Hypothesis-free evaluation of circulating metabolome provides cell-specific insights regarding the role of energy substrate availability in amyotrophic lateral sclerosis.
Overview
- Sheffield Institute for Translational Neuroscience, University of Sheffield,Glossop Road, Sheffield, S10 2HQ UK
- Faculty of Nursing, Taif University,Taif, Saudi Arabia
- NIHR Sheffield Biomedical Research Centre (BRC), Sheffield Teaching Hospitals NHS Foundation Trust,Glossop Road, Sheffield, S10 2JF UK
- Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester,Manchester, UK
- Christabel Pankhurst Institute, The University of Manchester,Manchester, UK
- Biomedical Research Center (BRC), QU Health, Qatar University,P.O. Box 2713, Doha, Qatar
- Anti-Doping Laboratory Qatar,Doha, Qatar
- Computer and Systems Engineering, Faculty of Engineering, Alexandria University,Alexandria, Egypt
- Department of Medical Biology, Tayfur Ata Sökmen Medical Faculty, Hatay Mustafa Kemal University,Antakya, Turkey
- School of Medicine and Population Health, University of Sheffield,Sheffield, UK
- Metabolon Inc,Durham, NC USA
Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with limited therapeutic options. The circulating metabolome comprises small molecules present in plasma/
Methods: We conducted hypothesis-free two-sample Mendelian randomisation (MR) analysis of the concentration of 575 plasma/
Results: MR causally associated five metabolites with ALS risk after multiple-testing correction. Higher serum concentration of glycoprotein acetyls (P = 9.7e − 9, β = 0.21) and the peptide DSGEGDFXAEGGGVR (P = 8.0e − 6, β = 0.22) was associated with increased ALS risk, whereas higher plasma concentration of phenylalanylserine, isobutyrylcarnitine, and acetylcarnitine was protective (P < 5e − 5, β = − 0.29 to − 0.72). DSGEGDFXAEGGGVR has been linked to glucose metabolism but we have used genetic fine-mapping to link DSGEGDFXAEGGGVR, neuronal glucose uptake through GLUT3, and ALS risk. Direct measurement of metabolite concentrations in patient biofluids revealed elevated acetylcarnitine levels in patients with ALS, which were associated with delayed symptom onset (Cox regression, P = 0.02, HR = 0.4). Similarly, lactate is elevated in ALS patient CSF (ANOVA, P = 1.3e − 3) and in patients with longer survival time (Cox regression, P = 0.03, HR = 0.3). Plasma fructose is elevated in ALS patients with shorter survival time (Cox regression, P = 0.02, HR = 1.1). In vitro, neurons and astrocytes carrying an ALS-associated G4C2-repeat expansion within C9orf72 demonstrated reduced metabolic flexibility.
Conclusions: We provide evidence that impaired energy substrate availability contributes to ALS risk and severity. CNS cell types differ in their use of energy substrates and therefore we postulate the relative importance of different cell types for different stages of disease. Our findings support further investigation of metabolic interventions to treat or prevent ALS.
Supplementary Information: The online version contains supplementary material available at 10.1186/
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- figshare:32004972, at figshare; found in DataCite
- figshare:32004975, at figshare; found in DataCite
Data availability
The raw data for the metabolic flux experiments can be found in Additional Data 1. Anonymised metabolic profiling data from the AMBRoSIA project can be provided upon request by a qualified researcher.
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 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 21 authors, 9 keywords, 12 MeSH terms, 9 funders, 60 references.
Cite
This paper
Alhathli, E., Cooper-Knock, J., Girach, Z.-U.-A., Julian, T. H., Bauer, C., Timmons, H. O., Ward, B. D., Walker, H., Azzouz, M., Elrayess, M. A., Al-Khelaifi, F., Yousri, N. A., Gul, A., Kelsall, A., Moll, T., Harvey, C., Gornall, S., Wong, K., Allen, S. P., . . . Shaw, P. J. (2026). Hypothesis-free evaluation of circulating metabolome provides cell-specific insights regarding the role of energy substrate availability in amyotrophic lateral sclerosis. BMC medicine, 24(1), 233. https://
BibTeX
@article{alhathli2026hyp
author = {Alhathli, Elham and Cooper-Knock, Johnathan and Girach, Zain-Ul-Abideen and Julian, Thomas H. and Bauer, Claudia and Timmons, Hannah O. and Ward, Billie D. and Walker, Heather and Azzouz, Mimoun and Elrayess, Mohamed A. and Al-Khelaifi, Fatima and Yousri, Noha A. and Gul, Aytac and Kelsall, Alan and Moll, Tobias and Harvey, Calum and Gornall, Sarah and Wong, Kari and Allen, Scott P. and Strange, Andrew and Shaw, Pamela J.},
title = {{Hypothesis-free evaluation of circulating metabolome provides cell-specific insights regarding the role of energy substrate availability in amyotrophic lateral sclerosis}},
journal = {BMC medicine},
year = {2026},
month = mar,
volume = {24},
number = {1},
pages = {233},
publisher = {BioMed Central},
issn = {1741-7015},
doi = {10.1186/
url = {https://
pmid = {41787388},
pmcid = {PMC13077999}
}
RIS
TY - JOUR
AU - Alhathli, Elham
AU - Cooper-Knock, Johnathan
AU - Girach, Zain-Ul-Abideen
AU - Julian, Thomas H.
AU - Bauer, Claudia
AU - Timmons, Hannah O.
AU - Ward, Billie D.
AU - Walker, Heather
AU - Azzouz, Mimoun
AU - Elrayess, Mohamed A.
AU - Al-Khelaifi, Fatima
AU - Yousri, Noha A.
AU - Gul, Aytac
AU - Kelsall, Alan
AU - Moll, Tobias
AU - Harvey, Calum
AU - Gornall, Sarah
AU - Wong, Kari
AU - Allen, Scott P.
AU - Strange, Andrew
AU - Shaw, Pamela J.
TI - Hypothesis-free evaluation of circulating metabolome provides cell-specific insights regarding the role of energy substrate availability in amyotrophic lateral sclerosis
T2 - BMC medicine
J2 - BMC Med
PY - 2026
DA - 2026/
VL - 24
IS - 1
SP - 233
SN - 1741-7015
PB - BioMed Central
DO - 10.1186/
UR - https://
LA - en
ER -
CSL-JSON
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