GM1 structural requirements to mediate neuronal functions.

Since the 1980s, it has been known that the administration of ganglioside GM1 to cultured cells induced or enhanced neuronal differentiation. GM1 mechanism of action relies on its direct interaction and subsequent activation of the membrane tyrosine kinase receptor, TrkA, which naturally serves as NGF receptor. This process is mediated by the sole oligosaccharide portion of GM1, the pentasaccharide β-Gal-(1-3)-β-GalNAc-(1-4)-[α-Neu5Ac-(2-3)]-β-Gal-(1-4)-β-Glc.

Loss of Lipid Carrier ApoE Exacerbates Brain Glial and Inflammatory Responses after Lysosomal GBA1 Inhibition.

Tightly regulated and highly adaptive lipid metabolic and transport pathways are critical to maintaining brain cellular lipid homeostasis and responding to lipid and inflammatory stress to preserve brain function and health. Deficits in the lipid handling genes and are the most significant genetic risk factors for Lewy body dementia and related dementia syndromes. Parkinson's disease patients who carry both APOE4 and GBA1 variants have accelerated cognitive decline compared to single variant carriers.

GM1 ganglioside exerts protective effects against glutamate-excitotoxicity via its oligosaccharide in wild-type and amyotrophic lateral sclerosis motor neurons.

Alterations in glycosphingolipid metabolism have been linked to the pathophysiological mechanisms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Accordingly, administration of GM1, a sialic acid-containing glycosphingolipid, is protective against neuronal damage and supports neuronal homeostasis, with these effects mediated by its bioactive component, the oligosaccharide head (GM1-OS). Here, we add new evidence to the therapeutic efficacy of GM1 in ALS: Its administration to WT and SOD1 motor neurons affected by glutamate-induced excitotoxicity significantly increased neuronal survival and preserved neurite networks, counteracting intracellular protein accumulation and mitochondria impairment.

GM1 oligosaccharide efficacy against α-synuclein aggregation and toxicity in vitro.

Fibrillary aggregated α-synuclein represents the neurologic hallmark of Parkinson's disease and is considered to play a causative role in the disease. Although the causes leading to α-synuclein aggregation are not clear, the GM1 ganglioside interaction is recognized to prevent this process. How GM1 exerts these functions is not completely clear, although a primary role of its soluble oligosaccharide (GM1-OS) is emerging.

GM1 Oligosaccharide Efficacy in Parkinson's Disease: Protection against MPTP.

Past evidence has shown that the exogenous administration of GM1 ganglioside slowed neuronal death in preclinical models of Parkinson's disease, a neurodegenerative disorder characterized by the progressive loss of dopamine-producing neurons: however, the physical and chemical properties of GM1 (i.e., amphiphilicity) limited its clinical application, as the crossing of the blood-brain barrier is denied.

Regulation of signal transduction by gangliosides in lipid rafts: focus on GM3-IR and GM1-TrkA interactions.

The interactions between gangliosides and proteins belonging to the same or different lipid domains and their influence on physiological and pathological states have been analysed in detail. A well-known factor impacting on lipid-protein interactions and their biological outcomes is the dynamic composition of plasma membrane. This review focuses on GM1 and GM3 gangliosides because they are an integral part of protein-receptor complexes and dysregulation of their concentration shows a direct correlation with the onset of pathological conditions.

Novel insights on GM1 and Parkinson's disease: A critical review.

GM1 is a crucial component of neuronal membrane residing both in the soma and nerve terminals. As reported in Parkinson's disease patients, the reduction of GM1 determines the failure of fundamental functional processes leading to cumulative cell distress up to neuron death. This review reports on the role of GM1 in the pathogenesis of the disease, illustrating the current data available but also hypotheses on the additional mechanisms in which GM1 could be involved and which require further study.

Glycosphingolipids.

Glycosphingolipids are amphiphilic plasma membrane components formed by a glycan linked to a specific lipid moiety. In this chapter we report on these compounds, on their role played in our cells to maintain the correct cell biology.In detail, we report on their structure, on their metabolic processes, on their interaction with proteins and from this, their property to modulate positively in health and negatively in disease, the cell signaling and cell biology.

The structure of gangliosides hides a code for determining neuronal functions.

Gangliosides are particularly abundant in the central nervous system, where they are mainly associated with the synaptic membranes. Their structure underlies a specific role in determining several cell physiological processes of the nervous system. The high number of different gangliosides available in nature suggests that their structure, related to both the hydrophobic and hydrophilic portion of the molecule, defines a code, although not completely understood, that through hydrophobic interactions and hydrogen bonds allows the transduction of signals starting at the plasma membranes.

Turning the spotlight on the oligosaccharide chain of GM1 ganglioside.

It is well over a century that glycosphingolipids are matter of interest in different fields of research. The hydrophilic oligosaccharide and the lipid moiety, the ceramide, both or separately have been considered in different moments as the crucial portion of the molecule, responsible for the role played by the glycosphingolipids associated to the plasma-membranes or to any other subcellular fraction. Glycosphingolipids are a family of compounds characterized by thousands of structures differing in both the oligosaccharide and the ceramide moieties, but among them, the nervous system monosialylated glycosphingolipid GM1, belonging to the group of gangliosides, has gained particular attention by a multitude of Scientists.

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

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.

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

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.

The oligosaccharide portion of ganglioside GM1 regulates mitochondrial function in neuroblastoma cells.

The crucial role of ganglioside GM1 in the regulation of neural homeostasis has been assessed by several studies. Recently we shed new light on the molecular basis underlying GM1 effects demonstrating that GM1 oligosaccharide directly binds TrkA receptor and triggers MAPK pathway activation leading to neuronal differentiation and protection. Following its exogenous administration, proteomic analysis revealed an increased expression of proteins involved in several biochemical mechanisms, including mitochondrial bioenergetics.

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

It has been recently reported by our group that GM1-oligosaccharide added to neuroblastoma cells or administered to mouse experimental model mimics the neurotrophic and neuroprotective properties of GM1 ganglioside. In addition to this, differently from GM1, GM1-oligosaccharide is not taken up by the cells, remaining solubilized into the extracellular environment interacting with cell surface proteins. Those characteristics make GM1-oligosaccharide a good tool to study the properties of the endogenous GM1, avoiding to interfere with the ganglioside natural metabolic pathway.

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

Many species of ganglioside GM1, differing for the sialic acid and ceramide content, have been characterized and their physico-chemical properties have been studied in detail since 1963. Scientists were immediately attracted to the GM1 molecule and have carried on an ever-increasing number of studies to understand its binding properties and its neurotrophic and neuroprotective role. GM1 displays a well balanced amphiphilic behavior that allows to establish strong both hydrophobic and hydrophilic interactions.

Parkinson's disease recovery by GM1 oligosaccharide treatment in the B4galnt1 mouse model.

Given the recent in vitro discovery that the free soluble oligosaccharide of GM1 is the bioactive portion of GM1 for neurotrophic functions, we investigated its therapeutic potential in the B4galnt1 mice, a model of sporadic Parkinson's disease. We found that the GM1 oligosaccharide, systemically administered, reaches the brain and completely rescues the physical symptoms, reduces the abnormal nigral α-synuclein content, restores nigral tyrosine hydroxylase expression and striatal neurotransmitter levels, overlapping the wild-type condition. Thus, this study supports the idea that the Parkinson's phenotype expressed by the B4galnt1 mice is due to a reduced level of neuronal ganglioside content and lack of interactions between the oligosaccharide portion of GM1 with specific membrane proteins.

The Neuroprotective Role of the GM1 Oligosaccharide, IINeu5Ac-Gg, in Neuroblastoma Cells.

Recently, we demonstrated that the GM1 oligosaccharide, IINeu5Ac-Gg (OligoGM1), administered to cultured murine Neuro2a neuroblastoma cells interacts with the NGF receptor TrkA, leading to the activation of the ERK1/2 downstream pathway and to cell differentiation. To understand how the activation of the TrkA pathway is able to trigger key biochemical signaling, we performed a proteomic analysis on Neuro2a cells treated with 50 μM OligoGM1 for 24 h. Over 3000 proteins were identified.

GM1 promotes TrkA-mediated neuroblastoma cell differentiation by occupying a plasma membrane domain different from TrkA.

Recently, we highlighted that the ganglioside GM1 promotes neuroblastoma cells differentiation by activating the TrkA receptor through the formation of a TrkA-GM1 oligosaccharide complex at the cell surface. To study the TrkA-GM1 interaction, we synthesized two radioactive GM1 derivatives presenting a photoactivable nitrophenylazide group at the end of lipid moiety, 1 or at position 6 of external galactose, 2; and a radioactive oligosaccharide portion of GM1 carrying the nitrophenylazide group at position 1 of glucose, 3. The three compounds were singly administered to cultured neuroblastoma Neuro2a cells under established conditions that allow cell surface interactions.

Desogestrel down-regulates PHOX2B and its target genes in progesterone responsive neuroblastoma cells.

The paired-like homeobox 2B gene (PHOX2B) encodes a key transcription factor that plays a role in the development of the autonomic nervous system and the neural structures involved in controlling breathing. In humans, PHOX2B over-expression plays a role in the pathogenesis of tumours arising from the sympathetic nervous system such as neuroblastomas, and heterozygous PHOX2B mutations cause Congenital Central Hypoventilation Syndrome (CCHS), a life-threatening neurocristopathy characterised by the defective autonomic control of breathing and involving altered CO/H chemosensitivity. The recovery of CO/H chemosensitivity and increased ventilation have been observed in two CCHS patients using the potent contraceptive progestin desogestrel.

Role of the GM1 ganglioside oligosaccharide portion in the TrkA-dependent neurite sprouting in neuroblastoma cells.

GM1 ganglioside (II NeuAc-Gg Cer) is known to promote neurite formation in neuroblastoma cells by activating TrkA-MAPK pathway. The molecular mechanism by which GM1 is involved in the neurodifferentiation process is still unknown, however, in vitro and in vivo evidences have suggested that the oligosaccharide portion of this ganglioside could be involved. Here, we report that, similarly to the entire GM1 molecule, its oligosaccharide II NeuAc-Gg rather than its ceramide (Cer) portion is responsible for the neurodifferentiation process by augmenting neurite elongation and increasing the neurofilament protein expression in murine neuroblastoma cells, Neuro2a.