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Gangliosides are membrane glycosphingolipids bearing sialic acid residues. Within membranes, gangliosides are specifically
enriched in highly organized domains, lipid rafts, and are attributed with diverse functions such as intercellular interactions,
cell recognition, neurotransmission, and signal transduction. The highest concentration and variab...
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Context 1
... are a diverse class of glycosphingolipids found in all mammalian membranes, although they are especially abundant in neural tissue. These amphipathic molecules consist of a hydrophobic ceramide core anchoring a polar carbohydrate chain, bearing one or more sialic acid residues in the outer leaflet of the plasma membrane ( Figure 1) [1]. Several hundreds of ganglioside structures have been characterized based on differences in either the oligosaccharide chain, or the fatty acids linked to the ceramide moiety of the molecule [2]. ...
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Diabetic neuropathy is a consequence of long-term hyperglycemia. The emergence of neuronal condition is a result of hyperglycemia-induced oxidative stress. In the present study, streptozotocin-induced diabetes exhibited notable decrease in the levels of phospholipids, glycolipids, gangliosides, and triglycerides in the sciatic nerve. The alteration...
Gangliosides are a family of sialic-acid-containing glycosphingolipids that form dynamic domains (lipid rafts) with proteins in cell plasma membranes (PMs), and are involved in various biological processes. The dynamic behavior of gangliosides can be elucidated by analyzing fluorescently-labeled molecules with a powerful technique known as single-m...
Background
Gangliosides are glycosphingolipids highly enriched in the brain, with important roles in cell signaling, cell-to-cell communication, and immunomodulation. Genetic defects in the ganglioside biosynthetic pathway result in severe neurodegenerative diseases, while a partial decrease in the levels of specific gangliosides was reported in Pa...
Background
Gangliosides are glycosphingolipids highly enriched in the brain, with important roles in cell signaling, cell-to-cell communication, and immunomodulation. Genetic defects in the ganglioside biosynthetic pathway result in severe neurodegenerative diseases, while a partial decrease in the levels of specific gangliosides was reported in Pa...
Citations
... Brain development is accompanied by the progressive accumulation of gangliosides, as has been demonstrated in teleost fish, chickens, mice, rats and humans [74][75][76][77][78][79]. The concentration plateau is reached during maturation and begins to decline with ageing [80][81][82]. In the adult organism, neural tissues have a one to two orders of magnitude higher concentration of glycosphingolipids compared to extraneural tissues [83]. ...
Lipid rafts, specialised microdomains within cell membranes, play a central role in orchestrating various aspects of neurodevelopment, ranging from neural differentiation to the formation of functional neuronal networks. This review focuses on the multifaceted involvement of lipid rafts in key neurodevelopmental processes, including neural differentiation, synaptogenesis and myelination. Through the spatial organisation of signalling components, lipid rafts facilitate precise signalling events that determine neural fate during embryonic development and in adulthood. The evolutionary conservation of lipid rafts underscores their fundamental importance for the structural and functional complexity of the nervous system in all species. Furthermore, there is increasing evidence that environmental factors can modulate the composition and function of lipid rafts and influence neurodevelopmental processes. Understanding the intricate interplay between lipid rafts and neurodevelopment not only sheds light on the fundamental mechanisms governing brain development but also has implications for therapeutic strategies aimed at cultivating neuronal networks and addressing neurodevelopmental disorders.
... From a pathophysiological point of view, disorders of calcium ion homeostasis in the neurons are involved in degenerative diseases, aging, and excitotoxicity, as well as ischemia and hypoglycemia. Changes in the amount and composition of gangliosides have been detected in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases [29]. Lack of interneurons is a possible link between cognitive dysfunction and variable neuronal activity in various neurodegenerative diseases [30]. ...
Gangliosides are major glycans on vertebrate nerve cells, and their metabolic disruption results in congenital disorders with marked cognitive and motor deficits. The sialyltransferase gene St3gal2 is responsible for terminal sialylation of two prominent brain gangliosides in mammals, GD1a and GT1b. In this study, we analyzed the expression of calcium-binding interneurons in primary sensory (somatic, visual, and auditory) and motor areas of the neocortex, hippocampus, and striatum of St3gal2-null mice as well as St3gal3-null and St3gal2/3-double null. Immunohistochemistry with highly specific primary antibodies for GABA, parvalbumin, calretinin, and calbindin were used for interneuron detection. St3gal2-null mice had decreased expression of all three analyzed types of calcium-binding interneurons in all analyzed regions of the neocortex. These results implicate gangliosides GD1a and GT1b in the process of interneuron migration and maturation.
... Synaptic vesicles are enriched in plasmalogens where it has been suggested that they play a role in facilitating trafficking and membrane fusion processes that are known to lead to efficient neurotransmitter delivery at the synapse (Brodde, Teigler, Brugger, Lehmann, Wieland, Berger, & Just, 2012;Dean, & Lodhi, 2018). Throughout life, the Gang content of the brain changes continuously, following a specific temporal and regional distribution pattern (Mlinac, & Bognar, 2010;Grassi, Giussani, Mauri, Prioni, Sonnino, & Prinetti, 2020). The diminution of Gang, and to a lesser extent of SM content found in TC might represent a compensatory mechanism in response to the increased concentration of PLs occurred in rats fed BMC supplement. ...
Aging is associated with a decline in cognitive abilities, mainly in memory and executive functioning. A similar but premature deterioration in cognitive capacities is the hallmark of mild cognitive impairment, Alzeimer’s disease and dementia. The biochemical mechanisms that cause these neurodegenerative disorders are poorly understood. However, some evidence suggests that insufficient dietary intakes of some phospholipids could impact on brain function and increase the risk of future cognitive impairment and dementia. We evaluated the cognitive and biochemical effects of supplementation with a milk fat globule membrane (MFGM) concentrate in aged rats.
We observed that, compared to control animals, MFGM supplemented rats showed enhanced spatial working memory, but both groups exhibited similar reference spatial learning and emotional memory abilities. No significant differences between BDNF levels in the hippocampus and frontal cortex of treated rats as compared to controls were found. The nootropic effects observed were accompanied by significant changes in the lipid composition of synaptic membranes. MFGM supplementation increased the levels of EPA and DHA acids as well as the plasmalogens content in the synaptosomes isolated from the hippocampus (Synapt-HP) and the frontal cortex (Synapt-FC). In addition enhanced levels of phosphatidyl serine (PS), particularly PS(18:1/18:1), and phosphatidyl inositol (PI) molecular species were observed in Synapt-HP and Synapt-FC of treated animals.Lipidomic analysis also revealed greater concentration of phosphatidyl ethanolamine (PE) molecular species containing very long-chain fatty acids and PE plasmenyls in Synapt-HP as well as an increase of the SM content in Synapt-FC from the MFGM group. Although further studies are needed to confirm the underlying mechanism (individual or synergistic), these results suggest that MFGM supplementation could be employed as a dietary implement to restore the proper cerebral concentration of some bioactive lipids and prevent or slow the progression of age-related cognitive impairment.
... Gangliosides are synthesized stepwise by a vast number of glycosyltransferases in a complex biosynthetic pathway in the Golgi apparatus from where they are trafficked to the plasma membrane [33,34]. They play a crucial role in various physiological processes including brain development, aging, and neurodegeneration by modulating the cell signal transduction pathways, neuronal differentiation, and structures and functions of membrane proteins [26,35]. The functions of gangliosides in the central nervous system can be revealed by the physiological manifestations of genetic mutations in the ganglioside biosynthetic pathway, observed both from studies of rare human diseases resulting from mutations in the ganglioside biosynthesis pathway and transgenic mouse models with impaired synthesis of gangliosides [36,37]. ...
Gangliosides, amphiphilic glycosphingolipids, tend to associate laterally with other membrane constituents and undergo extensive interactions with membrane proteins in cis or trans configurations. Studies of human diseases resulting from mutations in the ganglioside biosynthesis pathway and research on transgenic mice with the same mutations implicate gangliosides in the pathogenesis of epilepsy. Gangliosides are reported to affect the activity of the Na+/K+-ATPase, the ubiquitously expressed plasma membrane pump responsible for the stabilization of the resting membrane potential by hyperpolarization, firing up the action potential and ion homeostasis. Impaired Na+/K+-ATPase activity has also been hypothesized to cause seizures by several mechanisms. In this review we present different epileptic phenotypes that are caused by impaired activity of Na+/K+-ATPase or changed membrane ganglioside composition. We further discuss how gangliosides may influence Na+/K+-ATPase activity by acting as lipid sorting machinery providing the optimal stage for Na+/K+-ATPase function. By establishing a distinct lipid environment, together with other membrane lipids, gangliosides possibly modulate Na+/K+-ATPase activity and aid in “starting up” and “turning off” this vital pump. Therefore, structural changes of neuronal membranes caused by altered ganglioside composition can be a contributing factor leading to aberrant Na+/K+-ATPase activity and ion imbalance priming neurons for pathological firing.
... Thus, the utilization of highly sensitive modern mass spectrometric methods has so far enabled detailed structural characterization of human brain gangliosides, and revealed the presence of novel or modified ganglioside structures viewed as specific pathological, diagnostic markers or potential therapeutic targets [10,11]. Alterations in brain ganglioside composition or metabolism have been found in different neurological and neuropsychiatric conditions and are considered to be involved in complex molecular pathogenesis of neurodegeneration [12][13][14][15]. Certain human diseases such as refractory epilepsy are caused by the deficiency in enzymes involved in ganglioside synthesis [16,17]. ...
In this study, we developed a high-resolution tandem mass spectrometry (HR MS) approach to assess presumed changes in gangliosidome of a human hippocampus affected by temporal lobe epilepsy (TLE) in comparison with a normal hippocampus. Gangliosides, membrane glycolipids, are particularly diverse and abundant in the human brain, and participate in ion transport and modulation of neuronal excitability. Changes in structural ganglioside pattern potentially linked to TLE molecular pathogenesis have not been explored in detail. Aiming to characterize TLE-specific gangliosidome, we analyzed the native gangliosides purified from a human hippocampal tissue sample affected by TLE and a control hippocampus using HR MS. Marked differences of ganglioside expression were shown in TLE vs. control, particularly with respect to the sialylation degree of components, discovered as a characteristic feature of TLE. Another major finding is the occurrence of tetrasialofucogangliosides in TLE and species modified by either O-acetylation or CH3COO⁻. Structural analysis by higher-energy collisional dissociation (HCD) MS/MS gave rise to fragmentation patterns implying that the GQ1b (d18:1/18:0) isomer is specifically associated with TLE. Further investigation in a larger sample is needed in order to confirm the discovery of ganglioside structures specifically expressed in human TLE and to provide information on the probable role of gangliosides in the molecular events underlying seizures.
... Moreover, gangliosides are involved in a myriad of important cell functions, including cell-cell adhesion (25), growth regulation (26,27), Ca 2þ homeostasis (28), and cell-to-cell communication (29,30). Concomitantly, the impairment of ganglioside metabolism has been associated with numerous human pathologies, including several lysosomal storage diseases (26,31), Parkinson's (27,32,33) and Alzheimer's (34)(35)(36)(37) diseases, Guillain-Barr e syndrome (38), cancer progression (25,39,40, insulin sensitivity and diabetes (41,42, and bacterial toxin susceptibility43. The roles of gangliosides in health and disease have been thoroughly reviewed elsewhere (44)(45)(46). ...
Gangliosides form an important class of receptor lipids containing a large oligosaccharide headgroup whose ability to self-organize within lipid membranes results in the formation of nanoscopic platforms. Despite of their biological importance, the molecular basis for the nanoscopic segregation of gangliosides is not clear. In this work, we investigated the role of the ganglioside headgroup on the nanoscale organisation of gangliosides. We studied the effect of the reduction in the number of sugar units of the ganglioside oligosaccharide chain on the ability of gangliosides GM1, GM2 and GM3 to spontaneously self-organize into lipid nanodomains. To reach nanoscopic resolution and to identify molecular forces that drive ganglioside segregation, we combined an experimental technique MC-FRET offering high lateral and trans-bilayer resolution with molecular dynamics (MD) simulations. We show the ganglioside headgroup plays a key role in ganglioside self-assembly despite the negative charge of the sialic acid group. The nanodomains range from 7 to 120 nm in radius and are majorly composed of the surrounding bulk lipids, with gangliosides being a minor component of the nanodomains. The interactions between gangliosides are dominated by the hydrogen bonding network between the headgroups that facilitates ganglioside clustering. The N-acetylgalactosamine sugar moiety of GM2, however, seems to impair the stability of these clusters by disrupting hydrogen bonding of neighbouring sugars, which is in agreement with a broad size distribution of GM2 nanodomains. The simulations suggest that the formation of nanodomains are likely accompanied by several conformational changes in the gangliosides, which, however, have little impact on the solvent exposure of these receptor groups. Overall, this work identifies the key physicochemical factors that drive nanoscopic segregation of gangliosides.
... In turn, skeletal muscle and connective tissues are enriched in a short ganglioside GM3 almost entirely containing stearic acid in the ceramide moiety [49]. The tissue-specific pattern for ganglioside expression may vary throughout the embryogenesis [50], aging [51], and cellular differentiation [52]. During the prenatal development, GM1 and GM3 are delivered to the fetus across placenta [53], followed by their metabolic conversion into gangliosides with elongated sialic acid chains [54]. ...
Background
Gangliosides are an essential component of eukaryotic plasma membranes implicated in multiple physiological processes. Little is known about molecular mechanisms underlying the distribution and functions of membrane gangliosides. The overwhelmingly complex organization of glycocalyx impedes the structural analysis on cell surface and the interplay between the lipid components. Advanced X-ray analytical tools applicable to studying biological interfaces call for the simplistic models that mimic ganglioside-enriched cellular membranes.
Objective
To summarize the mechanistic evidences of ganglioside interactions with lipid environment and biologically active ligands using high-resolution synchrotron X-ray scattering.
Methods
A comprehensive review of studies published over the last decade was done to discuss recent accomplishments and future trends
Results
Langmuir monolayers represent an adequate model system to assess the effect of gangliosides on membrane structure. Grazing incidence X-ray diffraction reveals a condensation effect by gangliosides on zwitterionic phospholipids with the cooperative packing of sialo- and phosphate groups. In turn, the arrangement of negatively charged lipids in ganglioside mixture remains unchanged due to the stretched conformation of carbohydrate moieties. Upon interaction with biological ligands, such as cholera toxin and galectins, the ganglioside redistribution within the ordered regions of monolayer follows distinct mechanistic patterns. The cholera toxin pentamer attached to the oligosaccharide core induces local transition from oblique to the hexagonal lattice resulting in phase coexistence. The incorporation of the A subunit responsible for endocytosis is further promoted by the acidic environment characteristic for endosomal space. X-ray reflectivity shows in-plane orientation of galectin dimers with the spatial mismatch between the lectin binding sites and ganglioside carbohydrates to perturb ceramide alkyl chains. Recent data also demonstrate sialic acid groups to be potential targets for novel peptide mimicking anticancer therapeutics.
Conclusion
Coupled with surface X-ray scattering, the membrane mimetic approach allows for better understanding the biological role of gangliosides and their potential applications.
... One type of neuronal lipids -gangliosides -is of special interest, with some contradicting results as to what occurs to their levels as a result of AD. Reductions in the amount of gangliosides present in the membrane have been observed in several regions of AD brains compared to that of control brains [16][17][18] while other studies have suggested ganglioside plays a role in the formation of plaques and an increase in ganglioside monosialotetrahexosylganglioside (GM1) results in an increase of Aβ aggregation in vitro [19][20][21] . However, changes in membrane lipid composition may occur before the onset of AD symptoms and its corresponding cellular pathology. ...
Amyloid-beta peptides (Aβ), implicated in Alzheimer’s disease (AD), interact with the cellular membrane and induce amyloid toxicity. The composition of cellular membranes changes in aging and AD. We designed multi-component lipid models to mimic healthy and diseased states of the neuronal membrane. Using atomic force microscopy (AFM), Kelvin probe force microscopy (KPFM) and black lipid membrane (BLM) techniques, we demonstrated that these model membranes differ in their nanoscale structure and physical properties, and interact differently with Aβ1–42. Based on our data, we propose a new hypothesis that changes in lipid membrane due to aging and AD may trigger amyloid toxicity through electrostatic mechanisms, similar to the accepted mechanism of antimicrobial peptide action. Understanding the role of the membrane changes as a key activating amyloid toxicity may aid in the development of a new avenue for the prevention and treatment of AD.
... These shifts appear to be region dependent, with human hippocampus presenting only a slight decrease in GD1a (Kracun et al. 1992; Segler-Stahl et al. 1983). Whatever region or lipids are selectively affected, there is ever growing evidence that the lipids of neuronal membranes are affected in response to aging or inflammation as a need for cell adaptation for survival and preservation of function , but these lipid shifts are also involved in the onset of grave pathologies such as Alzheimer and Parkinson (Kristina Mlinac 2010). Thus, our results show that OUA alone has the potential of altering/modulating the membrane lipid composition of rat hippocampal membranes (RHM) of 3-month-old rats in the short term (2 h), since the ganglioside altered the content of total phospholipids and gangliosides. ...
The effects of ouabain (OUA) and lipopolysaccharide (LPS) in vivo on hippocampal membranes (RHM) of Wistar male rats aged 3 months were analyzed. After intraperitoneal (i.p.) injection of OUA only, LPS only, OUA plus LPS, or saline, the content of proteins, phospholipids, cholesterol and gangliosides from RHM was analyzed. The total protein and cholesterol contents of RHM were not significantly affected by OUA or LPS for the experimentally paired groups. In contrast, total phospholipids and gangliosides were strongly modulated by either OUA or LPS treatments. LPS reduced the total phospholipids (roughly 23 %) and increased the total gangliosides (approximately 40 %). OUA alone increased the total phospholipids (around 23 %) and also the total gangliosides (nearly 34 %). OUA pretreatment compensated the LPS-induced changes, preserving the total phospholipids and gangliosides around the same levels of the control. Thus, an acute treatment with OUA not only modulated the composition of hippocampal membranes from 3-month-old rats, but also was apparently able to counteract membrane alterations resulting from LPS-induced neuroinflammation. This study demonstrates for the first time that the OUA capacity modulates the lipid composition of hippocampal plasma membranes from rats with LPS-induced neuroinflammation.
... Our research group showed that LEF has affinity for fetuin, a glycoprotein that has sialic acid at the terminal sugar residues (Ashida et al., 2000) and for N-acetyl-D-neuramic acid (sialic acid) (Santos, 2001 and this study). Sialic acid is a component of the cell plasma membrane that modulates signal transduction particularly in gangliosides, a class of complex glycosphingolipids present in neuronal cell membranes (Mlinac and Bognar, 2010). There is evidence that sialic acids mediate specific cellular and molecular recognition by regulating association with glycan-binding proteins such as lectins (Zhuo and Bellis, 2011). ...
Natural intoxication of livestock by ingestion of Ipomoea asarifolia leaves has been reported to occur widely in Brazil. Previous studies carried out by our research group provided strong evidence that a lectin could be involved with the toxic properties of I. asarifolia. To reinforce this hypothesis, a lectin-enriched fraction (LEF) was isolated from I. asarifolia leaves and its toxic effects were assessed. Leaves of I. asarifolia were excised from plants growing widely in the field, mechanically wounded and maintained in a chamber at 25 ± 3 °C for 72h in the dark, under near 100% relative humidity. The leaf proteins were extracted, ammonium sulfate precipitated, chromatographed on DEAE-cellulose and Phenyl-Sepharose to produce LEF that under SDS-PAGE showed a molecular mass of 44.0 kDa and after N-terminal amino acid analysis a primary sequence composed of AGYTPVLDIGAEVLAAGEPY. The in vivo toxicity of LEF assessed by intraorbital injection in mice showed induced severe uncoordinated movements without death. LEF reduced the muscular contraction in a dose depend way and at 29.8 μg/mL (CE(50)) it produces 50% inhibition of contraction, suggesting that LEF blunts autonomic neurotransmission. Isolated rat kidneys were perfused with LEF and no effects on the perfusion pressure or renal vascular resistance were observed, but urinary flow and glomerular filtration rate increased. Moreover, the percentage of tubular transport of Na(+), K(+) and Cl(-) decreased. Histological examination of the kidneys perfused with LEF exhibited little alterations. These toxic effects observed above were concomitant with the increase of LEF hemagglutination activity, which strongly suggest that one of the toxic principles of I. asarifolia is a lectin present in its leaves.
