Journal Article

Neuronal polyunsaturated fatty acids are protective in ALS/FTD

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

2025

Overview

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. Lipidomics revealed that neurons of patients with ALS/FTD have reduced levels of polyunsaturated fatty acid (PUFA)-containing phospholipids. Increasing neuronal PUFA levels increased survival of Drosophila models of ALS/FTD and patient neurons, suggesting that interventions that increase neuronal PUFA levels in patients with ALS/FTD may also be beneficial.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 101/58 / 13/100 / 38/91 / 631/378/1689/1285 / 631/378/340 / 64 / 64/24 / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Animal Genetics and Genomics / Animals / Animals, Genetically Modified / Behavioral Sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Brain - metabolism / C9orf72 Protein - genetics / Cell death / Dementia disorders / Desaturase / Disease Models, Animal / Drosophila / Fatty Acid Desaturases - genetics / Fatty Acid Desaturases - metabolism / Fatty acids / Fatty Acids, Unsaturated - metabolism / Flies / Frontotemporal dementia / Frontotemporal Dementia - genetics / Frontotemporal Dementia - metabolism / Frontotemporal Dementia - pathology / Fruit flies / Gene expression / Humans / Induced Pluripotent Stem Cells - metabolism / Insects / Life span / Lipid metabolism / Lipids / Male / Neurobiology / Neurons / Neurons - metabolism / Neurosciences / Pathogenesis / Phospholipids / Pluripotency / Polyunsaturated fatty acids / Spinal cord / Survival / Transcriptomics