Neuronal polyunsaturated fatty acids are protective in ALS/FTD

Abstract

Here we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in a Drosophila model of C9orf72 repeat expansion, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), and in human postmortem ALS spinal cord. We performed lipidomics on C9 ALS/FTD Drosophila, induced pluripotent stem (iPS) cell neurons and postmortem FTD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). Feeding C9 ALS/FTD flies PUFAs yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of C9 ALS/FTD flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor-induced neuronal death in iPS cell neurons of patients with both C9 and TDP-43 ALS/FTD. These data implicate neuronal fatty acid saturation in the pathogenesis of ALS/FTD and suggest that interventions to increase neuronal PUFA levels may be beneficial.

Metadata

Item Type:	Article
Authors/Creators:	Giblin, A. https://orcid.org/0000-0001-8470-7908 Cammack, A.J. Blomberg, N. Anoar, S. Mikheenko, A. https://orcid.org/0000-0003-3400-9719 Carcolé, M. https://orcid.org/0000-0001-5054-9016 Atilano, M.L. https://orcid.org/0000-0002-3819-2023 Hull, A. https://orcid.org/0000-0002-9700-4926 Shen, D. Wei, X. Coneys, R. Zhou, L. Mohammed, Y. https://orcid.org/0000-0003-3265-3332 Olivier-Jimenez, D. https://orcid.org/0000-0002-6363-0857 Wang, L.Y. Kinghorn, K.J. Niccoli, T. https://orcid.org/0000-0001-9337-0411 Coyne, A.N. https://orcid.org/0000-0002-3658-5325 van der Kant, R. Lashley, T. https://orcid.org/0000-0001-7389-0348 Giera, M. https://orcid.org/0000-0003-1684-1894 Partridge, L. https://orcid.org/0000-0001-9615-0094 Isaacs, A.M. https://orcid.org/0000-0002-6820-5534
Copyright, Publisher and Additional Information:	© The Author(s) 2025. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Amyotrophic lateral sclerosis; Molecular neuroscience
Dates:	Published: 25 February 2025 Published (online): 25 February 2025 Accepted: 7 January 2025
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	28 Feb 2025 13:02
Last Modified:	28 Feb 2025 13:02
Status:	Published online
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41593-025-01889-3
Related URLs:	PubMed URL Dataset
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:223858