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. The peculiar structure of GM1 reduces the fluidity of the plasma membrane which implies a retention and enrichment of the ganglioside in specific membrane domains called lipid rafts. The dynamism of the GM1 oligosaccharide head allows it to assume different conformations and, in this way, to interact through hydrogen or ionic bonds with a wide range of membrane receptors as well as with extracellular ligands. After more than 60 years of studies, it is a milestone that GM1 is one of the main actors in determining the neuronal functions that allows humans to have an intellectual life. The progressive reduction of its biosynthesis along the lifespan is being considered as one of the causes underlying neuronal loss in aged people and severe neuronal decline in neurodegenerative diseases. In this review, we report on the main knowledge on ganglioside GM1, with an emphasis on the recent discoveries about its bioactive component.

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.

Lysosomal accumulation of undegraded materials is a common feature of lysosomal storage diseases, neurodegenerative disorders, and the aging process. To better understand the role of lysosomal storage in the onset of cell damage, we used human fibroblasts loaded with sucrose as a model of lysosomal accumulation. Sucrose‐loaded fibroblasts displayed increased lysosomal biogenesis followed by arrested cell proliferation. Notably, we found that reduced lysosomal catabolism and autophagy impairment led to an increase in sphingolipids (i.e. , sphingomyelin, glucosylceramide, ceramide, and the gangliosides GM3 and GD3), at both intracellular and plasma membrane (PM) levels. In addition, we observed an increase in the lysosomal membrane protein Lamp‐1 on the PM of sucrose‐loaded fibroblasts and a greater release of the soluble lysosomal protein cathepsin D in their extracellular medium compared with controls. These results indicate increased fusion between lysosomes and the PM, as also suggested by the increased activity of lysosomal glycosphingolipid hydrolases on the PM of sucrose‐loaded fibroblasts. The inhibition of β‐ glucocerebrosidase and nonlysosomal glucosylceramidase, both involved in ceramide production resulting from glycosphingolipid catabolism on the PM, partially restored cell proliferation. Our findings indicate the existence of a new molecular mechanism underlying cell damage triggered by lysosomal impairment.—Samarani, M., Loberto, N., Soldà, G., Straniero, L., Asselta, R., Duga, S., Lunghi, G., Zucca, F. A., Mauri, L., Ciampa, M. G., Schiumarini, D., Bassi, R., Giussani, P., Chiricozzi, E., Prinetti, A., Aureli, M., Sonnino, S. A lysosome‐plasma membrane‐sphingolipid axis linking lysosomal storage to cell growth arrest. FASEB J. 32, 5685–5702 (2018). www.fasebj.org

Gangliosides are glycosphingolipids which are particularly abundant in the plasma membrane of mammalian neurons. The knowledge of their presence in the human brain dates back to the end of 19th century, but their structure was determined much later, in the middle of the 1950s. From this time, neurochemical studies suggested that gangliosides, and particularly GM1 ganglioside, display neurotrophic and neuroprotective properties. The involvement of GM1 in modulating neuronal processes has been studied in detail by in vitro experiments, and the results indicated its direct role in modulating the activity of neurotrophin-dependent receptor signaling, the flux of calcium through the plasma membrane, and stabilizing the correct conformation of proteins, such as α-synuclein. Following, in vivo experiments supported the use of ganglioside drugs for the therapy of peripheral neuropathies, obtaining very positive results. However, the clinical use of gangliosides for the treatment of central neurodegeneration has not been followed due to the poor penetrability of these lipids at the central level. This, together with an ambiguous association (later denied) between ganglioside administration and Guillain-Barrè syndrome, led to the suspension of ganglioside drugs. In this critical review, we report on the evolution of research on gangliosides, on the current knowledge on the role played by gangliosides in regulating the biology of neurons, on the past and present use of ganglioside-based drugs used for therapy of peripheral neuropathies or used in human trials for central neurodegenerations, and on the therapeutic potential represented by the oligosaccharide chain of GM1 ganglioside for the treatment of neurodegenerative diseases.