Turning the spotlight on the oligosaccharide chain of GM1 ganglioside

Abstract

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. In recent years, a series of studies have been conducted on the functional roles played by the hydrophilic part of GM1, its oligosaccharide, that we have named “OligoGM1”. These studies allowed to shed new light on the mechanisms underlying the properties of GM1 defining the role of the OligoGM1 in determining precise interactions with membrane proteins instrumental for the neuronal functions, leaving to the ceramide the role of correctly positioning the GM1 in the membrane crucial for the oligosaccharide-protein interactions. In this review we aim to report the recent studies on the cascade of events modulated by OligoGM1, as the bioactive portion of GM1, to support neuronal differentiation and trophism together with preclinical studies on its potential to modify the progression of Parkinson’s disease.

Plasma membrane glycosphingolipid signaling: a turning point

“…Since 2015, my research activity has mainly been focused on GM1 ganglioside in relation to both neuronal physiological and pathological implication [31][32][33][34][35][36][37][38][39][40][41]. Together with my research group, I give a very important contribution to the understanding of the role of GM1 oligosaccharide as the bioactive portion of the GM1 molecule, opening a new prospective on the ganglioside-mediated signalling across the plasma membrane.…”

“…This enzyme removes sialic acid residues from brain polysialogangliosides (i.e., GD1a), thus increasing plasma membrane GM1, further evidence that the oligosaccharide may act as the mediator of GM1 function. Accordingly, my collaborators and I recently reported that the soluble OligoGM1 (II 3 Neu5Ac-Gg 4 ) replicates the neurotrophic and neuroprotective properties of the entire GM1 molecule: GM1 exerts its bioactivity through its hydrophilic head, which protrudes into the extracellular environment and therefore acts at the cell surface by interacting with plasma membrane proteins [31][32][33][34][35][36][37][38][39][40][41].…”

“…In fact, I reported in neuronal cells that, within the entire GM1 molecule, OligoGM1 is the actual moiety responsible for GM1 neurotrophic properties [31][32][33][34][35][36][37][38][39][40][41]. OligoGM1 directly interacts with the NGF receptor TrkA, leading to MAPK (i.e.…”

“…From this premise, it emerged our idea that the plasma membrane OligoGM1 decline could be the trigger for sustained pathway impairment as the etiopathogenetic target event of sporadic PD, which is characterized by a systemic reduction of GM1. Supported by extensive research into the physiological function and pathological implications of ganglioside GM1 [39,[45][46][47][48] and by solid data on OligoGM1 functions [31][32][33][34][35][36][37][38][39][40], I propose a new key to untying the knot of complex neurodegenerative Fig. 3 Proposed mechanism diagram of the GM1 oligosaccharide mediated functions.…”

“…The prompt restoration of all the mechanisms (i.e., oxidative stress and mitochondrial dysfunction, inflammation, excitotoxicity, loss of trophic support and protein accumulation/aggregation) that are likely to contribute and to exacerbate the pathogenesis of Parkinson and in general to multifactorial neurodegenerative disorders (i.e., Alzheimer's disease) is fundamental to the recovery of injured cells and tissues, particularly those with delicate equilibria (i.e., dopaminergic neurons). Otherwise, OligoGM1 should drive plasma membrane trophic signalling inducing a reduction in glia/microglia activation, oxidative stress, mitochondria dysfunction, excitotoxicity and α-synuclein aggregation resulting in the recovery of damaged neurons and the restoration of normal healthy phenotype [39]. These concepts bring out the OligoGM1 as a cutting-edge molecule able to recover and cope with all aspects of neurodegenerative diseases, for which, to date, there are no effective therapies.…”