Lipid Rafts and Neurological Diseases

Abstract

The different populations of brain cells are characterised by evident membrane polarisation with the creation of distinct morphological and functional subcompartments, whose formation, stabilisation and functions require sophisticated geometric features and a high level of lateral order, which are, at least in part, driven by the collective properties of membrane lipids. Lipid‐driven membrane organisation allows the segregation of membrane‐associated components into specific ‘lipid membrane domains’ or lipid rafts, which function as dynamic platforms for signal transduction, protein processing and membrane turnover. From this point of view, sphingolipids (SLs), polar membrane lipids present as minor components in all eukaryotic cell membranes but highly enriched in neuron and myelin membranes, play crucial roles. In fact, the metabolism of SLs is precisely regulated along the differentiation and development of neurons and oligodendrocytes, leading to the expression of peculiar cell‐specific SL patterns essential for the maintenance of the functional integrity of the nervous system, while, on the other hand, alterations in SL homeostasis, which lead to abnormal lipid raft organisation and consequent deregulation of lipid raft‐dependent events, are a common trait in diverse major brain diseases.

Key Concepts

  • Cellular membranes are highly organised structures with multiple and multi‐dimensional levels of order where lipid components are active players.
  • Membrane domains are ordered structures or regions in a biological membrane that differ from the surrounding membrane in their lipid and/or protein composition.
  • Lipid‐driven collective interactions are a major factor in determining the local structure of a membrane.
  • Among amphipatic membrane lipids, gangliosides are known to be major players in the creation of lateral order within biological membranes.
  • Sphingolipid metabolism is deeply altered in several neurological diseases.

Keywords: lipid rafts; liquid‐ordered phase; sphingolipids; gangliosides; cholesterol; Alzheimer's disease

Figure 1. The multifaceted roles of lipid membrane domains in the nervous system. Reproduced with permission from Aureli et al., 2015 © Elsevier.
Figure 2. The roles of lipid rafts in Alzheimer's disease. The targeting of amyloid precursor protein (APP) to lipid rafts with abnormal lipid composition can disrupt normal APP‐dependent signal transduction pathways and promote APP proteolytic processing via the sequential actions of α‐ and γ‐secretases (both associated with lipid rafts). The second event involves the generation of extracellularly released soluble fragment sAPPβ, membrane‐bound Aβ, and intracellularly released APP intracellular C‐terminus domain (AICD). AICD acts as a transcription factor regulating the lipid composition of lipid rafts. Membrane‐bound Aβ in lipid rafts interacts with GM1, triggering the formation of insoluble amyloid fibrils and the release of toxic soluble Aβ aggregates. The Aβ aggregates require interaction with lipid raft‐associated PrP to exert their detrimental effect on neurons. Reproduced with permission from Sonnino et al., 2014 © Springer.
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Further Reading

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Sonnino, Sandro, Grassi, Sara, Prioni, Simona, Ciampa, Maria G, Chiricozzi, Elena, and Prinetti, Alessandro(May 2016) Lipid Rafts and Neurological Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023405]