Sphingolipids and neuronal degeneration in lysosomal storage disorders

Abstract

Ceramide, sphingomyelin, and glycosphingolipids (both neutral and acidic) are characterized by the presence in the lipid moiety of an aliphatic base known as sphingosine. Altogether, they are called sphingolipids and are particularly abundant in neuronal plasma membranes, where, via interactions with the other membrane lipids and membrane proteins, they play a specific role in modulating the cell signaling processes. The metabolic pathways determining the plasma membrane sphingolipid composition are thus the key point for functional changes of the cell properties. Unnatural changes of the neuronal properties are observed in sphingolipidoses, lysosomal storage diseases occurring when a lysosomal sphingolipid hydrolase is not working, leading to the accumulation of the substrate and to its distribution to all the cell membranes interacting with lysosomes. Moreover, secondary accumulation of sphingolipids is a common trait of other lysosomal storage diseases. Keywords: gangliosides, lysosome, membrane fusion, sphingolipidoses, sphingolipids, sphingomyelin.This article is part of the Special Issue "Lysosomal Storage Disorders".Sphingolipids are amphiphilic membrane lipids characterized by the presence of sphingosine, an amino-and-hydroxy alkylic long chain. After more than a century of studies, we now know their structure, their physico-chemical properties, their distribution and content in cells and tissues of many animal species, including humans . The final cellular site for sphingolipids is the plasma membrane, however, their complex metabolic pathway requires many intracellular processes, so that a not negligible portion of them is also found intracellularly (Sandhoff and Kolter 2003;Schulze et al. 2009;Kolter and Sandhoff 2010;Hannun and Obeid 2018). As amphiphilic compounds they contain a hydrophilic head group, for example a saccharide, an oligosaccharide, a phosphocholine, protruding into the cell aqueous environment, and a hydrophobic chain called ceramide, in which the sphingosine is linked with a fatty acid via an amidic bond, inserted into the outer layer of plasma membrane.Sphingolipids are typically asymmetric components of the plasma membranes enriched in the outer leaflet (van Meer and Hoetzl 2010;van Meer 2011;Fujimoto and Parmryd 2016), however, it cannot be excluded that a minor pool of them could be transiently inserted into the inner layer with the hydrophilic group facing the cytosol. The hydrophilic group, thanks to the presence of carbohydrates and/or ionic charges, attracts water and ions, forms hydrogen bonds and easily interacts with the group of membrane components protruding from the membrane itself. At the water-lipid interface, the sphingolipid ceramide amide linkage accepts hydrogen bonds on the carbonyl group and donates hydrogen bonds via the N-H group, allowing the formation of a double linkage, which works as a padlock within molecules (Fig. 1). The lipid moiety inserted into the lipid layer interacts with the lipid portion of the cholesterol in the membrane and with dip...

Lysosomal storage disorders: pathology within the lysosome and beyond

“…This temporal relationship raises the possibility that the delay in clinical presentation of those LSDs that impact sphingolipid metabolism could result from the fact that these lipids are not a major constituent of neuronal membranes during development and compensatory mechanisms are operative (Grassi et al . ). Sphingolipids are also critical for remodeling and repair of cell membranes, both at the plasma membrane as well as other organelles.…”

“…The LSDs typified by abnormal accumulation of sphingolipids are nicely summarized by Grassi et al . (). It is clear that the blockade of proper sphingolipid metabolism in the context of lysosomal dysfunction leads to more widespread issues with metabolite flow and a better understanding of the complexity of such metabolite crosstalk represents an ongoing challenge in the LSD field.…”

“…), and sphingolipid biosynthesis and turnover (Grassi et al . ), all of which are critical toward our understanding of normal lysosomal function and how this is perturbed in the context of LSDs.…”

“…Following on the theme of metabolism is an elegant review by Grassi et al . () summarizing sphingolipid metabolism and how this influences cell membrane integrity. Sphingolipids are amphiphilic lipids that insert into the plasma membrane and are a component of lipid rafts, key hubs for signal transduction pathways.…”

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

“…As a completely novel and important insight, the mouse data revealed significant accumulations of sphingosines. This elevation is known to occur in cell culture upon serum deprivation [97] and might simply be due to the increased breakdown of glycosphingolipids in lysosomes, as a byproduct of the neurodegenerative process [98]. Similar increases of sphingosine with parallel decreases of myelin markers were observed in the inflammatory demyelination process of multiple sclerosis patients; in this autoimmune process it was shown that the conversion of ceramides to sphingosine can be toxic for oligodendrocytes [99].…”