Neuronal polyunsaturated fatty acids are protective in FTD/ALS

Giblin, A.; Cammack, A. J.; Blomberg, N.; Mikheenko, A.; Carcole, M.; Coneys, R.; Zhou, L.; Mohammed, Y.; Olivier-Jimenez, D.; Atilano, M. L.; Niccoli, T.; Coyne, A. N.; van der Kant, R.; Lashley, T.; Giera, M.; Partridge, L.; Isaacs, A. M.

doi:10.1101/2024.01.16.575677

bioRxiv · 10.1101/2024.01.16.575677

Neuronal polyunsaturated fatty acids are protective in FTD/ALS

Giblin, A.·Cammack, A. J.·Blomberg, N.·Mikheenko, A.·Carcole, M.·Coneys, R.·Zhou, L.·Mohammed, Y.·Olivier-Jimenez, D.·Atilano, M. L.·Niccoli, T.·Coyne, A. N.·van der Kant, R.·Lashley, T.·Giera, M.·Partridge, L.·Isaacs, A. M.

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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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Giblin, A., Cammack, A. J., Blomberg, N., Mikheenko, A., Carcole, M., Coneys, R., Zhou, L., Mohammed, Y., Olivier-Jimenez, D., Atilano, M. L., Niccoli, T., Coyne, A. N., van der Kant, R., Lashley, T., Giera, M., Partridge, L., Isaacs, A. M.. 2024-01-17. Neuronal polyunsaturated fatty acids are protective in FTD/ALS. https://doi.org/10.1101/2024.01.16.575677

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