Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications.

Simonetta Sipione,Vaibhavi Kadam,Noam Steinberg,Danny Galleguillos,John Monyror

doi:10.3389/fnins.2020.572965

Abstract

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.

Highlights

Gangliosides are glycosphingolipids composed of a ceramide lipid tail attached through glycosidic linkage to a glycan headgroup containing one or more sialic acid residues (Figure 1)
The authors of this study proposed a model whereby binding of GluR2 and AMPAR-trafficking complex (ATC) to GM1 and GT1b, respectively, would result in their sequestration within distinct membrane microdomains and away from each other, ensuring that AMPA receptor (AMPAR) are retained at the synaptic membrane
Evidence from human and mouse studies strongly suggests that a decrease in endogenous gangliosides plays a significant role in the pathogenesis of Parkinson’s disease (PD) and Huntington’s disease (HD), it remains unknown why this pathway becomes affected and whether cerebrospinal fluid (CSF) levels of gangliosides might be used as biomarkers of disease onset and/or progression

Summary

Introduction

Gangliosides are glycosphingolipids composed of a ceramide lipid tail attached through glycosidic linkage to a glycan headgroup containing one or more sialic acid residues (Figure 1). Enrichment of the plasma membrane with GM1 resulting from the activity of neuraminidase 3 (NEU3) – a ganglioside-specific sialidase that converts GD1a and GT1b to GM1 – was shown to trigger Ca2+ influx in neuronal cells through T-type calcium channels, and to induce neuritogenesis (Wu and Ledeen, 1994).

Results

Conclusion