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Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis

Ito, Daisuke LU ; Iida, Madoka ; Iguchi, Yohei ; Hashizume, Atsushi ; Yamada, Shinichiro ; Kishimoto, Yoshiyuki ; Komori, Shota ; Obara, Kazuki LU orcid ; Nishisaki, Shuto and Yokoi, Satoshi , et al. (2026) In JCI Insight
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... (More)

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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publishing date
type
Contribution to journal
publication status
epub
subject
in
JCI Insight
publisher
The American Society for Clinical Investigation
external identifiers
  • pmid:42275159
ISSN
2379-3708
DOI
10.1172/jci.insight.198842
language
English
LU publication?
no
id
35ec5712-4a39-4525-93bc-25fb35f1648b
date added to LUP
2026-06-15 11:36:26
date last changed
2026-06-15 13:40:06
@article{35ec5712-4a39-4525-93bc-25fb35f1648b,
  abstract     = {{<p>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.</p>}},
  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}},
  issn         = {{2379-3708}},
  language     = {{eng}},
  month        = {{06}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{JCI Insight}},
  title        = {{Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis}},
  url          = {{http://dx.doi.org/10.1172/jci.insight.198842}},
  doi          = {{10.1172/jci.insight.198842}},
  year         = {{2026}},
}