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The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders

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Abstract

Oxidative and nitrosative stress (O&NS) is causatively implicated in the pathogenesis of Alzheimer’s and Parkinson’s disease, multiple sclerosis, chronic fatigue syndrome, schizophrenia and depression. Many of the consequences stemming from O&NS, including damage to proteins, lipids and DNA, are well known, whereas the effects of O&NS on lipoprotein-based cellular signalling involving palmitoylation and plasma membrane lipid rafts are less well documented. The aim of this narrative review is to discuss the mechanisms involved in lipid-based signalling, including palmitoylation, membrane/lipid raft (MLR) and n-3 polyunsaturated fatty acid (PUFA) functions, the effects of O&NS processes on these processes and their role in the abovementioned diseases. S-palmitoylation is a post-translational modification, which regulates protein trafficking and association with the plasma membrane, protein subcellular location and functions. Palmitoylation and MRLs play a key role in neuronal functions, including glutamatergic neurotransmission, and immune-inflammatory responses. Palmitoylation, MLRs and n-3 PUFAs are vulnerable to the corruptive effects of O&NS. Chronic O&NS inhibits palmitoylation and causes profound changes in lipid membrane composition, e.g. n-3 PUFA depletion, increased membrane permeability and reduced fluidity, which together lead to disorders in intracellular signal transduction, receptor dysfunction and increased neurotoxicity. Disruption of lipid-based signalling is a source of the neuroimmune disorders involved in the pathophysiology of the abovementioned diseases. n-3 PUFA supplementation is a rational therapeutic approach targeting disruptions in lipid-based signalling.

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Acknowledgments

The authors would like to express their thanks to Victoria Storey for her invaluable secretarial services. No specific funding was obtained for this specific review.

Competing Interests

The authors declare that they have no competing interests.

Authors’ Contributions

GM and MM participated in the design of this review, while KW, BKP and MB helped to draft the paper. All authors read and approved the final version of the manuscript.

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Authors and Affiliations

  1. Tir Na Nog, Bryn Road seaside 87, Llanelli, SA152LW, Wales, UK

    Gerwyn Morris

  2. Metabolic Research Unit, Deakin University, Geelong, Australia

    Ken Walder

  3. Department of Medicine, Hammersmith Hospital, Imperial College London, London, W12 0HS, UK

    Basant K. Puri

  4. Orygen, The National Centre of Excellence in Youth Mental Health and the Centre of Youth Mental Health, Poplar Road 35, Parkville, 3052, Australia

    Michael Berk

  5. The Florey Institute for Neuroscience and Mental Health, University of Melbourne, Kenneth Myer Building, Royal Parade 30, Parkville, 3052, Australia

    Michael Berk

  6. Department of Psychiatry, Royal Melbourne Hospital, University of Melbourne, Level 1 North, Main Block, Parkville, 3052, Australia

    Michael Berk

  7. IMPACT Strategic Research Center, School of Medicine, Deakin University, P.O. Box 291, Geelong, 3220, Australia

    Michael Berk & Michael Maes

  8. Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Michael Maes

  9. Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil

    Michael Maes

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  1. Gerwyn Morris
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Correspondence to Michael Maes.

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Morris, G., Walder, K., Puri, B.K. et al. The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders. Mol Neurobiol 53, 4638–4658 (2016). https://doi.org/10.1007/s12035-015-9392-y

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