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<p>Here we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in a <i>Drosophila</i> model of <i>C9orf72</i> 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 <i>Drosophila</i>, 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.</p>

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Neuronal polyunsaturated fatty acids are protective in ALS/FTD

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月25日

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  • Ashling Giblin,
  • Alexander J. Cammack,
  • Niek Blomberg,
  • Sharifah Anoar,
  • Alla Mikheenko,
  • Mireia Carcolé,
  • Magda L. Atilano,
  • Alex Hull,
  • Dunxin Shen,
  • Xiaoya 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 Giera,
  • Linda Partridge,
  • Adrian M. Isaacs

摘要

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.