Reference - Detail
| RRC ID | 83799 |
|---|---|
| Author | Giblin A, Cammack AJ, Blomberg N, Anoar S, Mikheenko A, Carcolé M, Atilano ML, Hull A, Shen D, Wei X, Coneys R, Zhou L, Mohammed Y, Olivier-Jimenez D, Wang LY, Kinghorn KJ, Niccoli T, Coyne AN, van der Kant R, Lashley T, Giera M, Partridge L, Isaacs AM. |
| Title | Neuronal polyunsaturated fatty acids are protective in ALS/FTD. |
| Journal | Nat Neurosci |
| Abstract |
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. |
| Volume | 28(4) |
| Pages | 737-747 |
| Published | 2025-4-1 |
| DOI | 10.1038/s41593-025-01889-3 |
| PII | 10.1038/s41593-025-01889-3 |
| PMID | 40000803 |
| PMC | PMC11976277 |
| MeSH | Amyotrophic Lateral Sclerosis* / genetics Amyotrophic Lateral Sclerosis* / metabolism Amyotrophic Lateral Sclerosis* / pathology Animals Animals, Genetically Modified Brain / metabolism C9orf72 Protein / genetics Disease Models, Animal Drosophila Fatty Acid Desaturases / genetics Fatty Acid Desaturases / metabolism Fatty Acids, Unsaturated* / metabolism Frontotemporal Dementia* / genetics Frontotemporal Dementia* / metabolism Frontotemporal Dementia* / pathology Humans Induced Pluripotent Stem Cells / metabolism Male Neurons* / metabolism |
| IF | 20.071 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | News |
| Total number of mentions | 277 |
| Altmetric score changes over past 6months | 1.2 |
| Resource | |
| Drosophila | DGRC#118679 DGRC#118682 DGRC#118681 |