Abstract
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.
Highlights
Gangliosides are glycosphingolipids which are abundant in the plasma membrane of mammalian neurons
The earliest knowledgeand of glycosphingolipids dates to the end in the interest of many scientists, many studies onand thegangliosides role played byback gangliosides of the 19th century [3], but their precise structure remained unknown for decades
It was clearly verified that GM1 promotes neurite sprouting [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27] by interacting, at the plasma membrane level, with neurotrophin-dependent receptors, such as the nerve grow factor (NGF)-dependent tyrosine kinase family receptors Trk [16], and the glia cell-derived neurotrophic factor (GDNF) receptor complex RET [17,18]
Summary
Gangliosides [1,2] are sialic acid-containing glycosphingolipids They are inserted into the plasma membrane through the lipid fraction called ceramide and are characterized by a large hydrophilic head group that protrudes into the extracellular environment and is free to interact with neighboring molecules (lipids and/or proteins). The earliest knowledgeand of glycosphingolipids dates to the end in the interest of many scientists, many studies onand thegangliosides role played byback gangliosides of the 19th century [3], but their precise structure remained unknown for decades It was in human brain quickly appeared, introducing the concept that gangliosides exhibit neurothe mid-twentieth century that their structure was clarified [4,5,6]. The following models for modulating natural ganglioside contents deserve a mention: (i) by the addition of exogenous gangliosides to cell culture media that, under defined experimental conditions, are taken up by the cells and become components of the plasma membranes, becoming almost identical to the endogenous one; (ii) by silencing or overexpressing those enzymes involved in the ganglioside biosynthesis, both in vitro and in vivo, allowing the development of cell and animal models with altered (reduced or increased) ganglioside content
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