Parkinson’s disease recovery by GM1 oligosaccharide treatment in the B4galnt1+/− mouse model

Given the recent in vitro discovery that the free soluble oligosaccharide of GM1 is the bioactive portion of GM1 for neurotrophic functions, we investigated its therapeutic potential in the B4galnt1+/− mice, a model of sporadic Parkinson’s disease. We found that the GM1 oligosaccharide, systemically administered, reaches the brain and completely rescues the physical symptoms, reduces the abnormal nigral α-synuclein content, restores nigral tyrosine hydroxylase expression and striatal neurotransmitter levels, overlapping the wild-type condition. Thus, this study supports the idea that the Parkinson’s phenotype expressed by the B4galnt1+/− mice is due to a reduced level of neuronal ganglioside content and lack of interactions between the oligosaccharide portion of GM1 with specific membrane proteins. It also points to the therapeutic potential of the GM1 oligosaccharide for treatment of sporadic Parkinson’s disease.

Pre-diagnosing and managing patients with GM1 gangliosidosis and related disorders by the evaluation of GM1 ganglioside content

GM1 ganglioside, a monosialic glycosphingolipid and a crucial component of plasma membranes, accumulates in lysosomal storage disorders, primarily in GM1 gangliosidosis. The development of biomarkers for simplifying diagnosis, monitoring disease progression and evaluating drug therapies is an important objective in research into neurodegenerative lysosomal disorders. With this in mind, we established fluorescent imaging and flow-cytometric methods to track changes in GM1 ganglioside levels in patients with GM1 gangliosidosis and in control cells. We also evaluated GM1 ganglioside content in patients’ cells treated with the commercially available Miglustat, a substrate inhibitor potentially suitable for the treatment of late-onset GM1 gangliosidosis. The flow-cytometric method proved to be sensitive, unbiased, and rapid in determining variations in GM1 ganglioside content in human lymphocytes derived from small amounts of fresh blood. We detected a strong correlation between GM1 ganglioside content and the clinical severity of GM1 gangliosidosis. We confirm the ability of Miglustat to act as a substrate reduction agent in the patients’ treated cells. As well as being suitable for diagnosing and managing patients with GM1 gangliosidosis this method could be useful in the diagnosis and management of other lysosomal diseases, such as galactosialidosis, Type C Niemann-Pick, and any other disease with pathologic variations of GM1 ganglioside.

Dietary Ganglioside Reduces Proinflammatory Signaling in the Intestine

Gangliosides are integral to the structure and function of cell membranes. Ganglioside composition of the intestinal brush border and apical surface of the colon influences numerous cell processes including microbial attachment, cell division, differentiation, and signaling. Accelerated catabolism of ganglioside in intestinal disease results in increased proinflammatory signaling. Restoring proper structure and function to the diseased intestine can resolve inflammation, increase resistance to infection, and improve gut integrity to induce remission of conditions like necrotizing enterocolitis (NEC) and Crohn's disease (CD). Maintaining inactive state of disease may be achieved by reducing the rate that gangliosides are degraded or by increasing intake of dietary ganglioside. Collectively, the studies outlined in this paper indicate that the amount of gangliosides GM3 and GD3 in intestinal mucosa is decreased with inflammation, low level of GM3 is associated with higher production of proinflammatory signals, and ganglioside content of intestinal mucosa can be increased by dietary ganglioside.

Role of gangliosides in brain aging and neurodegeneration

Gangliosides are membrane glycosphingolipids bearing sialic acid residues. Within membranes, gangliosides are specifically enriched in highly organized domains, lipid rafts, and are attributed with diverse functions such as intercellular interactions, cell recognition, neurotransmission, and signal transduction. The highest concentration and variability of ganglioside structures are found in the human brain. Specific temporal and regional distribution of brain gangliosides has been reported; moreover, gangliosides may serve as markers of neurodevelopmental stages, aging and neurodegeneration. Brain ganglioside content and composition as well as ganglioside metabolism are altered in Alzheimer’s disease. It appears that the alterations of ganglioside metabolism leading to changes in membrane physico-chemical properties are not merely a consequence of primary pathology, but may also be involved in the early pathogenesis of Alzheimer’s disease through documented effects on APP proteolytic processing and amyloid aggregation. Investigations of glycolipid metabolic alterations which accompany neurodegenerative disorders provide insight into pathogenetic mechanisms and enable recognition of diagnostic markers as well as molecular structures acting as therapeutic tools interfering with cascade of pathological events.

Ganglioside composition of differentiated Caco-2 cells resembles human colostrum and neonatal rat intestine

Gangliosides are glycosphingolipids found in cell membranes and human milk with important roles in cell proliferation, differentiation, growth, adhesion, migration, signalling and apoptosis. Similar changes in ganglioside composition occur during embryonic development, lactation and cancer cell differentiation. It is not known, however, whether ganglioside compositional changes that occur in differentiating colon cancer cells reflect changes that occur during intestinal development. The Caco-2 cell line is commonly used to study physiological and pathophysiological processes in the small intestine and colon. Therefore, to examine this question, undifferentiated and differentiated Caco-2 cells were grown and total lipid was extracted from cell supernatant fractions using the Folch method. The upper aqueous phase containing gangliosides was collected and purified. Total gangliosides were measured as ganglioside-bound N-acetyl neuraminic acid, while individual ganglioside content was quantified via a colorimetric assay for sialic acid and scanning densitometry. The total ganglioside content of differentiated Caco-2 cells was 2·5 times higher compared with undifferentiated cells. Differentiated Caco-2 cells had significantly more (N-acetylneuraminyl) 2-galactosylglucosyl ceramide (GD3) and polar gangliosides, and a lower N-acetylneuraminylgalactosylglucosylceramide (GM3):GD3ratio than undifferentiated cells. The present study demonstrates that the total ganglioside content and individual ganglioside composition of differentiated Caco-2 cells are similar to those of human colostrum and neonatal rat intestine. Differentiated Caco-2 cells may therefore be an alternative model for studying physiological and pathological processes in the small intestine and colon, and may help to elucidate possible functions for specific gangliosides in development and differentiation. Further research using more sensitive techniques of ganglioside analysis is needed to confirm these findings.