Neuronal polyunsaturated fatty acids are protective in FTD/ALS

Author:

Giblin AORCID,Cammack AJORCID,Blomberg N,Mikheenko AORCID,Carcolé M,Coneys R,Zhou L,Mohammed Y,Olivier-Jimenez D,Atilano MLORCID,Niccoli TORCID,Coyne AN,van der Kant RORCID,Lashley TORCID,Giera MORCID,Partridge LORCID,Isaacs AMORCID

Abstract

AbstractWe report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in human post-mortem ALS spinal cord and aDrosophilamodel of the most common genetic cause of FTD/ALS, a repeat expansion inC9orf72. 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 theC9orf72flies, 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.

Publisher

Cold Spring Harbor Laboratory

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