Neuronal polyunsaturated fatty acids are protective in ALS/FTD
Nature Neuroscience, vol. 28, pp. 737–747
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.
Authors 23
-
MRC Laboratory of Molecular Biology · UK Dementia Research Institute · University College London
Affiliation as printed
Institute of Healthy Ageing, UCL, London, UK
MRC Laboratory of Molecular Biology, Cambridge, UK
UK Dementia Research Institute, UCL, London, UK
-
UK Dementia Research Institute · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
UK Dementia Research Institute, UCL, London, UK
-
Leiden University Medical Center
Affiliation as printed
Center for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
-
Affiliation as printed
Institute of Healthy Ageing, UCL, London, UK
-
UK Dementia Research Institute · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
UK Dementia Research Institute, UCL, London, UK
-
UK Dementia Research Institute · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
UK Dementia Research Institute, UCL, London, UK
-
Affiliation as printed
Institute of Healthy Ageing, UCL, London, UK
-
Affiliation as printed
Institute of Healthy Ageing, UCL, London, UK
-
Affiliation as printed
Institute of Healthy Ageing, UCL, London, UK
-
Affiliation as printed
Institute of Healthy Ageing, UCL, London, UK
-
UK Dementia Research Institute · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
UK Dementia Research Institute, UCL, London, UK
-
UK Dementia Research Institute · University College London
Affiliation as printed
Institute of Healthy Ageing, UCL, London, UK
UK Dementia Research Institute, UCL, London, UK
-
Leiden University Medical Center
Affiliation as printed
Center for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
-
Leiden University Medical Center
Affiliation as printed
Center for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
-
Leiden University Medical Center
Affiliation as printed
Center for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
-
Affiliation as printed
Institute of Healthy Ageing, UCL, London, UK
-
Affiliation as printed
Institute of Healthy Ageing, UCL, London, UK
-
Affiliation as printed
Brain Science Institute, Johns Hopkins University, Baltimore, MA, USA
Department of Neurology, Johns Hopkins University, Baltimore, MA, USA
-
Amsterdam University Medical Centers
Affiliation as printed
Alzheimer Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands
-
UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
-
Leiden University Medical Center · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Center for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
-
Linda Partridge corresponding
Affiliation as printed
Institute of Healthy Ageing, UCL, London, UK. l.partridge@ucl.ac.uk
Institute of Healthy Ageing, UCL, London, UK
-
Adrian M. Isaacs corresponding
UK Dementia Research Institute · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. a.isaacs@ucl.ac.uk
UK Dementia Research Institute, UCL, London, UK. a.isaacs@ucl.ac.uk
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
UK Dementia Research Institute, UCL, London, UK
Cited by 41 stored of 42
No patents citing this paper on Lens.org (checked 2026-10-11).