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J Neurosci Res. Author manuscript; available in PMC 2017 May 1.
Published in final edited form as:
PMCID: PMC5027976
NIHMSID: NIHMS774021

THE FLUID LEVITY OF THE CELL: THE ROLE OF MEMBRANE LIPID ARCHITECTURE IN GENETIC SPHINGOLIPIDOSES

Abstract

Sphingolipidoses arise from inherited loss-of-function of key enzymes regulating the sphingolipid metabolism, and the accumulation of large quantities of these lipids in affected cells. Most frequently, toxicity is manifested in the nervous system, where survival and function of neurons and glial cells are most impacted. Although detailed information is available about neuroglial alterations during terminal stages of the disease, the initial pathogenic mechanisms triggering neuropathology are largely unclear. Being key components of biological membranes, changes in the local concentration of sphingolipids are likely to impact in the organization of membrane domains and functions. This essay proposes that sphingolipids' toxicity involves initial defects in the integrity of lipid domains, membrane fluidity, and membrane bending, leading to membrane deformation, and deregulation of cell signaling and function. Understanding how sphingolipids alter membrane architecture may provide breakthroughs for more efficient treatment of sphingolipidoses.

Keywords: lipid rafts, psychosine, sphingolipids, caveolin, fluidity, Krabbe’s disease, neurodegeneration

Graphical Abstract

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Object name is nihms774021f2.jpg

Sphingolipidoses are severe and incurable neurological diseases, where sphingolipids accumulate to high and toxic levels by unknown mechanism. Sphingolipids such as psychosine in Krabbe disease could insert in membrane, decreasing fluidity and disrupting functional lipid domains and/or induce changes in membrane curvature, leading to membrane fragility and cell signaling/function deregulation.

INTRODUCTION AND HYPOTHESIS

Sphingolipidoses represent a large group of neurologically handicapping diseases caused by inherited loss-of-function of key enzymes in lipid catabolism, and the consequent accumulation of undigested lipid material (for a review, Platt 2014). Although promising results are being obtained from gene therapy and hematopoietic replacement studies, the field has remained largely stalled in curing most of these diseases (Cox and Cachon-Gonzalez 2012). This shortage of positive treatments could be in part due to an incomplete understanding of how sphingolipids (SLs) initiate cellular dysfunction (Schulze and Sandhoff 2011). Emerging roles of SLs in different physiological processes may hold the key to understand their toxicity in non-physiological conditions such as sphingolipidoses. For example, several SLs have been reported to play major roles as bioactive lipids (Bartke and Hannun 2009), suggesting that they are not mere bricks in the big wall of biological membranes, but rather integral, active, and functional constituents. Importantly, the organization of SLs in cellular membranes is not regarded as random and inert anymore (Singer and Nicolson 1972). Rather, we know that SLs are key components arranged into plasma membrane (PM) realms, ranging from nanometric or lipid rafts (Lingwood and Simons 2010; Simons and Ikonen 1997) to submicrometric size (Carquin et al. 2015) domains. Furthermore, it is now accepted that SLs play roles in the macroscopic arrangement and shaping of cell membranes (Cooke and Deserno 2006). These SL features are essential to host proteins and to regulate physiological events such as surface tension, force sensing (Mollinedo and Gajate 2015) or cell signaling (Gomez-Mouton et al. 2004; Iwabuchi et al. 2010).

In pathological conditions, when SLs homeostasis is compromised, specific SLs accumulate one or more orders of magnitude. This alteration in the local stoichiometry of the membrane could lead to rapid changes in lipid aggregation and the disruption of membrane architecture, changes in membrane curvature, stability, and consequently the impairment of vital membrane-dependent cellular processes (Carquin et al. 2015).

This essay postulates that in sphingolipidoses, the insertion of abnormal quantities of SLs in cell membranes destabilizes lipid domains and impairs the associated functions, inducing membrane changes (e.g. bending, vesiculation, etc) incompatible with normal cellular activities and leading to toxicity and cellular dysfunction.

EXPERIMENTAL CHALLENGES TO STUDY MEMBRANE LIPID DOMAINS

Largely, three major lipid classes define the lipid organization of the PM (Figure 1A). Cholesterol is the most abundant membrane lipid with a non-polar backbone inserted within the membrane bilayer and outwardly exposing a single hydroxyl group. Glycerophospholipids (phosphaticylcholine, PC; phosphatidylserine, PS; phosphatidylethanolamine, PE) are abundant lipids in PM, composed by saturated-straight and unsaturated-bended fatty acyl chains and a polar head-group. Sphingolipids (SLs) have a hydrophobic core formed by the sphingoid base sphingosine, which in most cases is acetylated with a fatty acyl chain to form a ceramide. Ceramides are bound to different head-groups including choline (i.e. sphingomyelin, SM), sugars (i.e. glycosphingolipids, GSLs, such as in galactosylceramide, GalCer or glucosylceramide, GlucCer) or even more complex and larger head-groups (i.e. sulfatides; gangliosides). There are also lysolipids, formed by sphingosine and a sugar (i.e. galactosyl-sphingosine or psychosine).

Figure 1
Potential pathological mechanisms initiated by SLs accumulation illustrated in Krabbe disease

These lipids spontaneously assemble to form membrane bilayers in a non-random fashion. The biophysical mechanisms and dynamics of membrane lipid organization are essential to understand how SLs modulate lipid domains and the consequent impact during disease. Artificial membrane models provided a major contribution in understanding lipid organization by studying the effects of lipid content in controlled environment. One of the basic models is the ternary lipid phase diagrams, a chart reporting thermodynamically distinct phases that coexist at equilibrium, namely liquid-disordered (Ld), liquid-ordered (Lo) and solid ordered (So) phases (Goni et al. 2008). Most of mixtures are made of low-melting temperature lipids (Glycerophospholipids) with high-melting temperature lipids (SLs) and cholesterol (de Almeida et al. 2003). The lipid composition is key in the formation and maintenance of membrane domains, particularly to modulate their shape and size (for a review, see Bagatolli et al. 2010). SLs form Lo or So domains in glycerophospholipid-fluid phase (for a review, see Westerlund and Slotte 2009). Studies using simple planar lipid bilayers (Fidorra et al. 2006), giant unilamellar vesicles (GUVs) (Dietrich et al. 2001; Kahya et al. 2003; Pinto et al. 2008) and cell-derived PM (Baumgart et al. 2007; Bernardino de la Serna et al. 2004; Plasencia et al. 2007) have been critical in determining that SLs-cholesterol interactions are essential for domain formation, which is the cornerstone of the lipid-raft theory (Ramstedt and Slotte 2002). Among SLs, ceramide was shown to exert striking effects on domain formation with high lateral separation at low concentration with atypical shape capable to alter the packing of the fluid phase (Castro et al. 2014).

The lipid domain concept is well-established in artificial systems but its occurrence in PM cells has been unclear (Bagatolli 2006; Munro 2003). Innovative imaging approaches are rapidly contributing to address this. Submicrometric domains can be observed with optical techniques such as with high-resolution confocal, two-photon microscopy, and total internal reflection microscopy. These microscopy techniques are versatile and can be combined with other approaches to study dynamics of lipid and the lipid-lipid or lipid-protein interactions such as fluorescence recovery after photobleaching (FRAP), fluorescence lifetime imaging (FLIM) and fluorescence correlation spectroscopy (FCS). The advent of superresolution microscopy techniques have overcome the limitation of the resolution limit (~200nm) to analyze the nanometric lipid rafts. These include 1) photo-activation localization microscopy (PALM), 2) structured illumination microscopy (SIM), 3) stimulated emission depletion microscopy (STED), 4) atomic force microscopy (AFM), 5) near-field scanning optical microscopy (NSOM) and 6) ion mass spectrometry (SIMS) and 7) single dye tracing (SDT). Nanometric molecular interactions can be also measured by Forster resonance energy transfer (FRET) combined with superresolution microscopes. Altogether, these techniques are becoming gold-standards to study micrometric (Carquin et al. 2015) and nanometric (Castro et al. 2013) dynamic parameters of lipid domains in biological membranes.

ALTERATION OF MEMBRANE DOMAINS IN SPHINGOLIPIDOSES

Brain cells are highly polarized and specifically enriched in various types of SLs (e.g. gangliosides in neurons; GalCer, sulfatides, and SM in myelin) (for a review, Aureli et al. 2015). A growing body of evidence shows that the pathological accumulation of SLs affects the highly organized architecture of brain membranes. For example, Krabbe’s disease is a sphingolipidosis with one the most severe neurodegenerative conditions, caused by the deficiency of the lysosomal enzyme galactosyl-ceramidase and the accumulation of high amounts of psychosine. Psychosine is present in very low levels in healthy conditions but its physiological function remains undetermined, being considered as a biologically irrelevant intermediate (Suzuki 1998). We have actively investigated the physicochemical properties of psychosine, aiming to understand its physiological function in health and disease. Psychosine accumulates in lipid rafts in central and peripheral nervous tissue from the murine twitcher model of Krabbe’s disease as well as in the brain of Krabbe patients (White et al. 2009). Increased levels of psychosine promoted significant changes in rafts, with enrichment of cholesterol, altered flotillin-2 and caveolin-1 distribution, and abnormal activation of protein kinase C (PKC) (White et al. 2009). In neurons, psychosine negatively impacted on fast axonal transport and neurofilament cytoskeleton via deregulation of raft associated protein phosphatase 1 and 2 and GSK3β (Cantuti-Castelvetri et al. 2012; Cantuti Castelvetri et al. 2013). Further evidence that psychosine alters membrane architecture via destabilization of lipid domains was also recently reported (Hawkins-Salsbury et al. 2013). New evidence from our laboratory underlines that psychosine disrupts endogenous submicrometric lipid domains but promotes the formation of new and likely aberrant high-order submicrometric domains leading to increase of PM rigidity (D’auria & Bongarzone, submitted).

Similar effects are found in other sphingolipidoses. For example, in Niemann-Pick type A disease, the accumulation of SM in lipid rafts impairs membrane RhoA targeting and activation (Galvan et al. 2008). Furthermore, accumulation of SM at synaptic membranes disrupted synaptic plasticity dependent on the phosphoinositides pathway (Trovo et al. 2015). In these studies, the addition of SM in normal neurons reproduced these effects, suggesting that SM membrane accumulation was sufficient to induce the defect. GM1 is another lipid raft component which can lead to major alteration of membranes and cellular processes. For example, neurons from GM1 gangliosidosis (Purpura 1978; Purpura and Baker 1977) or after exogenous administration of GM1 (Byrne et al. 1983) exhibit enlarged neurites. In metachromatic leukodystrophy, the accumulation of sulfatides (sulfated GalCer) decreased the content of MAL in myelin rafts (Saravanan et al. 2004) and affected the association of PDGFRα with lipid rafts, impacting on oligodendrocyte formation (Pituch et al. 2015). A recent work on immune cells analyzed the perturbation of specific SL metabolism on the Toll-like receptor dependent immune signaling, leading to a specific inflammation phenotypes. Furthermore, predictions of inflammatory states in cells of patients affected by lipid storage disorders could be elaborated (Koberlin et al. 2015). As stated previously, ceramide represents a sphingolipid with a particular behavior. Generated via the hydrolysis of SM by sphingomyelinase, ceramide forms submicrometric domains also called ceramide-rich platforms. These platforms participate in membrane fragility (Montes et al. 2008) and changes in normal physiological functions such as in transmembrane signaling, clustering of specific proteins, membrane destabilization by flip-flop diffusion (for reviews, see Castro et al. 2014; Stancevic and Kolesnick 2010) and may be relevant in neuronal deficits in sphingolipidoses (Prinetti et al. 2001).

DESTABILIZATION OF MEMBRANE ARCHITECTURE: A LETHAL KICKOFF FOR SPHINGOLIPIDOSES

The physiological and structural architecture of cell membranes is highly dependent on two key properties: fluidity and membrane curvature. Fluidity is a biophysical parameter of membranes that refers to the average membrane viscosity generated by the rotational and lateral mobility of individual molecules and their interactions with surrounding molecules (Lenaz 1987). Fluidity is a fundamental property of cell membranes that influences the correct positioning of key proteins, receptors, and even lipids. Fluidity within the PM depends on its composition. For example: short and unsaturated lipid will promote highly fluid membranes while packing of long and saturated fatty acid chains of SLs with cholesterol will decrease membrane fluidity (i.e. increase order, rigidity, or viscosity). Most SLs such as GM1 (Nishio et al. 2004), SM (Galvan et al. 2008; Koike et al. 1998; von Einem et al. 2012) and even psychosine (D’auria & Bongarzone, submitted) appear to alter cell membranes by decreasing fluidity. It is then conceivable that one of the first pathological changes in sphingolipidoses results from focal decreases in membrane fluidity, impairing the mobility of proteins and lipids essential for vital cellular functions.

Intimately linked to fluidity, membrane curvature is fundamental to regulate cell shape, endo and exocytosis, process formation, and even synaptic activity. The shapes of different lipids influence how much a membrane can curve (i.e. bend). The intrinsic molecular volume of the head-group and composition of the fatty acyl chains (i.e. saturated vs unsaturated) in lipids will determine strict steric dimensions and distinct shapes for each lipid species. Based on this consideration, lipids can be classified as cylinders (head-group is similar to the tail, PC, PS), truncated cones (head-group is smaller than the tail, PE), cones or triangles (head-group is minimal, cholesterol), truncated inverted-cones (head-group is larger than the tail, SM), and inverted cones (tail is minimal, GSLs, psychosine and LPC) (Figure 1A). The type of lipid and its abundance are major factors influencing morphological features of cell membranes (McMahon and Boucrot 2015). The degree of membrane curvature of a bilayered membrane is determined by the difference resulting from the combined curvatures of the inner versus the outer monolayer leaflets. For example: a monolayer of inverted cone lipids promotes a positive curvature, while conical lipids favors negative curvatures. Cylindrical lipids or associations between cone with inverted cone lipids tend to produce flat monolayers (Cooke and Deserno 2006). The asymmetric distribution of lipid species across the bilayer, (i.e. SLs are mainly located in the outer leaflet whereas PS and PE are mainly associated with the inner leaflet) influence the resulting membrane curvature (Devaux et al. 2008). Although specialized proteins play active roles in membrane curvature (for a review McMahon and Boucrot 2015), the strong dependence between shape/composition and membrane curvature underlines the idea that increased SLs in sphingolipidoses change the composition of lipid domains, inducing positive (outward) membrane bending (Figure 1B). This structural alteration is likely to impact on membrane topology, and the activity of associated signaling pathways.

Changes in membrane curvature could explain some of the phenotypic changes such as membrane swelling observed in various sphingolipidoses. For example, neurons from GM1 and GM2 gangliosidoses displayed large axonal and dendritic swellings (Purpura 1978; Purpura and Baker 1977). In Krabbe’s disease, our group reported in vivo axonal swellings in spinal cords and peripheral nerves of twitcher mice and also in cultured mutant neurons as well as motoneurons incubated with psychosine (Castelvetri et al. 2011). In sphingolipidoses, where there is a progressive accumulation of SLs in the membrane, increased bending could lead to exacerbated shedding of the membrane, an emerging mechanism with significant roles in pathophysiology (Herring et al. 2013) (see also Scesa et al., this issue). Altogether, these data underline the activation of common pathological changes of membranes, including increased rigidity, bending, swelling and vesiculation promoted by the presence of SLs (Figure 1B).

SIGNIFICANCE

The successful treatment of sphingolipidoses has been hampered not only by the rapidity and severity of their phenotype but also by an incomplete mechanistic understanding of how SLs inflict damage to brain cells. We have discussed the idea that SLs could impair physiological signals through (1) disruption of functional lipid domains, (2) membrane rigidification, and (3) cellular deformation by changes in membrane curvature (Figure 1B). The consequences that these early changes in membrane architecture impose to brain physiology are major. Decreases of membrane fluidity and curvature may have far reaching effects, from reducing the efficiency of synaptic vesicles docking and their release to alterations in internodal myelin, to the aberrant activation of microglia and formation of the glial scar (Jana and Pahan 2010; Paintlia et al. 2003; Seyfried et al. 1984). Furthermore, it is probable that these early alterations are limiting factors in current treatments (White et al. 2011), which in most cases require long periods of time to elicit the first clinical improvements. Future therapies may take this aspect into consideration by addressing for example protection of membrane curvature, by the use of cone shaped lipids or membrane-stabilizing proteins (for a review, see McMahon and Boucrot 2015). Although our discussion opted for a more simplistic view of singular lipids, future work should complement our analysis by including other more complex lipids and proteins (Koberlin et al. 2015). Decoding toxicity mechanisms in sphingolipidoses also represents an unique opportunity to understand the physiological function and organization of sphingolipids implicated in diseases other than sphingolipidoses (Gulbins and Petrache 2013).

SIGNIFICANCE

Sphingolipidoses are severe and currently, incurable neurological diseases, where sphingolipids accumulate to high and toxic levels. Little is known about the mechanism by which sphingolipids elicit toxicity. This essay proposes that the insertion of sphingolipids in biological membranes disrupts functional lipid domains and/or induce changes in membrane fluidity and curvature, leading to deregulation of cellular signaling and function.

Acknowledgments

This work was partially funded by the National Multiple Sclerosis Society to LD, and by grants from NIH (R01NS065808 and R21NS087474) and the Legacy of Angels Foundation to ERB.

Footnotes

DISCLOSURE OF CONFLICT OF INTEREST

ERB is a consultant with Lysosomal Therapeutics, Inc.

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