Neuronal polyunsaturated fatty acids are protective in FTD/ALS

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

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.

Authors 17

1. Ashling Giblin

   UK Dementia Research Institute · University College London

   Affiliation as printed

   Institute of Healthy Ageing, UCL, London, United Kingdom

   UK Dementia Research Institute, UCL, London, United Kingdom

2. Alexander J. Cammack

   UK Dementia Research Institute · UCL Queen Square Institute of Neurology · University College London

   Affiliation as printed

   UCL Queen Square Institute of Neurology, Dept of Neurodegenerative Disease, London, United Kingdom

   UK Dementia Research Institute, UCL, London, United Kingdom

3. Nienke J. Blomberg Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The Netherlands

4. Alla Mikheenko

   UK Dementia Research Institute · UCL Queen Square Institute of Neurology · University College London

   Affiliation as printed

   UCL Queen Square Institute of Neurology, Dept of Neurodegenerative Disease, London, United Kingdom

   UK Dementia Research Institute, UCL, London, United Kingdom

5. Mireia Carcolé

   UK Dementia Research Institute · UCL Queen Square Institute of Neurology · University College London

   Affiliation as printed

   UCL Queen Square Institute of Neurology, Dept of Neurodegenerative Disease, London, United Kingdom

   UK Dementia Research Institute, UCL, London, United Kingdom

6. Rachel Coneys

   UK Dementia Research Institute · UCL Queen Square Institute of Neurology · University College London

   Affiliation as printed

   UCL Queen Square Institute of Neurology, Dept of Neurodegenerative Disease, London, United Kingdom

   UK Dementia Research Institute, UCL, London, United Kingdom

7. Lin Zhou

   UK Dementia Research Institute · University College London

   Affiliation as printed

   Institute of Healthy Ageing, UCL, London, United Kingdom

   UK Dementia Research Institute, UCL, London, United Kingdom

8. Yassene Mohammed Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The Netherlands

9. Damien Olivier‐Jimenez Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The Netherlands

10. Magda Luciana Atilano

    University College London

    Affiliation as printed

    Institute of Healthy Ageing, UCL, London, United Kingdom

11. Teresa Niccoli

    University College London

    Affiliation as printed

    Institute of Healthy Ageing, UCL, London, United Kingdom

12. AN Coyne

    Johns Hopkins University

    Affiliation as printed

    Brain Science Institute, Johns Hopkins University, Baltimore, USA

    Department of Neurology, Johns Hopkins University, Baltimore, USA

13. Rik van der Kant

    Amsterdam University Medical Centers

    Affiliation as printed

    Alzheimer Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands

14. Tammaryn Lashley

    UCL Queen Square Institute of Neurology · University College London

    Affiliation as printed

    UCL Queen Square Institute of Neurology, Dept of Neurodegenerative Disease, London, United Kingdom

15. Martin A. Giera Aachen Center for Proteomics and Metabolomics

    Leiden University Medical Center

    Affiliation as printed

    Center for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The Netherlands

16. Linda Partridge corresponding

    University College London

    Affiliation as printed

    Institute of Healthy Ageing, UCL, London, United Kingdom

17. Adrian M. Isaacs corresponding

    UK Dementia Research Institute · UCL Queen Square Institute of Neurology · University College London

    Affiliation as printed

    UCL Queen Square Institute of Neurology, Dept of Neurodegenerative Disease, London, United Kingdom

    UK Dementia Research Institute, UCL, London, United Kingdom