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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.

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. [ABSTRACT FROM AUTHOR]

Huntington Disease (HD) is a genetic neurodegenerative disorder characterized by broad types of cellular and molecular dysfunctions that may affect both neuronal and non-neuronal cell populations. Among all the molecular mechanisms underlying the complex pathogenesis of the disease, alteration of sphingolipids has been identified as one of the most important determinants in the last years. In the present study, besides the purpose of further confirming the evidence of perturbed metabolism of gangliosides GM1, GD1a and GT1b, the most abundant cerebral glycosphingolipids, in the striatal and cortical tissues of HD transgenic mice, we aimed to test the hypothesis that abnormal levels of these lipids may be found also in the corpus callosum white matter, a ganglioside-enriched brain region described being dysfunctional early in the disease. Semi-quantitative analysis of GM1, GD1a and GT1b content indicated that ganglioside metabolism is a common feature in two different HD animal models (YAC128 and R6/2 mice) and importantly, demonstrated that levels of these gangliosides were significantly reduced in the corpus callosum white matter of both models starting from the early stages of the disease. Besides corroborating the evidence of aberrant ganglioside metabolism in HD, here, we found out for the first time, that ganglioside dysfunction is an early event in HD models and it may potentially represent a critical molecular change influencing the pathogenesis of the disease.

Huntington Disease (HD) is a genetic neurodegenerative disorder characterized by broad types of cellular and molecular dysfunctions that may affect both neuronal and non-neuronal cell populations. Among all the molecular mechanisms underlying the complex pathogenesis of the disease, alteration of sphingolipids has been identified as one of the most important determinants in the last years. In the present study, besides the purpose of further confirming the evidence of perturbed metabolism of gangliosides GM1, GD1a, and GT1b the most abundant cerebral glycosphingolipids, in the striatal and cortical tissues of HD transgenic mice, we aimed to test the hypothesis that abnormal levels of these lipids may be found also in the corpus callosum white matter, a ganglioside-enriched brain region described being dysfunctional early in the disease. Semi-quantitative analysis of GM1, GD1a, and GT1b content indicated that ganglioside metabolism is a common feature in two different HD animal models (YAC128 and R6/2 mice) and importantly, demonstrated that levels of these gangliosides were significantly reduced in the corpus callosum white matter of both models starting from the early stages of the disease. Besides corroborating the evidence of aberrant ganglioside metabolism in HD, here, we found out for the first time, that ganglioside dysfunction is an early event in HD models and it may potentially represent a critical molecular change influencing the pathogenesis of the disease. [ABSTRACT FROM AUTHOR]