GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration

Chiricozzi, Elena; Lunghi, Giulia; Biase, Erika Di; Fazzari, Maria; Sonnino, Sandro; Mauri, Laura

doi:10.3390/ijms21030868

Cited by 99 publications

(150 citation statements)

References 194 publications

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“…For several years ganglioside GM1 has been widely studied for its essential role in neuronal differentiation, protection and restoration [3,5,6,29], accomplished through the cooperation with several players expressed on the PM.…”

Section: Discussionmentioning

confidence: 99%

“…Among gangliosides, a particular class of sialic acidcontaining glycosphingolipids enriched in neuronal membranes, particular attention is given to GM1, β-Gal-(1-3)-β-GalNAc-(1-4)-[α-Neu5Ac-(2-3)]-β-Gal-(1-4)-β-Glc-(1-1)-Cer (II 3 Neu5Ac-Gg 4 Cer) by virtue of its relevant implication in neuronal differentiation and in neuronal recovery and protection [1][2][3][4][5][6]. Component of all mammalian brains, GM1 is inserted into the outer layer of the plasma membrane (PM) with the hydrophobic moiety, the ceramide, while the saccharide portion protrudes into the extracellular milieu interacting with a wide range of membrane-associated proteins, including receptors and enzymes [1][2][3][4][5][6]. It has been extensively studied how GM1 induction of neurite outgrowth and neuroprotective phenomena are accomplished through GM1 specific interaction with neurotrophin tyrosine kinase receptors (Trk) and via its ability to modulate cellular calcium (Ca 2+ ) levels, acting on Ca 2+ influx channels, Ca 2+ exchangers, and various Ca 2+ -utilizing enzymes [3,7,8].…”

Section: Introductionmentioning

confidence: 99%

“…Among gangliosides, a particular class of sialic acid-containing glycosphingolipids enriched in neuronal membranes, particular attention is given to GM1, β-Gal-(1–3)-β-GalNAc-(1–4)-[α-Neu5Ac-(2–3)]-β-Gal-(1–4)-β-Glc-(1–1)-Cer (II 3 Neu5Ac-Gg 4 Cer) by virtue of its relevant implication in neuronal differentiation and in neuronal recovery and protection [ 1 – 6 ]. Component of all mammalian brains, GM1 is inserted into the outer layer of the plasma membrane (PM) with the hydrophobic moiety, the ceramide, while the saccharide portion protrudes into the extracellular milieu interacting with a wide range of membrane-associated proteins, including receptors and enzymes [ 1 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Modulation of calcium signaling depends on the oligosaccharide of GM1 in Neuro2a mouse neuroblastoma cells

et al. 2020

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Recently, we demonstrated that the oligosaccharide portion of ganglioside GM1 is responsible, via direct interaction and activation of the TrkA pathway, for the ability of GM1 to promote neuritogenesis and to confer neuroprotection in Neuro2a mouse neuroblastoma cells. Recalling the knowledge that ganglioside GM1 modulates calcium channels activity, thus regulating the cytosolic calcium concentration necessary for neuronal functions, we investigated if the GM1-oligosaccharide would be able to overlap the GM1 properties in the regulation of calcium signaling, excluding a specific role played by the ceramide moiety inserted into the external layer of plasma membrane. We observed, by calcium imaging, that GM1-oligosaccharide administration to undifferentiated Neuro2a cells resulted in an increased calcium influx, which turned out to be mediated by the activation of TrkA receptor. The biochemical analysis demonstrated that PLCγ and PKC activation follows the TrkA stimulation by GM1-oligosaccharide, leading to the opening of calcium channels both on the plasma membrane and on intracellular storages, as confirmed by calcium imaging experiments performed with IP3 receptor inhibitor. Subsequently, we found that neurite elongation in Neuro2a cells was blocked by subtoxic administration of extracellular and intracellular calcium chelators, suggesting that the increase of intracellular calcium is responsible of GM1-oligosaccharide mediated differentiation. These results suggest that GM1-oligosaccharide is responsible for the regulation of calcium signaling and homeostasis at the base of the neuronal functions mediated by plasma membrane GM1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modulation of calcium signaling depends on the oligosaccharide of GM1 in Neuro2a mouse neuroblastoma cells

et al. 2020

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“…Ganglioside GM1 (GM1) has been known for its neurotrophic properties for at least half a century [1], as outlined by several authors in recent years [2][3][4]. GM1 is an integral and fundamental lipid component located on the outer leaflets of membranes of all mammalian cells, and is particularly enriched on the neuronal plasma membrane, where it interacts with the neighboring proteins to modulate intracellular signaling, mainly of biochemical pathways of neuronal differentiation, homeostasis, protection, and restoration [5,6]. GM1 s physiological capacity to recover the functions of damaged central nervous system (CNS) has been widely reported, both in vitro and in vivo [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

Biase

Lunghi

Maggioni

et al. 2020

IJMS

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Ganglioside GM1 (GM1) has been reported to functionally recover degenerated nervous system in vitro and in vivo, but the possibility to translate GM1 s potential in clinical settings is counteracted by its low ability to overcome the blood-brain barrier (BBB) due to its amphiphilic nature. Interestingly, the soluble and hydrophilic GM1-oligosaccharide (OligoGM1) is able to punctually replace GM1 neurotrophic functions alone, both in vitro and in vivo. In order to take advantage of OligoGM1 properties, which overcome GM1 s pharmacological limitations, here we characterize the OligoGM1 brain transport by using a human in vitro BBB model. OligoGM1 showed a 20-fold higher crossing rate than GM1 and time-concentration-dependent transport. Additionally, OligoGM1 crossed the barrier at 4 • C and in inverse transport experiments, allowing consideration of the passive paracellular route. This was confirmed by the exclusion of a direct interaction with the active ATP-binding cassette (ABC) transporters using the "pump out" system. Finally, after barrier crossing, OligoGM1 remained intact and able to induce Neuro2a cell neuritogenesis by activating the TrkA pathway. Importantly, these in vitro data demonstrated that OligoGM1, lacking the hydrophobic ceramide, can advantageously cross the BBB in comparison with GM1, while maintaining its neuroproperties. This study has improved the knowledge about OligoGM1 s pharmacological potential, offering a tangible therapeutic strategy.However, transferring the GM1 neuronal potential from the preclinical models to the clinic depends on its ability to reach the brain structures when administered peripherally. This last aspect is actually severely limited by GM1 s amphiphilicity, which hampers the passage across the blood-brain barrier (BBB) [2,7,8]. This barrier is located at the brain microvessel level and strongly restricts the entry of cells and xenobiotics into the CNS. The BBB anatomical support is the specialized brain endothelial cells of these vessels. These cells do not show any fenestrations and are specifically characterized by the presence of tight junctions (TJ), composed of junctional proteins and TJ-associated proteins. Additionally, these cells express several proteins belonging to the ATP-binding cassette (ABC) transporters family, which act as efflux pumps and play an important role by limiting BBB crossing of several drugs and biological molecules [9,10]. The major efflux pumps expressed at the BBB are P-glycoprotein (P-gp, aka ABCB1), breast cancer resistance protein (BCRP, aka ABCG2), and the multidrug-resistance-associated proteins (MRPs, aka ABCCs).Importantly, the fate of peripherally administered GM1 observed in the rodent models has not been determined in humans, as often the two species display different BBB permeability rates for the same molecule [7,8]. One of the possible explanations for these discrepancies is the species difference recently reported between rodents and human for the expression of several receptors and transporters expressed in the BBB, in...

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“…GM1 is a glycosphingolipid formed by a hydrophobic portion called ceramide, and by a hydrophilic head composed of a sequence of five saccharides: glucose, galactose, n-acetyl-neuraminic acid, n-acetyl-galactosamine, and galactose. GM1 is particularly abundant in neurons where it both exerts important physiological properties, ranging from neuronal plasticity to neuroprotection, and modulates the activity of TrkA receptors by direct interaction [39].…”

Section: Introductionmentioning

confidence: 99%

GM1 as Adjuvant of Innovative Therapies for Cystic Fibrosis Disease

Mancini

Loberto

Olioso

et al. 2020

IJMS

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Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is expressed at the apical plasma membrane (PM) of different epithelial cells. The most common mutation responsible for the onset of cystic fibrosis (CF), F508del, inhibits the biosynthesis and transport of the protein at PM, and also presents gating and stability defects of the membrane anion channel upon its rescue by the use of correctors and potentiators. This prompted a multiple drug strategy for F508delCFTR aimed simultaneously at its rescue, functional potentiation and PM stabilization. Since ganglioside GM1 is involved in the functional stabilization of transmembrane proteins, we investigated its role as an adjuvant to increase the effectiveness of CFTR modulators. According to our results, we found that GM1 resides in the same PM microenvironment as CFTR. In CF cells, the expression of the mutated channel is accompanied by a decrease in the PM GM1 content. Interestingly, by the exogenous administration of GM1, it becomes a component of the PM, reducing the destabilizing effect of the potentiator VX-770 on rescued CFTR protein expression/function and improving its stabilization. This evidence could represent a starting point for developing innovative therapeutic strategies based on the co-administration of GM1, correctors and potentiators, with the aim of improving F508del CFTR function.

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GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration

Cited by 99 publications

References 194 publications

Modulation of calcium signaling depends on the oligosaccharide of GM1 in Neuro2a mouse neuroblastoma cells

Modulation of calcium signaling depends on the oligosaccharide of GM1 in Neuro2a mouse neuroblastoma cells

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

GM1 as Adjuvant of Innovative Therapies for Cystic Fibrosis Disease

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