Neuronal polyunsaturated fatty acids are protective in FTD/ALS

Ashling Giblin; Alexander J. Cammack; Niek Blomberg; Sharifah Anoar; Alla Mikheenko; Mireia Carcolé; Magda Luciana Atilano; Alexander J. Hull; Dunxin Shen; Xiao‐Ya Wei; Rachel Coneys; Lele Zhou; Yassene Mohammed; Damien Olivier‐Jimenez; Lian Y. Wang; Kerri J. Kinghorn; Teresa Niccoli; Alyssa N. Coyne; Rik van der Kant; Tammaryn Lashley; Martin A. Giera; Linda Partridge; Adrian M. Isaacs

doi:10.1038/s41593-025-01889-3

NeuroscienceNature NeuroscienceFeb 25, 2025

Peer-reviewed journal article

Neuronal polyunsaturated fatty acids are protective in FTD/ALS

Ashling Giblin iD, Alexander J. Cammack iD, Niek Blomberg, Sharifah Anoar iD, Alla Mikheenko iD, Mireia Carcolé iD, Magda Luciana Atilano iD, Alexander J. Hull iD, Dunxin Shen iD, Xiao‐Ya Wei iD, Rachel Coneys iD, Lele Zhou, Yassene Mohammed iD, Damien Olivier‐Jimenez iD, Lian Y. Wang iD, Kerri J. Kinghorn iD, Teresa Niccoli iD, Alyssa N. Coyne iD, Rik van der Kant iD, Tammaryn Lashley iD, Martin A. Giera iD, Linda Partridge iD, Adrian M. Isaacs iD

Abstract

We report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in human post-mortem ALS spinal cord and a Drosophila model of the most common genetic cause of FTD/ALS, a repeat expansion in C9orf72. To investigate lipid alterations, we performed lipidomics on C9FTD/ALS iPSC-neurons and post-mortem FTLD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). To determine whether this PUFA deficit contributes to neurodegeneration, we fed C9FTD/ALS flies PUFAs, which yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of the C9orf72 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 C9FTD/ALS patient iPSC-neurons. These data implicate neuronal fatty acid saturation in the pathogenesis of FTD/ALS and suggest that interventions to increase PUFA levels specifically within neurons will be beneficial.

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