Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Biomolecular Concepts

Editor-in-Chief: Di Cera, Enrico


Covered by Web of Science (BIOSIS Previews)

PubMed Indexed

CiteScore 2018: 3.35

SCImago Journal Rank (SJR) 2018: 1.475
Source Normalized Impact per Paper (SNIP) 2018: 0.825

ICV 2018: 124.31

Open Access
Online
ISSN
1868-503X
See all formats and pricing
More options …
Volume 5, Issue 1

Issues

GM1 and GM2 gangliosides: recent developments

Blaine Bisel
  • European Laboratory for Non-linear Spectroscopy (LENS), University of Florence, 50019 Florence, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Francesco S. Pavone
  • European Laboratory for Non-linear Spectroscopy (LENS), University of Florence, 50019 Florence, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Martino Calamai
  • Corresponding author
  • European Laboratory for Non-linear Spectroscopy (LENS), University of Florence, 50019 Florence, Italy
  • National Institute of Optics, National Research Council of Italy (CNR), Florence, Italy
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2014-02-10 | DOI: https://doi.org/10.1515/bmc-2013-0039

Abstract

GM1 and GM2 gangliosides are important components of the cell membrane and play an integral role in cell signaling and metabolism. In this conceptual overview, we discuss recent developments in our understanding of the basic biological functions of GM1 and GM2 and their involvement in several diseases. In addition to a well-established spectrum of disorders known as gangliosidoses, such as Tay-Sachs disease, more and more evidence points at an involvement of GM1 in Alzheimer’s and Parkinson’s diseases. New emerging methodologies spanning from single-molecule imaging in vivo to simulations in silico have complemented standard studies based on ganglioside extraction.

Keywords: GM1; GM2; membrane raft; neurodegenerative diseases; polarization

Introduction

GM1 and GM2 are monosialic gangliosides, a class of glycosphingolipids that are found predominantly in the outer leaflet of the plasma membrane and, to a lesser extent, in intracellular membranes. Gangliosides are amphipathic molecules with a negatively charged head group modified with carbohydrate groups that vary among the more than 200 identified species of ganglioside. In the case of GM1 and GM2, the head group consists of a single sialic acid. Two hydrocarbon chains of the ceramide moiety anchor gangliosides in the plasma membrane. Gangliosides are found in the plasma membrane of vertebrate cells and are particularly enriched in the nervous system.

Gangliosides are constantly synthesized and catabolized by highly regulated pathways. Ceramide, which forms the hydrophobic backbone of gangliosides, is synthesized in the endoplasmic reticulum, and glycosylated and sialylated in the Golgi apparatus. Glycoslytransferases add the final complement of carbohydrate groups to form individual gangliosides before vesicles of the secretory pathway transport the gangliosides to the cell surface.

Gangliosides undergo catabolism via the lysosomal recycling pathway. Endocytosis and endosomal sorting pathways chaperone gangliosides to endosomes and eventually lysosomes, where they are sequentially degraded by a series of hydrolytic enzymes assisted by lipid-binding proteins. Defects in the catabolic pathway lead to an accumulation of ganglioside species and result in lysosomal storage disorders and gangliosidoses, including Tay-Sachs disease (1).

In this paper, we survey the latest methods and developments in our understanding of the gangliosides GM1 and GM2, from their basic biochemistry and cellular function to the interactions with amyloid β (Aβ) peptide in Alzheimer’s disease. We also focus on the influence of GM1 and GM2 in other diseases including cancer, viral infection, and diabetes.

New approaches to study the cell biology and membrane biochemistry of gangliosides

The gangliosides GM1 and, to a lesser extent, GM2 are primarily recognized as essential components of membrane rafts. Membrane rafts, or lipid rafts, are heterogeneous clusters of cholesterol, sphingolipids, gangliosides, and membrane-associated proteins, including G protein-coupled receptors (GPCRs). These clusters form stabilized, liquid-ordered nanostructures important in a variety of physiological processes including signal transduction, protein and lipid sorting, and trafficking. Here, we mention the most innovative methods that have been recently used to gain new knowledge on the complex biology of gangliosides (Table 1).

Table 1

Updated methods to study GM1.

The segregation of plasma membrane lipids into membrane microdomains has been reviewed extensively (2). A new study demonstrates the colocalization of cholesterol and GM1 in membrane microdomains with unprecedented precision using secondary ion mass spectrometry (SIMS) of individual isotope-labeled lipid components in model membranes (3). The results suggest several regimes of membrane domains classified by size: broad micrometer-scale domains and nanometer-scale domains that can be found either within the larger domains or outside of them. The micrometer-scale domains contained cholesterol and GM1 to the exclusion of other species. Nanometer-scale domains within larger domains contained increased palmitoyl sphingomyelin, whereas the nanometer-scale domains outside the larger domains have increased GM1. The detailed molecular information made visible by the SIMS technique represents a new step into the conceptual overview of membrane raft distribution.

Liquid-ordered (Lo) domains in model membranes have also been shown recently to respond to acidic gradients in a GM1-dependent manner (4). GM1-containing domains (but not GM1-free or asialo-GM1, which lacks the acidic head group) reorganized into larger clusters facing away from the source of the gradient. The authors speculate that this could constitute a potential mechanism by which membranes segregate into polarized regions during cell polarization.

GM1 in membrane raft domains has been shown to influence the functions of lipid raft-associated proteins. Mahmood et al. have recently demonstrated a direct relationship between the lipid composition in model bilayers and the distinct conformational states of a GPCR, the β2 adrenergic receptor (5). The addition of GM1 to these synthetic membranes increased the stability of both the unbound and the ligand-bound β2 adrenergic receptor. Their report suggests that beyond the role that lipid rafts play in recruiting membrane receptors and cofactors into close proximity, they may also play a direct role in the activation of membrane receptors. At the same time, another group has described a new method for identifying interactions between gangliosides, including GM1 and GM2, and membrane-associated proteins (6). Gangliosides extracted from a cell pellet are purified and passed through a column of immobilized beads functionalized with a target protein. Mass spectrometry allows the identification of minute amounts of an array of ganglioside species. The protocol improves upon earlier methods in its sensitivity to low concentrations of ganglioside species and has the potential to identify other GPCRs with activity-modulating interactions with GM1 or GM2.

GM1 has also been shown to regulate the formation of cell-cell junctions. Cell-cell junctions promote cell adhesion in tissues and play important roles in collective cell migration and the invasion of cancer cells in metastasis. New results indicate that flotillin mediates the interaction of cadherin with GM1 during the formation of cell-cell junctions (7). Another group demonstrated that GM1 localizes rapidly (within 10 s) to newly formed focal adhesions induced by a fibronectin-coated nanoelectrode (8). They further show that after recruitment of GM1, focal adhesions act as mechanosensors, transmitting signals from mechanical perturbations across the cell length.

GM1 gangliosides have also been shown to be central in cell polarization and motility. GM1 accumulates at the leading edge of migrating cells, and we have recently shown that this polarization is dependent on activation of phosphatidylinositide 3-kinases (PI3K), but not mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinases (ERK) (9). GM1 polarization was also demonstrated to be mechanistically and biochemically independent of the polarization of the Golgi apparatus, suggesting that de novo synthesis and transport are not responsible for the polarized localization. Other recently published results suggest that actin filaments form nucleation sites at the plasma membrane that enrich GM1-containing microdomains (10). Stabilized actin filaments with attachments to the plasma membrane at the leading edge are a common feature of polarized cell architecture, so these results indicate a plausible mechanism for enrichment of GM1 at the leading edge.

A general protocol for GM1 extraction that can potentially be applied to the analysis of disease-associated changes to GM1-enriched intracellular membranes has been recently proposed by Waugh (11).

Pathological involvement of GM1 and GM2

GM1 in Alzheimer’s disease and other amyloid pathologies

A growing body of data point at GM1 as one of the crucial factors involved with the development of amyloid disorders such as Alzheimer’s disease and type II diabetes (12–18). In the latter two pathologies, the binding of aggregates formed by the Aβ peptides (1–40 and 1–42) and amylin (also known as human islet polypeptide, hIAPP) to the plasma membrane triggers pathways eventually leading to the impairment and death of neuronal and pancreatic β cells (19), respectively. Both the formation of these aggregates and their interaction with the plasma membrane have been proposed to be mediated by GM1 (12, 20, 21). Experiments carried out in vitro show that the presence of GM1 enhances the seeding and aggregation of Aβ and amylin peptides on synthetic membranes (20, 22, 23). These results are in agreement with in vivo studies where aggregation seems to be increased at the level of membrane rafts (21, 24, 25). However, the binding of preformed Aβ oligomers and amylin aggregates to synthetic lipid vesicles, an event that induces membrane permeabilization, appears to be driven by GM1 (21, 26). It has also been demonstrated that exogenous Aβ1–42 oligomers applied to cultured neurons tend to accumulate on the membrane at the level of rafts enriched in GM1 (25). By contrast, a protective role for GM1 in Alzheimer’s disease is proposed in a work performed using triple transgenic APP/PSEN1/GD3S-/- mice, where a dramatic decrease in cognitive dysfunction and Aβ plaque burden was observed despite a significant increase in GM1 levels (27).

Innovative approaches have been recently used to improve the understanding of the interaction between amyloid aggregates and GM1. Single-particle tracking experiments in living cells have revealed that amyloid aggregates can change the lateral diffusion of GM1 molecules labeled with cholera toxin B coupled to quantum dots (28, 29). Preformed amylin aggregates and Aβ1–42 oligomers added to living neuroblastoma cells display a low mobility on the plasma membrane (30). We have shown that GM1 interacts with the aggregates of both peptides and undergoes a dramatic reduction in diffusion rate (29). The altered mobility of GM1 may have consequences on its regulatory role in neurodevelopment and neuroprotection (31) or affect cellular pathways dependent on raft dynamics. An example demonstrating that the binding of amyloid aggregates can imply a loss of function for molecules linked to lipid rafts is represented by the binding of Sup35 amyloid fibrils to GM1 on the plasma membrane. The consequent accumulation of Fas receptors associated with GM1 appears to induce the activation of extrinsic apoptotic pathways (28).

These results are in agreement with data obtained by Sasahara et al. on the influence of Aβ aggregation on membrane fluidity in vitro (32). They examined the aggregation of Aβ on supported lipid bilayers containing the typical raft components and found an enhancement in phase separation of lipids as a result of interactions between aggregating Aβ and GM1. The sequestration of GM1 into Aβ aggregates resulted in induced membrane damage.

GM1 has been also found to be involved in the processing of the amyloid precursor protein (APP), a transmembrane protein that can be cleaved by alternative proteases, leading to the release of toxic Aβ peptide. In particular, the addition of exogenous GM1 promotes Aβ production and decreases the secretion of sAPPα in neuroblastoma cells and primary cultures of rat cortical neurons (33).

Evangelisti et al. have shown that GM1 has a pivotal role also on the cellular binding and toxicity of amyloid aggregates formed by a model protein not associated to disease (17). Moreover, the same group has demonstrated that modest depletion of GM1 content decreases the interaction of Aβ oligomers with the plasma membrane in fibroblasts of patients with familial Alzheimer’s disease and in rat brain cortical neurons, causing a reduction in cytotoxicity (34).

Atomistic-scale computer simulations have been used to investigate the behavior of Aβ monomers and dimers in GM1-containing raft-like membrane. The oligosaccharide head group of GM1 was observed to act as a scaffold for Aβ binding and subsequent structural rearrangement, an event that did not occur in the absence of GM1 (35). In another molecular dynamics study, the authors report that in the presence of ganglioside GM1, monomeric Aβ1–40 seems to be released more frequently from the plasma membrane, whereas the aggregated form of Aβ develops more rapidly than in other membrane environments and remains bound to the membrane (36).

Although at the level of the central nervous system GM1 is predominately found in the white matter (37), GM1 appears to be redistributed in cells located in the frontal gray matter of patients affected by Alzheimer’s disease, possibly reflecting a pathological connection (38).

GM1 in other neurodegenerative pathologies

GM1 appears to be involved in two additional neurodegenerative disorders related to protein aggregation: Huntington’s and Parkinson’s diseases. A reduced synthesis of the ganglioside GM1 has been found in fibroblasts obtained from Huntington’s disease patients, leading to increased cell susceptibility to apoptosis (39). Restoration of GM1 levels in these cells promotes phosphorylation of mutant Htt, inducing a reduction in toxicity and increased survival. Moreover, intraventricular infusion of GM1 appears to restore normal motor function when administered to symptomatic Huntington’s disease mice. These studies suggest a potential therapy for Huntington’s disease based on the posttranslational modification of mutant huntingtin (40).

During the past 20 years, several studies have tried to clarify the role of GM1 in Parkinson’s disease. Immunohistochemical analysis of paraffin sections from Parkinson’s disease patients has revealed significant GM1 deficiency in nigral dopaminergic neurons. In agreement with this finding, B4galnt1(-/-) genetically engineered mice devoid of GM1 have been found to acquire the symptoms characteristic of this disorder (41). The symptoms in the mice were reduced with administration of analogs of GM1. One hypothesis on the protective role of GM1 is that ganglioside treatment can promote autophagy and clearance of α-synuclein (42), the accumulation of which is associated with Parkinson’s disease. By contrast, another study reveals that GM3, rather than GM1, can specifically regulate the permeabilization of the membrane caused by α-synuclein pore formation (43). GM1 has also been used in human clinical trials to treat Parkinson’s disease. The results suggest that long-term GM1 use is safe and may provide some clinical benefit for Parkinson’s disease patients (44, 45).

Multifocal motor neuropathy, a rare autoimmune disease, appears to be linked to GM1. Anti-GM1 antibodies can be found in some patients with multifocal motor neuropathy, but it is unclear whether these antibodies are pathogenic. Antibodies against gangliosides are associated with a wide range of inflammatory neuropathies, including the Guillain-Barré syndrome, and growing evidence points at ganglioside-specific IgG antibodies as culprits. Although the conventional hypothesis claims that the primary pathology is segmental demyelination, recent research raises the possibility of a primary axonopathy related to the anti-GM1 antibodies (46).

GM1 and GM2 in infections, cancer, and insulin metabolism

Gangliosides have long been known to play a central role in cholera infection, but recently, new reports suggest apparent roles in diseases as diverse as cancer (47–49), serotype 1 reovirus infection (50), and insulin secretion and regulation (51). GM2 appears to play an important role in adhesion, motility, and proliferation in tumor cells through interactions with growth factor receptors and focal adhesion proteins, including integrins, and caveolins [for a review, see (47)]. GM2 plays a protective role, and when its expression is decreased, characteristics of greater cancer malignancy are observed. More recently, analysis of glycosphingolipid profiles, including GM1 and GM2, in cancer stem cells revealed that GM2 and GM1 are upregulated in breast cancer stem cells compared to cancer non-stem cells and may provide a useful target against the development of cancer stem cell phenotypes (49). Interestingly, hexosaminidase subunit β (HEXB), which is involved in the catabolism of GM2, was found to be upregulated, presumably along with a downregulation of GM2 in blood vessels associated with invasive human breast cancer (48). Depletion of HEXB via siRNA was found to decrease the angiogenic potential. Another study using GM2 and GM3 synthase double knockout oncogene-transformed fibroblasts in a cancer model in mice found that downregulation of GM1 induces strikingly slower tumor growth (52). Although the precise role of GM2 in cancer progression is still not completely understood, it may prove to be an interesting therapeutic target.

GM2 was also identified recently to be a specific receptor for reovirus strain type 1 Lang (T1L) (50). Given the uneven distribution of GM2 in different tissue types, with a prominent expression in neural tissues, this finding could open the door to understanding other viral tissue infection patterns. It is also particularly interesting as reoviruses are currently being developed as delivery systems for cancer therapy, and given that GM2 expression is altered in many cancer types, understanding the interaction between reoviruses and GM2 could prove essential to these cancer therapies.

Finally, the GM2 activator protein (GM2AP), which acts as a cofactor to HexA in the catabolism of GM2, has been recently identified to be an adipokine that increases insulin secretion while at the same time impairing insulin and nerve growth factor signal transduction. Insulin receptors are localized in lipid rafts, and diabetes and insulin resistance have been hypothesized to be related to membrane microdomain function (51). GM2AP now appears to play a significant role in insulin metabolism, although a direct connection to GM2 has not yet been observed.

Considerations on the role of gangliosides in disease

Gangliosides are involved in important aspects of homeostasis, and levels of GM1 and GM2 gangliosides must be tightly and accurately regulated. Misregulation of GM1 or GM2 is implicated in a diverse array of diseases mostly associated with the nervous system (Figure 1). An accumulation of GM1 in neurons can lead to the deleterious effects observed in gangliosidoses. By contrast, GM1 depletion is associated to Parkinson’s and Huntington’s diseases, and administration of exogenous GM1 seems to reduce the pathological symptoms (in humans and mice) in both cases. Moreover, interaction of virus components and amyloid species with GM1 can trigger pathological pathways in cholera infection and Alzheimer’s disease, respectively. Finally, high levels of anti-ganglioside antibodies are frequently found in the serum of patients affected by autoimmune neuropathy, where they are suggested to play a pathogenic role. The importance of gangliosides, especially GM1, is evident from these types of diseases, showing that perturbations in one sense or in the other can result in dramatic consequences for the organism.

Pathological involvement of GM1 and GM2.
Figure 1

Pathological involvement of GM1 and GM2.

Acknowledgments

We thank Fondazione Italiana per la Ricerca sul Cancro (FIRC), the European Community’s Seventh Framework Programme [FP7 2007-2013, Grant Agreement (GA) no. PIEF-GA-2009-254791, LASERLAB-EUROPE GA no. 284464, GA no. B0 211383, B0 228334, and B0 241526], and the Italian Ministry of University and Research (FIRB 2011 RBAP11X42L006 and Flagship Project NANOMAX).

References

  • 1.

    Sandhoff K, Harzer K. Gangliosides and gangliosidoses: principles of molecular and metabolic pathogenesis. J Neurosci 2013; 33: 10195–208.PubMedCrossrefGoogle Scholar

  • 2.

    Sonnino S, Prinetti A. Membrane domains and the “lipid raft” concept. Curr Med Chem 2013; 20: 4–21.PubMedGoogle Scholar

  • 3.

    Lozano MM, Liu Z, Sunnick E, Janshoff A, Kumar K, Boxer SG. Colocalization of the ganglioside G(M1) and cholesterol detected by secondary ion mass spectrometry. J Am Chem Soc 2013; 135: 5620–30.Google Scholar

  • 4.

    Staneva G, Puff N, Seigneuret M, Conjeaud H, Angelova MI. Segregative clustering of Lo and Ld membrane microdomains induced by local pH gradients in GM1-containing giant vesicles: a lipid model for cellular polarization. Langmuir 2012; 28: 16327–37.CrossrefPubMedGoogle Scholar

  • 5.

    Mahmood I, Liu X, Neya S, Hoshino T. Influence of lipid composition on the structural stability of G-protein coupled receptor. Chem Pharm Bull (Tokyo) 2013; 61: 426–37.Google Scholar

  • 6.

    Tian R, Jin J, Taylor L, Larsen B, Quaggin SE, Pawson T. Rapid and sensitive MRM-based mass spectrometry approach for systematically exploring ganglioside-protein interactions. Proteomics 2013; 13: 1334–8.PubMedCrossrefGoogle Scholar

  • 7.

    Guillaume E, Comunale F, Do Khoa N, Planchon D, Bodin S, Gauthier-Rouviere C. Flotillin microdomains stabilize cadherins at cell-cell junctions. J Cell Sci 2013; 126(Pt 22): 5293–304.Google Scholar

  • 8.

    Fuentes DE, Butler PJ. Coordinated mechanosensitivity of membrane rafts and focal adhesions. Cell Mol Bioeng 2012; 5: 143–54.PubMedCrossrefGoogle Scholar

  • 9.

    Bisel B, Calamai M, Vanzi F, Pavone FS. Decoupling polarization of the Golgi apparatus and GM1 in the plasma membrane. PLoS One 2013; 8: e80446.PubMedGoogle Scholar

  • 10.

    Dinic J, Ashrafzadeh P, Parmryd I. Actin filaments attachment at the plasma membrane in live cells cause the formation of ordered lipid domains. Biochim Biophys Acta 2013; 1828: 1102–11.Google Scholar

  • 11.

    Waugh MG. Raft-like membranes from the trans-Golgi network and endosomal compartments. Nat Protoc 2013; 8: 2429–39.PubMedCrossrefGoogle Scholar

  • 12.

    Gellermann GP, Appel TR, Tannert A, Radestock A, Hortschansky P, Schroeckh V, Leisner C, Lütkepohl T, Shtrasburg S, Röcken C, Pras M, Linke RP, Diekmann S, Fändrich M. Raft lipids as common components of human extracellular amyloid fibrils. Proc Natl Acad Sci USA 2005; 102: 6297–302.CrossrefGoogle Scholar

  • 13.

    McLaurin J, Chakrabartty A. Membrane disruption by Alzheimer β-amyloid peptides mediated through specific binding to either phospholipids or gangliosides. Implications for neurotoxicity. J Biol Chem 1996; 271: 26482–9.Google Scholar

  • 14.

    Yanagisawa K. Role of gangliosides in Alzheimer’s disease. Biochim Biophys Acta 2007; 1768: 1943–51.Google Scholar

  • 15.

    Cecchi C, Nichino D, Zampagni M, Bernacchioni C, Evangelisti E, Pensalfini A, Liguri G, Gliozzi A, Stefani M, Relini A. A protective role for lipid raft cholesterol against amyloid-induced membrane damage in human neuroblastoma cells. Biochim Biophys Acta 2009; 1788: 2204–16.Google Scholar

  • 16.

    Matsuzaki K, Kato K, Yanagisawa K. Aβ polymerization through interaction with membrane gangliosides. Biochim Biophys Acta 2010; 1801: 868–77.Google Scholar

  • 17.

    Evangelisti E, Cecchi C, Cascella R, Sgromo C, Becatti M, Dobson CM, Chiti F, Stefani M. Membrane lipid composition and its physicochemical properties define cell vulnerability to aberrant protein oligomers. J Cell Sci 2012; 125(Pt 10): 2416–27.Google Scholar

  • 18.

    Cecchi C, Stefani M. The amyloid-cell membrane system. The interplay between the biophysical features of oligomers/fibrils and cell membrane defines amyloid toxicity. Biophys Chem 2013; 182: 30–43.Google Scholar

  • 19.

    Engel MF. Membrane permeabilization by Islet Amyloid Polypeptide. Chem Phys Lipids 2009; 160: 1–10.Google Scholar

  • 20.

    Kurganov B, Doh M, Arispe N. Aggregation of liposomes induced by the toxic peptides Alzheimer’s Aβs, human amylin and prion (106–126): facilitation by membrane-bound GM1 ganglioside. Peptides 2004; 25: 217–32.Google Scholar

  • 21.

    Wakabayashi M, Matsuzaki K. Ganglioside-induced amyloid formation by human islet amyloid polypeptide in lipid rafts. FEBS Lett 2009; 583: 2854–8.Google Scholar

  • 22.

    Ikeda K, Yamaguchi T, Fukunaga S, Hoshino M, Matsuzaki K. Mechanism of amyloid β-protein aggregation mediated by GM1 ganglioside clusters. Biochemistry 2011; 50: 6433–40.CrossrefPubMedGoogle Scholar

  • 23.

    Okada T, Ikeda K, Wakabayashi M, Ogawa M, Matsuzaki K. Formation of toxic Aβ (1–40) fibrils on GM1 ganglioside-containing membranes mimicking lipid rafts: polymorphisms in Aβ (1–40) fibrils. J Mol Biol 2008; 382: 1066–74.Google Scholar

  • 24.

    Wakabayashi M, Okada T, Kozutsumi Y, Matsuzaki K. GM1 ganglioside-mediated accumulation of amyloid β-protein on cell membranes. Biochem Biophys Res Commun 2005; 328: 1019–23.Google Scholar

  • 25.

    Williamson R, Usardi A, Hanger DP, Anderton BH. Membrane-bound β-amyloid oligomers are recruited into lipid rafts by a fyn-dependent mechanism. FASEB J 2008; 22: 1552–9.PubMedGoogle Scholar

  • 26.

    Williams TL, Johnson BR, Urbanc B, Jenkins AT, Connell SD, Serpell LC. Aβ42 oligomers, but not fibrils, simultaneously bind to and cause damage to ganglioside-containing lipid membranes. Biochem J 2011; 439: 67–77.Google Scholar

  • 27.

    Bernardo A, Harrison FE, McCord M, Zhao J, Bruchey A, Davies SS, Jackson Roberts L 2nd, Mathews PM, Matsuoka Y, Ariga T, Yu RK, Thompson R, McDonald MP. Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice. Neurobiol Aging 2009; 30: 1777–91.CrossrefGoogle Scholar

  • 28.

    Bucciantini M, Nosi D, Forzan M, Russo E, Calamai M, Pieri L, Formigli L, Quercioli F, Soria S, Pavone F, Savistchenko J, Melki R, Stefani M. Toxic effects of amyloid fibrils on cell membranes: the importance of ganglioside GM1. FASEB J 2012; 26: 818–31.CrossrefGoogle Scholar

  • 29.

    Calamai M, Pavone FS. Partitioning and confinement of GM1 ganglioside induced by amyloid aggregates. FEBS Lett 2013; 587: 1385–91.Google Scholar

  • 30.

    Calamai M, Pavone FS. Single molecule tracking analysis reveals that the surface mobility of amyloid oligomers is driven by their conformational structure. J Am Chem Soc 2011; 133: 12001–8.Google Scholar

  • 31.

    Yu RK, Tsai YT, Ariga T. Functional roles of gangliosides in neurodevelopment: an overview of recent advances. Neurochem Res 2012; 37: 1230–44.CrossrefPubMedGoogle Scholar

  • 32.

    Sasahara K, Morigaki K, Shinya K. Effects of membrane interaction and aggregation of amyloid β-peptide on lipid mobility and membrane domain structure. Phys Chem Chem Phys 2013; 15: 8929–39.PubMedCrossrefGoogle Scholar

  • 33.

    Zha Q, Ruan Y, Hartmann T, Beyreuther K, Zhang D. GM1 ganglioside regulates the proteolysis of amyloid precursor protein. Mol Psychiatry 2004; 9: 946–52.PubMedCrossrefGoogle Scholar

  • 34.

    Evangelisti E, Wright D, Zampagni M, Cascella R, Fiorillo C, Bagnoli S, Relini A, Nichino D, Scartabelli T, Nacmias B, Sorbi S, Cecchi C. Lipid rafts mediate amyloid-induced calcium dyshomeostasis and oxidative stress in Alzheimer’s disease. Curr Alzheimer Res 2013; 10: 143–53.CrossrefGoogle Scholar

  • 35.

    Manna M, Mukhopadhyay C. Binding, conformational transition and dimerization of amyloid-β peptide on GM1-containing ternary membrane: insights from molecular dynamics simulation. PLoS One 2013; 8: e71308.PubMedGoogle Scholar

  • 36.

    Lemkul JA, Bevan DR. Aggregation of Alzheimer’s amyloid β-peptide in biological membranes: a molecular dynamics study. Biochemistry 2013; 52: 4971–80.PubMedCrossrefGoogle Scholar

  • 37.

    Vajn K, Viljetic B, Degmecic IV, Schnaar RL, Heffer M. Differential distribution of major brain gangliosides in the adult mouse central nervous system. PLoS One 2013; 8: e75720.PubMedGoogle Scholar

  • 38.

    Pernber Z, Blennow K, Bogdanovic N, Mansson JE, Blomqvist M. Altered distribution of the gangliosides GM1 and GM2 in Alzheimer’s disease. Dement Geriatr Cogn Disord 2012; 33: 174–88.PubMedCrossrefGoogle Scholar

  • 39.

    Maglione V, Marchi P, Di Pardo A, Lingrell S, Horkey M, Tidmarsh E, Sipione S. Impaired ganglioside metabolism in Huntington’s disease and neuroprotective role of GM1. J Neurosci 2010; 30: 4072–80.CrossrefGoogle Scholar

  • 40.

    Di Pardo A, Maglione V, Alpaugh M, Horkey M, Atwal RS, Sassone J, Ciammola A, Steffan JS, Fouad K, Truant R, Sipione S. Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice. Proc Natl Acad Sci USA 2012; 109: 3528–33.CrossrefGoogle Scholar

  • 41.

    Wu G, Lu ZH, Kulkarni N, Ledeen RW. Deficiency of ganglioside GM1 correlates with Parkinson’s disease in mice and humans. J Neurosci Res 2012; 90: 1997–2008.CrossrefGoogle Scholar

  • 42.

    Wei J, Fujita M, Sekigawa A, Sekiyama K, Waragai M, Hashimoto M. Gangliosides’ protection against lysosomal pathology of synucleinopathies. Autophagy 2009; 5: 860–1.PubMedCrossrefGoogle Scholar

  • 43.

    Di Pasquale E, Fantini J, Chahinian H, Maresca M, Taieb N, Yahi N. Altered ion channel formation by the Parkinson’s-disease-linked E46K mutant of α-synuclein is corrected by GM3 but not by GM1 gangliosides. J Mol Biol 2010; 397: 202–18.Google Scholar

  • 44.

    Schneider JS, Sendek S, Daskalakis C, Cambi F. GM1 ganglioside in Parkinson’s disease: results of a five year open study. J Neurol Sci 2010; 292: 45–51.Google Scholar

  • 45.

    Schneider JS, Gollomp SM, Sendek S, Colcher A, Cambi F, Du W. A randomized, controlled, delayed start trial of GM1 ganglioside in treated Parkinson’s disease patients. J Neurol Sci 2013; 324: 140–8.Google Scholar

  • 46.

    Vlam L, van den Berg LH, Cats EA, Piepers S, van der Pol WL. Immune pathogenesis and treatment of multifocal motor neuropathy. J Clin Immunol 2013; 33(Suppl 1): S38–42.CrossrefGoogle Scholar

  • 47.

    Hakomori SI. Glycosynaptic microdomains controlling tumor cell phenotype through alteration of cell growth, adhesion, and motility. FEBS Lett 2010; 584: 1901–6.Google Scholar

  • 48.

    Jones DT, Lechertier T, Mitter R, Herbert JM, Bicknell R, Jones JL, Li JL, Buffa F, Harris AL, Hodivala-Dilke K. Gene expression analysis in human breast cancer associated blood vessels. PLoS One 2012; 7: e44294.PubMedGoogle Scholar

  • 49.

    Liang YJ, Ding Y, Levery SB, Lobaton M, Handa K, Hakomori SI. Differential expression profiles of glycosphingolipids in human breast cancer stem cells vs. cancer non-stem cells. Proc Natl Acad Sci USA 2013; 110: 4968–73.CrossrefGoogle Scholar

  • 50.

    Reiss K, Stencel JE, Liu Y, Blaum BS, Reiter DM, Feizi T, Dermody TS, Stehle T. The GM2 glycan serves as a functional coreceptor for serotype 1 reovirus. PLoS Pathog 2012; 8: e1003078.PubMedGoogle Scholar

  • 51.

    Higashi K, Kubo H, Watanabe H, Fujimori K, Mikami T, Kaneko H. Adipokine ganglioside GM2 activator protein stimulates insulin secretion. FEBS Lett 2011; 585: 2587–91.Google Scholar

  • 52.

    Liu Y, Yan S, Wondimu A, Bob D, Weiss M, Sliwinski K, Villar J, Notario V, Sutherland M, Colberg-Poley AM, Ladisch S. Ganglioside synthase knockout in oncogene-transformed fibroblasts depletes gangliosides and impairs tumor growth. Oncogene 2010; 29: 3297–306.CrossrefGoogle Scholar

About the article

Corresponding author: Martino Calamai, European Laboratory for Non-linear Spectroscopy (LENS), University of Florence, 50019 Florence, Italy, e-mail: ; and National Institute of Optics, National Research Council of Italy (CNR), Florence, Italy


Received: 2013-12-09

Accepted: 2014-01-08

Published Online: 2014-02-10

Published in Print: 2014-03-01


Citation Information: BioMolecular Concepts, Volume 5, Issue 1, Pages 87–93, ISSN (Online) 1868-503X, ISSN (Print) 1868-5021, DOI: https://doi.org/10.1515/bmc-2013-0039.

Export Citation

©2014 by Walter de Gruyter Berlin/Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Rodolfo Tonin, Anna Caciotti, Elena Procopio, Rita Fischetto, Federica Deodato, Maria Margherita Mancardi, Maja Di Rocco, Anna Ardissone, Alessandro Salviati, Antonio Marangi, Pietro Strisciuglio, Giusi Mangone, Arianna Casini, Silvia Ricci, Agata Fiumara, Rossella Parini, Francesco Saverio Pavone, Renzo Guerrini, Martino Calamai, and Amelia Morrone
Scientific Reports, 2019, Volume 9, Number 1
[2]
Haoqi Du, Hanjie Yu, Tianran Ma, Fuquan Yang, Liyuan Jia, Chen Zhang, Jiaxu Zhang, Lili Niu, Jiajun Yang, Zhiwei Zhang, Kun Zhang, and Zheng Li
Analytical Chemistry, 2019, Volume 91, Number 16, Page 10663
[4]
Sumangala Darsandhari, Jae Yoon Bae, Biplav Shrestha, Tokutaro Yamaguchi, Hye Jin Jung, Jang Mi Han, Chan-Su Rha, Ramesh Prasad Pandey, and Jae Kyung Sohng
Natural Product Research, 2018, Page 1
[5]
Mirela Sarbu, Adrian C. Robu, Roxana M. Ghiulai, Željka Vukelić, David E. Clemmer, and Alina D. Zamfir
Analytical Chemistry, 2016, Volume 88, Number 10, Page 5166
[6]
Kate Palmano, Angela Rowan, Rozey Guillermo, Jian Guan, and Paul Jarrow
Nutrients, 2015, Volume 7, Number 5, Page 3891
[7]
Prakash Parajuli, Ramesh Prasad Pandey, Rit Bahadur Gurung, Ju Yong Shin, Hye Jin Jung, Dae Hee Kim, and Jae Kyung Sohng
Glycoconjugate Journal, 2016, Volume 33, Number 2, Page 137

Comments (0)

Please log in or register to comment.
Log in