:10.17632/f8gtkwfs6s.1). The snRNA-Seq and bulk RNA-Seq raw data files have been deposited into the NCBI Gene Expression Omnibus (GEO) under accession no. GSE242942 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242942) and are publicly available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242942

Values for all data points in graphs are reported in the Supporting Data Values file.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Authors: added Teppei Shimamura (0000-0003-2994-872X); Yohei Okada (0000-0001-5253-8556); Takehiko Yokomizo (0000-0002-5219-1553); removed Teppei Shimamura; Yohei Okada; Takehiko Yokomizo
  • Funding: added Japan Agency for Medical Research and Development: JP24wm0625301, 22nk0101575h0002, JP21wm0425008, JP22am0401007, JP21wm0425008,JP21wm0425013,JP22nk0101575,JP22am0401007,JP23bm1423006,JP24wm0625301, JP21wm0425013; Mitsubishi Tanabe Pharma Corporation; Japan Society for the Promotion of Science: JP22am0401007, 20H00527, 21K15677, 23H00420, 23K14773, JP22nk0101575

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 23 authors, 5 keywords, 15 MeSH terms, 75 references.

Cite

This paper

Ito, D., Iida, M., Iguchi, Y., Hashizume, A., Yamada, S., Kishimoto, Y., Komori, S., Obara, K., Nishisaki, S., Yokoi, S., Shimamura, T., Takemoto, Y., Nakatochi, M., Akashi, T., Hinohara, K., Lee-Okada, H.-C., Okada, Y., Niwa, J., Sobue, G., . . . Katsuno, M. (2026). Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis. JCI insight, 11(15), e198842. https://doi.org/10.1172/jci.insight.198842

BibTeX

@article{ito2026fatty,
author = {Ito, Daisuke and Iida, Madoka and Iguchi, Yohei and Hashizume, Atsushi and Yamada, Shinichiro and Kishimoto, Yoshiyuki and Komori, Shota and Obara, Kazuki and Nishisaki, Shuto and Yokoi, Satoshi and Shimamura, Teppei and Takemoto, Yuto and Nakatochi, Masahiro and Akashi, Tomohiro and Hinohara, Kunihiko and Lee-Okada, Hyeon-Cheol and Okada, Yohei and Niwa, Junichi and Sobue, Gen and Tanaka, Shinji and Takashina, Ken and Yokomizo, Takehiko and Katsuno, Masahisa},
title = {{Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis}},
journal = {JCI insight},
year = {2026},
month = jun,
volume = {11},
number = {15},
pages = {e198842},
publisher = {American Society for Clinical Investigation},
issn = {2379-3708},
doi = {10.1172/jci.insight.198842},
url = {https://doi.org/10.1172/jci.insight.198842},
pmid = {42275159},
pmcid = {PMC13463617}
}

RIS

TY - JOUR
AU - Ito, Daisuke
AU - Iida, Madoka
AU - Iguchi, Yohei
AU - Hashizume, Atsushi
AU - Yamada, Shinichiro
AU - Kishimoto, Yoshiyuki
AU - Komori, Shota
AU - Obara, Kazuki
AU - Nishisaki, Shuto
AU - Yokoi, Satoshi
AU - Shimamura, Teppei
AU - Takemoto, Yuto
AU - Nakatochi, Masahiro
AU - Akashi, Tomohiro
AU - Hinohara, Kunihiko
AU - Lee-Okada, Hyeon-Cheol
AU - Okada, Yohei
AU - Niwa, Junichi
AU - Sobue, Gen
AU - Tanaka, Shinji
AU - Takashina, Ken
AU - Yokomizo, Takehiko
AU - Katsuno, Masahisa
TI - Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis
T2 - JCI insight
J2 - JCI Insight
PY - 2026
DA - 2026/06/11
VL - 11
IS - 15
SP - e198842
SN - 2379-3708
PB - American Society for Clinical Investigation
DO - 10.1172/jci.insight.198842
UR - https://doi.org/10.1172/jci.insight.198842
LA - en
ER -

CSL-JSON

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