Gangliosides in the differentiation process of primary neurons: the specific role of GM1-oligosaccharide

Biase, Erika Di; Lunghi, Giulia; Fazzari, Maria; Maggioni, Margherita; Pomè, Diego Yuri; Valsecchi, Manuela; Samarani, Maura; Fato, Pamela; Ciampa, Maria Grazia; Prioni, Simona; Mauri, Laura; Sonnino, Sandro; Chiricozzi, Elena

doi:10.1007/s10719-020-09919-x

Cited by 24 publications

(43 citation statements)

References 67 publications

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“…It has been proved that GM1-oligosaccharide, β-Gal-(1-3)-β-GalNAc-(1-4)-[α-Neu5Ac-(2-3)]-β-Gal-(1-4)-Glc (OligoGM1; II 3 Neu5Ac-Gg 4 ), exogenously added to the culture medium of N2a neuroblastoma cells, was able alone to induce the neuritogenesis process by directly interacting with nerve growth factor (NGF)-specific receptor TrkA at the PM, reserving to the ceramide an exclusively anchor and structural role [13]. Subsequently we found that OligoGM1 administered to cerebellar granule neurons enhanced neuron clustering, neurite sprouting and networking, thus confirming the specific role of the oligosaccharide chain in the processes of neuronal differentiation and maturation, known to be regulated by the entire GM1 [14]. Additionally, the OligoGM1 was found to mediate also the neuroprotective phenomena attributed to ganglioside GM1, being able to induce protection from 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine hydrochloride (MPTP) neurotoxicity in N2a neuroblastoma cells [15] acting on mitochondria [16], and to rescue the physical and biochemical defects due to the partial lack of GM1 content in a mouse model of Parkinson's disease [17].…”

Section: Introductionsupporting

confidence: 65%

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: Introductionsupporting

confidence: 65%

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

et al. 2020

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“…On the other hand, binding of GM1 to the tropomyosin-receptor kinase A (TrkA) promotes receptor dimerization and activation, and downstream outcomes such as neurite outgrowth and neuroprotection (Mutoh et al, 1995;Farooqui et al, 2002;Da Silva et al, 2005;Duchemin et al, 2008). Recent studies showed that the GM1 pentasaccharide headgroup is able to mimic the effects of the entire GM1 molecule (including the ceramide tail) on TrkA activation and signaling (Chiricozzi et al, 2017;Di Biase et al, 2020a). In contrast, both the glycan headgroup and the ceramide tail of GT1b are required for the interaction of this ganglioside with synaptotagmin 1/2 in order to form a high-affinity receptor complex for the botulinum toxin B at nerve endings (Flores et al, 2019).…”

Section: Cis-interactions Of Gangliosides With Membrane Proteinsmentioning

confidence: 99%

“…The development of strategies to overcome issues with drug delivery across the blood-brain barrier (BBB) (Revunov et al, 2020) will be crucial to this endeavor, even for the treatment of neurodegenerative/trauma-related conditions where the BBB might be partially compromised. Recent studies suggested that the pentasaccharide component of the GM1 molecule, which can reproduce the ganglioside effects on TrkA receptor activation and signaling (Chiricozzi et al, 2017;Di Biase et al, 2020a), can cross an in vitro model of BBB through a paracellular route (Di Biase et al, 2020b). However, whether the pentasaccharide can cross the BBB in more stringent conditions and in vivo, where the paracellular transport is very limited (Sweeney et al, 2019) remains to be determined.…”

Section: Additional Considerations and Conclusionmentioning

confidence: 99%

Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

et al. 2020

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Gangliosides are glycosphingolipids highly abundant in the nervous system, and carry most of the sialic acid residues in the brain. Gangliosides are enriched in cell membrane microdomains ("lipid rafts") and play important roles in the modulation of membrane proteins and ion channels, in cell signaling and in the communication among cells. The importance of gangliosides in the brain is highlighted by the fact that loss of function mutations in ganglioside biosynthetic enzymes result in severe neurodegenerative disorders, often characterized by very early or childhood onset. In addition, changes in the ganglioside profile (i.e., in the relative abundance of specific gangliosides) were reported in healthy aging and in common neurological conditions, including Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis and epilepsy. At least in HD, PD and in some forms of epilepsy, experimental evidence strongly suggests a potential role of gangliosides in disease pathogenesis and potential treatment. In this review, we will summarize ganglioside functions that are crucial to maintain brain health, we will review changes in ganglioside levels that occur in major neurological conditions and we will discuss their contribution to cellular dysfunctions and disease pathogenesis. Finally, we will review evidence of the beneficial roles exerted by gangliosides, GM1 in particular, in disease models and in clinical trials.

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“…To date, although the missing association between GM1 injection and Guillain-Barré syndrome development seems to have been accepted, the disadvantage of GM1 s inability to cross the BBB still means its potential is underexploited. Importantly, our studies to disclose the mechanism of action underlying the neurotrophic and reparative properties of GM1 have revealed that the bioactive portion of the molecule is the oligosaccharide chain [22][23][24]26,27], which surprisingly, if administered peripherally into mice, is detectable within the brain [25]. Even more noteworthy is the finding that OligoGM1 injection in a sporadic Parkinson's disease model, the B4galnt1 +/mouse, in which the neuronal GM1 content is decreased due to a reduced expression of B4galnt1 glycosyltransferase, promoted a recovery of both behavioral and biochemical features, reaching healthy conditions [25].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, we recently recognized that GM1 exerts its neurotrophic functions by interacting with and activating plasma membrane receptors throughout its oligosaccharide portion-GM1-oligosaccharide (OligoGM1) [22][23][24][25]. We demonstrated that OligoGM1, alone and without entering into the cells, perfectly replicates the neuronal differentiative properties of GM1 in neuroblastoma Neuro2a (N2a) cells and in primary neurons [22,26]. Additionally, OligoGM1 confers protection from 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity and oxidative stress by increasing mitochondrial biogenesis and activity [24,27].…”

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confidence: 91%

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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Gangliosides in the differentiation process of primary neurons: the specific role of GM1-oligosaccharide

Cited by 24 publications

References 67 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

Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

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

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