Giblin, A., Cammack, A.J., Blomberg, N., Anoar, S., Mikheenko, A., Carcolé, M., Atilano, M.L., Hull, A., Shen, D., Wei, X., Coneys, R., Zhou, L., Mohammed, Y., Olivier-Jimenez, D., Wang, L.Y., Kinghorn, K.J., Niccoli, T., Coyne, A.N., van der Kant, R., Lashley, T., Giera, M., Partridge, L., Isaacs, A.M. (2025). Neuronal polyunsaturated fatty acids are protective in ALS/FTD.  Nat. Neurosci. 28(4): 737--747.

FBrf0262048

Research paper

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.

PMC11976277 (PMC) (EuropePMC)