Sphingolipids: membrane microdomains in brain development, function and neurological diseases

Abstract

Sphingolipids are highly enriched in the nervous system where they are pivotal constituents of the plasma membranes and are important for proper brain development and functions. Sphingolipids are not merely structural elements, but are also recognized as regulators of cellular events by their ability to form microdomains in the plasma membrane. The significance of such compartmentalization spans broadly from being involved in differentiation of neurons and synaptic transmission to neuronal–glial interactions and myelin stability. Thus, perturbations of the sphingolipid metabolism can lead to rearrangements in the plasma membrane, which has been linked to the development of various neurological diseases. Studying microdomains and their functions has for a long time been synonymous with studying the role of cholesterol. However, it is becoming increasingly clear that microdomains are very heterogeneous, which among others can be ascribed to the vast number of sphingolipids. In this review, we discuss the importance of microdomains with emphasis on sphingolipids in brain development and function as well as how disruption of the sphingolipid metabolism (and hence microdomains) contributes to the pathogenesis of several neurological diseases.

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

“…The accompanying upregulation of selected ceramide species may not only signal apoptosis, but also affect the regulation of β-and γ-secretases and AβPP processing [12,[14][15][16]. The influence of sphingolipids may be largely mediated through their role in plasma membrane microdomains called lipid rafts [17], which display extensive links with AβPP metabolism, Aβ production, and aggregation [18,19]. Moreover, S1PRs modulate neuronmicroglia interactions, microglial activation, and secretion of neurotoxic compounds and seem to influence the fine balance between the restorative and destructive outcomes of astrogliosis [20,21].…”

The crosstalk between glycosphingolipids and neural stem cells

“…It is also interesting the role of glycosphingolipid complexity in NSC differentiation. The correct level of complexity is important for the tropomyosin receptor kinase A signaling response changing the cellular localization of nerve growth factor receptors (NGFR) (Olsen and Faergeman ) (Fig. ).…”

“…Indeed, during development, GM3 and GD3 are highly expressed during neural tube formation in neuroepithelial cells, in radial glial cells of the embryo ventricular zone, and NSCs proliferation of the adult SVZ; they then decrease in neural differentiation. GM1, GD1a, GD1b, and GT1b increase during neural differentiation and are elevated during axonal/dendritic arborization, synaptogenesis, myelination, up to adulthood (Olsen and Faergeman ) (Table ).…”

GT 1b functions as a novel endogenous agonist of toll‐like receptor 2 inducing neuropathic pain

“…Four major gangliosides (GM1, GD1a, GD1b, and GT1b) constitute up to 97% of gangliosides in the human brain (Tettamanti et al, 1973;Ando, 1983). Of note, the ganglioside profile is highly plastic, changing in brain development and pathophysiology (Olsen & Faergeman, 2017). For example, GD1a and GM1 levels increase at early brain developmental stages and contribute to neural differentiation and axonal outgrowth (Olsen & Faergeman, 2017).…”

“…Of note, the ganglioside profile is highly plastic, changing in brain development and pathophysiology (Olsen & Faergeman, 2017). For example, GD1a and GM1 levels increase at early brain developmental stages and contribute to neural differentiation and axonal outgrowth (Olsen & Faergeman, 2017). An increase of GT1b at a later stage contributes to axon-myelin stability of differentiated neurons (Olsen & Faergeman, 2017).…”