The Biology of Gangliosides

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The Biology of Gangliosides

Ronald L. Schnaar
Departments of Pharmacology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore,
MD, United States
Contents
1. Ganglioside Structures, Distribution, and Biosynthesis 1
2. Ganglioside Functions: cis Regulation and trans Recognition 5
3. Gangliosides Regulate Receptor Tyrosine Kinases 7
4. Gangliosides Impact Human Proteinopathies 9
5. Gangliosides Are Cell-Surface Receptors for Bacterial Toxins 12
6. Gangliosides Are Cell-Surface Receptors for Myelin-Associated Glycoprotein 18
7. Intellectual Disability and Seizures in Humans and Mice With Altered Ganglioside
Biosynthetic Genes 22
8. Gangliosides in Human Disease 27
Acknowledgments 28
References 28
1. GANGLIOSIDE STRUCTURES, DISTRIBUTION,

AND BIOSYNTHESIS
Sialic acid was first isolated from bovine saliva by Gunnar Blix and con-
currently from human brain lipids by Ernst Klenk, who coined the term neur-
aminic acid for his brain-derived monosaccharide.1–3 Klenk went on to purify
sialic acid-containing glycosphingolipids from human brain and rec-
ommended the name “ganglioside” for them as a group.4 Consistent with
his structural determination, gangliosides are defined as a ceramide lipid
in glycosidic linkage to a glycan (of any size and structure) that contains at least
one sialic acid residue. Naturally occurring gangliosides may be as small
as a disaccharide linked to ceramide (Neu5Acα2-3Galβ1-10 Cer, GM4)5 or
as large as at least an octadecamer with the glycan composition
Neu5Ac1Gal7GlcNAc6Fuc3Glc1Cer1.6 Although many gangliosides are part
of the “gangliotetraose” family, with sialic acids carried on the neutral core
Advances in Carbohydrate Chemistry and Biochemistry # 2018 Elsevier Inc. 1

ISSN 0065-2318 All rights reserved.
https://doi.org/10.1016/bs.accb.2018.09.002
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2 Ronald L. Schnaar
glycan Galβ1-3GalNAcβ1-4Galβ1-4Glcβ1-10 Cer, other gangliosides consist

of sialic acids on alternative glycosphingolipid cores including the lacto-,
neolacto-, and globotetraosyl families.7,8 Over 200 ganglioside structures have
been identified based on their distinct glycans alone, with many more chem-
ical compositions based on variations of their ceramide moieties.8–10
In evolution, gangliosides appeared in deuterostomes, with structures
reported in several echinoderms (starfish, sea urchins)10 and in all verte-
brates.11 Ganglioside sialic acids in vertebrates are linked via α-glycosidic
linkages typically to galactose (Gal) or N-acetylgalactosamine (GalNAc) res-
idues on various neutral core glycosphingolipids.7 Sialic acids in vertebrate
gangliosides are not further extended except by additional α2,8-linked sialic
acids in short di- or tri-sialic chains.12 Most gangliosides carry a total of one
to three sialic acids on their neutral glycan cores, with four to five sialic acids
not uncommon, and recent high sensitivity techniques report detection of
rare gangliosides with up to eight sialic acids on a neutral tetrasaccharide
core.13 The unusual gangliosides of echinoderms, which include non-
terminal sialic acids in the core and disubstitution on galactose residues,10
will not be discussed further here.
Several of the most abundant ganglioside structures of vertebrates are
shown in Fig. 1. Their formal nomenclature is cumbersome,14 so a non-
systematic shorthand nomenclature introduced by Svennerholm is broadly
used.15 The internationally accepted symbol nomenclature for glycans
provides a more intuitive basis for structural comparisons.17 Svennerholm,
symbol, and IUPAC nomenclatures of many of the gangliotetraose-based
gangliosides discussed in this chapter are shown in Fig. 1.
Although most abundantly expressed in the brain, from which they were
first isolated, gangliosides are found in all human tissues (Table 1), where
different glycan and ceramide structures and ganglioside quantities are found
in cell-specific patterns. Whereas nerve cell gangliosides are almost exclu-
sively built on the gangliotetraose core, those on human leukocytes include
sialic acids on neolactosylceramides,6,19 and those on human red blood cells
include sialic acids on globosylceramides.20 Some functions of gangliosides
appear to be cell-type specific and involve gangliosides that are narrowly
expressed,21 while others are shared across cell types and involve gangliosides
that are widely distributed.22 The simple ganglioside GM3 quantitatively
predominates many mammalian peripheral tissues, representing more than
half of the total gangliosides in human heart, skeletal muscle, kidney, liver,
and adipose tissues.23 In contrast, four more complex gangliosides—GM1,
GD1a, GD1b, and GT1b—represent >90% of brain gangliosides in all
mammals (96% in humans).
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Biology of Gangliosides 3
Fig. 1 See legend on next page.

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4 Ronald L. Schnaar
Table 1 Concentration of Gangliosides in Some Human Organsa

Gangliosides
Source (nmol NeuAc/g Fresh Weight)
Brain: cerebral cortex 3000–3500
Cerebral white matter 1000–1250
Retina 100–150
Peripheral nerve 35–80
Skeletal muscle 50–80
Liver 50–100
Spleen 200–300
Placenta 100–200
Thyroid 60–100
Kidney 30–60
Fat tissue 10–15
Small intestine, mucosa 5–8
Small intestine, muscular layer 50–80
a
Reproduced from Svennerholm,18 with permission.
Fig. 1 Selected vertebrate gangliosides. Top panel: Ganglioside GT1b. The gangliotetraose
neutral glycan core structure (Galβ1-3GalNAcβ1-4Galβ1-4GlcβCer) is shown with each gly-
can designated by a Roman numeral according to IUPAC14 shorthand nomenclature.
In the widely used nomenclature of Svennerholm,15 the “ganglio” series core saccharide
is designated by a capital “G” followed by a capital letter (M, D, T, Q, P) designating the total
number of sialic acids. This is followed by an Arabic numeral (1, 2, 3, 4) designating the
length of the neutral core as shown in the brackets above the structure, with larger num-
bers designating shorter glycan chains. Common attachment positions of sialic acids are
indicated: the number of sialic acids at Gal (II) is indicated by a lower case Latin letter, those
at GalNAc (III) as a lower case Greek letter, and any remaining sialic acids are attached to the
terminal Gal (IV). Gangliosides are embedded into membranes by their variable ceramide
structures with most of the glycan extending outward.16 Bottom panel: Structures and
nomenclature of some common vertebrate gangliosides. Sialic acids (Neu5Ac) are all
considered to be in α linkage. Formal IUPAC nomenclature14 includes the anomeric link-
age between hyphens in the shorthand version, such as II3-α-NeuAc-LacCer for GM3.
Reproduced from Schnaar, R. L.; Lopez, P. H. Preface and Ganglioside Nomenclature. Prog.
Mol. Biol. Transl. Sci. 2018, 156, xvii–xxi, with permission.
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Gangliosides are biosynthesized stepwise starting with addition of glu-

cose (or galactose) to ceramide (Fig. 2). Except for GM4 (Neu5Acα2-
3Galβ1,10 Cer), gangliosides are based on the lactosylceramide disaccharide
core (LacCer, Galβ1-4Glcβ1-10 Cer). Sialylation of LacCer generates the
abundant mammalian ganglioside GM3, which is the precursor for most
other mammalian gangliosides, including the major brain gangliosides. The
enzymes that perform early steps in GM3 and brain ganglioside biosynthesis
are unique and devoted specifically to glycosphingolipid biosynthesis. These
include GM3 synthase (CMP-Sia:lactosylceramide α-2,3-sialyltransferase,
ST3GAL5 gene); GD3 synthase (CMP-Sia:GM3 α-2,8-sialyltransferase,
ST8SIA1 gene); and GM2/GD2 synthase (UDP-GalNAc:GM3/GD3
β1-4 GalNAc transferase, B4GALNT1 gene). Mutations in these genes are
the subject of function-revealing mouse genetic studies and human disease.
2. GANGLIOSIDE FUNCTIONS: cis REGULATION

AND trans RECOGNITION
Gangliosides are synthesized on the intraluminal face of the Golgi
apparatus and traffic to the outer leaflet of the plasma membrane24 with
their glycans extending outward into the extracellular space.16 Although
gangliosides traffic through and to other subcellular compartments,24–26
the functional focus of this review will be the plasma membrane. Because
gangliosides are sphingolipids, most with a fully saturated fatty acid amide
and a long linear saturated alkane on sphingosine (Fig. 1), they spontaneously
associate laterally in the plane of the outer leaflet of the plasma membrane
along with other sphingolipids, cholesterol, GPI-anchored proteins, and
select transmembrane proteins.27 These lateral associations, which are alter-
natively called lipid rafts, microdomains, or (more recently) nanodomains,
are small in scale and highly dynamic.28 Spontaneous lateral associations
are postulated to enhance ganglioside contact with selected proteins in
the same membrane, with which they functionally interact.29 This also
favors self-association that may enhance binding of clustered ganglioside
glycans to multivalent glycan-recognition proteins on other cells or in the
extracellular environment.30 These two modes of association, cis and trans
interactions, respectively, are distinct mechanisms for ganglioside-mediated
functions.12 The up- and downregulation of the activities of various recep-
tor tyrosine kinases (RTKs) by gangliosides provide an excellent example
of cis regulation with implications ranging from diabetes to cancer to nerve
regeneration.22,31,32 The functional binding of gangliosides to highly
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Fig. 2 Biosynthetic pathways of gangliosides in mammals, with emphasis on major brain gangliosides. The genes encoding the enzymes
responsible for each step are boxed. Mutations in the genes in red font are responsible for human congenital disorders of ganglioside bio-
synthesis. Mouse genetic models have been generated for genes homologous to those in red as well as those in blue font. Minor brain gan-
gliosides of the 0-series are faded in the image. The branch point from LacCer to major gangliosides of nonneural tissues is boxed.
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specific ganglioside-binding proteins either in the extracellular environment

or on apposing cells exemplifies trans interactions, which range from the
binding of bacterial toxins to regulatory cell–cell recognition.33,34 From
infection and immunity to regulation of metabolism to neuronal stability
and degeneration, examples of gangliosides functioning via cis and trans
interactions are rapidly emerging.
3. GANGLIOSIDES REGULATE RECEPTOR TYROSINE

KINASES
Early studies discovered that exogenously added gangliosides inhibited
the proliferation of cells in culture, and more specifically blocked prolifer-
ation induced by purified growth factors including epidermal growth factor
(EGF) and platelet-derived growth factor (PDGF) without changing the
number or decreasing the affinity of their receptors.35 Subsequently,
ganglioside GM3 was found to allosterically reduce the intracellular tyrosine
kinase activity of the EGF receptor by laterally associating with a specific
juxtamembrane polypeptide domain and with N-linked EGF receptor
glycans.36–38 GM3-mediated inhibition of the EGF receptor provided a
paradigm for structurally specific lateral association of membrane ganglio-
sides with proteins in the same membrane leading to changes in ligand-
activated signaling.32 The activities of several other receptor protein tyrosine
kinases were found to be inhibited and/or activated by lateral association with
different gangliosides including fibroblast growth factor receptor (FGFR),
PDGF receptor, vascular endothelial growth factor receptor (VEGFR), hepa-
tocyte growth factor receptor (c-Met), the insulin receptor (IR), insulin-like
growth factor 1 receptor (IGF1R), and the nerve cell growth factor
TrkA.31,32,39,40 The mechanisms by which gangliosides modulate RTKs
vary and include direct ganglioside–ligand interactions, regulation of receptor
dimerization, or competition between receptor binding to gangliosides and
other membrane regulators.41 An example of the latter mechanism, well
supported by varied lines of evidence, is GM3 regulation of the insulin receptor
and its potential pathological role in insulin resistance.22,42
Investigations into ganglioside-mediated control of cell proliferation
unexpectedly initiated the study of GM3 regulation of the insulin receptor
in metabolic diseases. Random mutagenesis of a mouse breast carcinoma
cell line, followed by selection using an anti-LacCer-antibody, resulted in
a subline that had lost lactosylceramide (LacCer, Galβ1-4Glcβ1-10 Cer)
and gained its sialylated product, GM3.43 Under normal growth conditions
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8 Ronald L. Schnaar
(in the presence of serum), the mutant cell line had a modestly reduced
growth rate compared to the parent line, but it was completely resistant
to the proliferative effect of insulin. When GM3 was added to the parent
line, it became insulin resistant as well. Significantly, GM3 is a major
ganglioside in adipocytes of mammals including humans,44 raising the
possibility that GM3 regulates adipose metabolic state by inhibiting insu-
lin action there as well. This hypothesis was strongly supported by the
finding that TNFα-induced insulin resistance in cultured mouse adipocytes
was accompanied by increased expression of GM3 via increased expres-
sion of GM3 synthase (CMP-N-acetylneuraminate lactosylceramide
α-2,3-sialyltransferase), coded by the St3gal5 gene.45 Remarkably, addition
of a general inhibitor of glycosphingolipid biosynthesis to the cells reduced
GM3 expression and restored insulin sensitivity, even in the presence of
TNFα. As with the EGFR, addition of exogenous GM3 blocked insulin-
mediated IR tyrosine phosphorylation without altering insulin binding.
Consistent with the hypothesis that GM3 is a regulator of insulin sensi-
tivity in vivo, in rat and mouse obesity models the expression of St3gal5 was
increased.45 Notably, mice engineered with a disrupted St3gal5 gene lack
GM3, display enhanced insulin sensitivity, improved glucose tolerance,
and are protected from high fat diet-induced insulin resistance.46 A mech-
anism by which increased GM3 may regulate insulin sensitivity involves its
lateral association with the IR. Under normal conditions, the IR associates
with caveolin-1, an interaction required for optimal insulin responsive-
ness.47 A combination of immunoprecipitation, colocalization, and fluo-
rescence recovery after photobleaching (FRAP) studies supports a model
in which IR binding to caveolin-1 and GM3 is competitive.48 In the
absence of GM3, IRs associate with caveolin-1, are relatively immobile,
and are insulin sensitive. When GM3 is increased (as it is after TNFα
treatment), IRs associate selectively with GM3, are released from their
interaction with caveolin 1, are relatively mobile, and become insulin
resistant. As with the EGFR,37 mutation of a juxtamembrane cationic res-
idue on the IR (K944R) resulted in loss of its GM3 association.
The discovery that ganglioside GM3 may regulate insulin resistance
by direct interaction with the IR provides an opportunity for therapeutic
intervention using a GM3-reducing drug. Although a specific drug
blocking GM3 synthase has not been developed, administration of small-
molecule glycosphingolipid biosynthesis inhibitors enhanced insulin sensi-
tivity in multiple animal models of obesity and type 2 diabetes.49–52
Together, these findings demonstrate the modulatory effects of cis
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interactions of gangliosides with membrane proteins and indicate that

enhanced knowledge of these interactions can reveal biological and patho-
logical mechanisms as well as new drug targets.
4. GANGLIOSIDES IMPACT HUMAN PROTEINOPATHIES

Proteinopathies are diseases caused by the buildup of aggregates of
pathogenic polypeptide conformers.53 The most prevalent proteinopathies
are Alzheimer’s disease (AD), in which extracellular β-amyloid (Aβ) plaques
and intracellular tau tangles accumulate in the brain cortex, and Parkinson’s
disease, in which α-synuclein aggregates. A hypothesis for proteinopathy
initiation is that a very small population of normal polypeptide assumes a
toxic conformation that becomes the “seed” for conversion of more and more
of that polypeptide into that same toxic conformation until toxic amyloid pro-
tein aggregates are formed.54 A possible mechanistic role for gangliosides
in this process arose when a portion of Aβ in postmortem brain tissue of sub-
jects with diffuse plaques was found tightly associated with lipids, including
GM1 (detected using labeled cholera toxin as a probe).55 Subsequent studies
revealed that in the proper membrane environment gangliosides accelerate
conversion of Aβ polypeptide into fibrils.56 In the absence of Aβ fibril
seeds, soluble Aβ peptides that have the capacity to assume conformations
associated with pathology (Aβ40, Aβ42) fail to aggregate over several hours
in vitro. However, in the presence of liposomes comprised of ganglioside
GM1 along with other lipid raft components (cholesterol and sphingomyelin),
robust aggregation (fibril formation) is induced (Fig. 3A and B). Aβ binds
to all of the major brain gangliosides, with modest preference for GD1a/
GT1b > GD1b > GM1 (Fig. 3C).57 Notably, however, enhanced induction
of fibril formation has the opposite specificity with GM1 > GD1b > GD1a/
GT1b (Fig. 3D). These data support the hypothesis that brain gangliosides
bind to Aβ and induce a conformational change that exacerbates fibril
formation. This is consistent with the findings that ganglioside-associated
Aβ appears early in human AD progression and mouse models of AD.
A current model (Fig. 3E) is that brain gangliosides, particularly GM1 and/or
GD1b, cluster in lipid rafts in neurons, where they engage soluble Aβ and,
under appropriate conditions, accelerate toxic fibril formation.58
In contrast to gangliosides accelerating Aβ fibrillogenesis, the associa-
tion between α-synuclein and gangliosides diminishes fibril formation.59
Consistent with a biological role for major brain gangliosides in protecting
against α-synuclein-mediated disease, mice genetically engineered to lack
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10 Ronald L. Schnaar
Fig. 3 See legend on opposite page.

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GM2/GD2 synthase (B4galnt1-null, see Fig. 2), and which lack all major
brain gangliosides, have increased α-synuclein aggregation in the substantia
nigra.60 Detection of ganglioside GM1 (using labeled cholera toxin) in
dopaminergic neurons of human substantia nigra revealed a decrease of this
ganglioside in Parkinson’s disease subjects. The ganglioside structural spec-
ificity of ganglioside-α-synuclein functional interactions has not been thor-
oughly studied (as they were for Aβ fibrillogenesis, Fig. 3D). In one study,
however, mice heterozygote for B4galnt1 disruption demonstrated a selec-
tive loss of GD1a (90%) and GM1 (50%) during aging, along with increased
α-synuclein deposition.61
Fig. 3 (A, B) Aβ fibrillogenesis of two different Aβ peptides is induced by GM1 lipo-

somes. Soluble monomeric Aβ (Aβ40 and Aβ42) was incubated at 50 μm and 37°C in
the presence of GM1-containing liposomes (filled circles) or GM1-lacking liposomes (plus
signs) or was incubated in the absence of liposomes (open circles). The GM1-containing
liposomes alone were also incubated in the absence of Aβ (triangles). The fluorescence
intensity of thioflavin T, which detects amyloid accumulation, is plotted after back-
ground (0 h) subtraction. (C) Binding of fluorescently labeled (DAC) Aβ peptide
(0.5 μM) to increasing amounts of ganglioside-containing liposomes comprised of
ganglioside/cholesterol/sphingomyelin (1:2:2 molar ratio). Circles, GM1; squares,
GD1a; triangles, GD1b; inverted triangles, GT1b; diamonds, equimolar GM1/GD1a/
GD1b/GT1b. Standard deviations for two to three preparations are shown by error
bars. (D) Acceleration of Aβ fibril formation (thioflavin T fluorescence) by ganglioside-
containing liposomes of the above composition. Native human Aβ(1–40, 15 μM) was
incubated alone, with preformed Aβ fibril seeds (fAβ, 0.75 μM) or liposomes composed
of ganglioside/cholesterol/SM (1:2:2) for 1 day at 37°C. (E) Schematic representation of
Aβ–GM1 interactions. Aβ is in equilibrium between a random conformation and a hair-
pin structure, with the equilibrium greatly toward the random coil. Aβ does not bind to
membranes as long as GM1 is uniformly distributed in the membrane. When GM1 forms
a cluster, Aβ recognizes it, assuming an α-helix-rich conformation. At Aβ/GM1 ratios
between 0.013 and 0.044, the helical form and aggregated β-sheets (10–20 mer)
coexist. However, the β-structure is nontoxic and stable. At higher Aβ densities, the
β-structure is converted to a second, seed-prone β-structure, which recruits monomers
from the aqueous phase to form toxic amyloid fibrils containing antiparallel β-sheets.
Panels (A) and (B): Reproduced from Hayashi, H.; Kimura, N.; Yamaguchi, H.;
Hasegawa, K.; Yokoseki, T.; Shibata, M.; Yamamoto, N.; Michikawa, M.; Yoshikawa, Y.;
Terao, K.; Matsuzaki, K.; Lemere, C. A.; Selkoe, D. J.; Naiki, H.; Yanagisawa, K. A Seed for
Alzheimer Amyloid in the Brain. J. Neurosci. 2004, 24, 4894–4902, with permission. Panels
(C) and (D): Reproduced from Kakio, A.; Nishimoto, S.; Yanagisawa, K.; Kozutsumi, Y.;
Matsuzaki, K. Interactions of Amyloid β-Protein With Various Gangliosides in Raft-Like
Membranes: Importance of GM1 Ganglioside-Bound Form as an Endogenous Seed for
Alzheimer Amyloid. Biochemistry 2002, 41, 7385–7390, with permission. Panel (E):
Reproduced from Matsuzaki, K.; Kato, K.; Yanagisawa, K. Ganglioside-Mediated Assembly
of Amyloid β-Protein: Roles in Alzheimer’s Disease. Prog. Mol. Biol. Transl. Sci. 2018,
156, 413–434, with permission.
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5. GANGLIOSIDES ARE CELL-SURFACE RECEPTORS

FOR BACTERIAL TOXINS
As molecular determinants at the cell surface, gangliosides act as
membrane-bound receptors for molecules outside the cell, including soluble
molecules in the extracellular milieu and molecules on other cells. Early
evidence for this function came from screening studies searching for a tissue
receptor for the bacterial toxin from Vibrio cholerae, cholera toxin (Ctx).62
Cholera is a severe diarrheal disease caused by a soluble protein toxin
released into the intestinal lumen. The toxin is a heterohexamer with five
identical binding (B) subunits and a single toxic A subunit (Fig. 4A). It binds
to the surface of intestinal epithelial cells via its B subunits and inserts the
A subunit into the cytoplasm where it enzymatically ADP-ribosylates Gsα
leading to increased cAMP, chloride ion imbalance, and water release into
the gut lumen. Soon after the soluble toxin was isolated, a broad screen of
various rabbit tissue extracts revealed relatively potent toxin deactivation by
preincubation with a lipid extract of gut epithelium but much more potent
inhibition by lipids extracted from brain, and particularly by polar lipids
with the properties of gangliosides.62 Tests using different purified brain
gangliosides revealed that GM1 was >1000-fold more potent in neutralizing
Ctx than other gangliosides including those of the same structure without a
sialic acid (GA1), with extra sialic acids (GD1a, GD1b, GT1b) or without
the terminal galactose (GM2).64 Eventual structural studies revealed why.63
Both arms of GM1, the Gal β1-3 GalNAc arm and the sialic acid, extensively
engage the GM1-binding site of Ctx via a network of hydrogen bonds,
explaining the requirement for the unsubstituted terminal Gal, the subterminal
GalNAc, and the sialic acid, all in the particular relative orientation of
GM1 (Fig. 4C). Because pentameric binding (Fig. 4B) ensures the high bind-
ing avidity of the toxin,30 potent glycan inhibitors have been designed by
building multivalent scaffolds with appropriately oriented pentameric glycan
ligands.65 It is interesting to note that among human tissues, the intestinal epi-
thelium expresses the lowest concentration of gangliosides (Table 1), although
still enough for cholera intoxication, as well as that of other ganglioside-
binding diarrheal bacterial toxins, notably those from pathogenic E. coli.34
Enterotoxigenic E. coli (ETEC) is the major cause of bacterial diarrhea
in children and travelers worldwide. ETEC produces AB5 toxins, called
heat-labile toxins (LTs) with similar properties to Ctx (Table 2). There
are several variants of LTs, all of which require ganglioside binding prior
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Fig. 4 (A) AB5 structure of cholera toxin (1S5F.pdb). The toxin binds to cell membranes
via a GM1-binding pocket at the bottom of each of the five B subunits. (B) Cholera toxin
B pentamer with GM1 glycan depicted as a stick structure (3CHB.pdb). (C) Schematic rep-
resentation of the toxin–GM1 complex. Structures after Merritt et al.63 Reproduced with
permission from Branson, T. R.; Turnbull, W. B. Bacterial Toxin Inhibitors Based on Multiva-
lent Scaffolds. Chem. Soc. Rev. 2013, 42, 4613–4622; Turnbull, W. B.; Precious, B. L.;
Homans, S. W. Dissecting the Cholera Toxin-Ganglioside GM1 Interaction by Isothermal
Titration Calorimetry. J. Am. Chem. Soc. 2004, 126, 1047–1054.
Table 2 Examples of Ganglioside-Binding Bacterial Toxins
Primary Ganglioside Toxin
Pathogen Toxin Structure Receptor(s) Toxin Enzyme Activity Substrate Disease
V. cholerae Ctx AB5 GM1 ADP-ribosyl Gαs Diarrheal
transferase disease
Enterotoxigenic LT-I AB5 GM1 ADP-ribosyl Gαs Diarrheal
E. coli transferase disease
LT-IIa GM1, GD1a, GD1b, GT1b
LT-IIb GD1a, GT1b, LM1
LT-IIc GM1, GD1a, GD1b, GT1b
C. tetani TeNT Single-chain AB GT1b, GD1b GD1a > GM1 Zn2+ metalloprotease VAMP Spastic paralysis
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2+
C. botulinum BoNT/A Single-chain AB GT1b > GD1a, GD1b > GM1 Zn metalloprotease SNAP-25 Flaccid paralysis
LM1, Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4Glcβ1-10 Cer. LT-IIb also binds longer terminally sialylated poly-N-acetyllactosamine (Galβ1-4GlcNAcβ1-3)n
structures.66
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to entry of their toxic A subunits, which ADP-ribosylate the Gαs subunit

like Ctx.67 The LT-I ganglioside-binding site is nearly identical to that of
Ctx, with high specificity for GM1.66,68 However, LT-II series toxins have
broader ganglioside-binding specificities.66,69,70 LT-IIa and LT-IIc bind all
of the major brain gangliosides (GM1, GD1a, GD1b, GT1b), LT-IIb binds
GD1a, GT1b, and terminally sialylated neolactoseries gangliosides, and
LT-IIc binds certain long-chain ceramide forms of GM1, but not shorter
chain forms.70 Structural studies comparing Ctx, LT-I, and LT-IIb reveal
a nearly identical GM1 glycan-binding pocket for Ctx and LT-I, but a
more open sialoglycan-binding site for LT-IIb.66 Interest in AB5 toxins
intensified when they were found to be potent adjuvants or immunomod-
ulators via ganglioside-mediated docking to toll-like receptors, making
engineered toxins potential therapeutics.71,72
A second structural class of soluble ganglioside-binding bacterial toxins
is represented by the clostridial neurotoxins, among which are tetanus toxin
(TeNT) and botulinum toxins (BoNTs).73,74 They are among the most
potent toxins in nature, with lethal doses in the ng/kg body weight range.
They are of great interest not only for their pathology, but because BoNT
is an approved therapeutic for a growing number of clinical indications
from migraine to spasticity to overactive bladder. While there is a single
TeNT, there are at least 40 BoNT variants classified into at least 7 serotypes,
of which BoNT/A is the focus here.73,74 TeNT and BoNTs are similar
in structure and function. They are synthesized as 150 kDa single-chain
polypeptides that are cleaved into an enzymatic A chain and a ganglioside-
binding B chain held together by disulfide and protein–protein interactions.
The B chains bind gangliosides, primarily on motoneuron terminals at
neuromuscular junctions. The A chains are zinc proteases that target the
intracellular components of synaptic vesicle release, blocking neurotrans-
mission. The reason TeNT and BoNT/A have opposite effects is their
final sites of action.75 BoTN binds to the motoneuron presynaptic mem-
brane, enters the presynaptic terminal, and disrupts acetylcholine release
at the neuromuscular junction causing flaccid paralysis. In contrast, TeNT
binds to and enters the same motoneuron presynaptic terminal but is
retrogradely transported to the motoneuron soma, is trancytosed into
inhibitory interneurons that synapse on the motoneuron, and blocks their
neurotransmission resulting in hyperactive muscle contraction and spastic
paralysis. The difference in their sites of action relates to their modes of
binding.
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Interestingly, both TeNT and BoNT use dual binding sites to asso-
ciate with presynaptic membranes.73 For TeNT, both sites appear to be
gangliosides, whereas for BoNTs, a ganglioside and a protein-binding
site cooperate. In vitro binding studies demonstrate that TeNT binds
to all of the major brain gangliosides with a preference for the b-series
(GT1b GD1b GD1a > GM1).76,77 Structural studies revealed two
glycan-binding sites, termed the “W” and “R” sites based on key binding
amino acids. Mutating the R site left GM1 binding intact, but knocked
down GT1b binding. Knocking out the W site eliminated GM1 binding
and knocked down GT1b binding, and knocking out both sites completely
eliminated ganglioside binding.77 These data imply that GT1b is a dual-
site binder, whereas other gangliosides may preferentially bind one or the
other site. In cells that lack major brain gangliosides, reconstituting with
gangliosides that bind both pockets—either GT1b alone or GD3 + GM1—
reconstitutes TeNT binding and cell entry, supporting a dual ganglioside-
binding model for TeNT.78
In contrast to TeNT, BoNTs have a single ganglioside-binding site that
cooperates with a separate protein-binding site to generate high-avidity
binding (Fig. 5).79 For BoNT/A, the functional ganglioside-binding site pre-
fers GT1b,80 and the protein-binding site engages synaptic protein SV2.81
The ganglioside-binding site (Fig. 5B) consists of an extensive web of
hydrogen bonds that bind the terminal and internal sialic acids, the terminal
galactose, and the N-acetylgalactosamine.
Evidence that gangliosides are obligatory coreceptors for TeNT and
BoNT/A comes from ganglioside blocking and ganglioside metabolic
inhibitors in vitro,80,82 but more convincingly from mouse genetic studies.
As described more extensively in the following sections, mice engineered to
lack a key enzyme in the biosynthetic pathway to all of the major nervous
system gangliosides, GM2/GD2 synthase (coded by the B4galnt1 gene),
express the truncated structures GM3 and GD3 as their major brain gangli-
osides instead of the four major brain gangliosides GM1, GD1a, GD1b, and
GT1b (see Fig. 2). Whereas these mice have relatively normal neuromuscu-
lar junction electrophysiology, they are completely resistant to BoNT/A
inhibition.83 Likewise, they are markedly less susceptible to tetanus toxin.84
Mice with a different mutation (St8sia1 gene) express a-series (GM1 and
GD1a) but not b-series (GD1b or GT1b) gangliosides. Compared to
wild-type mice, they are equally susceptible to BoNT/A (and other BoNTs)
but less responsive to tetanus toxin. Together, these data confirm in vivo
roles of gangliosides in clostridial toxin susceptibility. Likewise, although
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Fig. 5 (A) Proposed model for simultaneous ganglioside and SV2 binding by BoNT/A.
Membrane-resident GT1b and SV2C luminal domain (blue) are shown binding to oppo-
site sides of the BoNT/A receptor-binding domain (green). The toxin translocation
domain (red) and protease (yellow) point away from the binding site. The SV2C trans-
membrane portion (gray) was modeled. The relationship to the membrane is proposed.
Linker regions are shown as black dotted lines. (B) Schematic picture of GT1b and its
(Continued)
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wild-type mice are relatively resistant to cholera toxin-induced diarrhea,

B4galnt1-null mice were resistant to cholera toxin’s adjuvant effects, again
implicating gangliosides as toxin receptors in vivo.85 The discovery of
cell-surface gangliosides as highly specific binding receptors for extracellular
toxins led to the concept that gangliosides support specific binding of
physiologically important endogenous ganglioside-binding proteins.
6. GANGLIOSIDES ARE CELL-SURFACE RECEPTORS

FOR MYELIN-ASSOCIATED GLYCOPROTEIN
The discovery that cell-surface gangliosides are receptors for bacterial
toxins suggested that they may also engage endogenous binding proteins.
A search for complementary ganglioside-binding proteins in the brain
revealed significant binding of a tagged multivalent GT1b construct to mye-
lin.86 Soon thereafter, myelin-associated glycoprotein (MAG) was discov-
ered to share sequence similarity with other vertebrate sialic acid-binding
lectins,87 now called the Siglec family.88 There are 14 human siglecs,89 all
of which are expressed on hemopoietic lineage cells except MAG (now also
called Siglec-4), which is expressed only by myelinating cells, oligodendrog-
lia in the central nervous system, and Schwann cells in the peripheral nervous
system.90 Subsequent studies defined the selective binding of MAG to the
Neu5Acα2-3Galβ1-3GalNAc arm of the major brain gangliosides GD1a
and GT1b.91,92 Additional studies revealed that MAG is very selective for
binding to Neu5Ac, in that gangliosides with Neu5Gc or with synthetic
modifications of the sialic acid hydroxyls fail to bind.93,94 Structural studies
confirmed the specificity of Neu5Acα2-3Gal binding to a shallow pocket
in the terminal Ig-like domain of MAG (Fig. 6A),33 anchored by a salt bridge
to an arginine (R118), a shared feature of all Siglecs. The engagement of
Fig. 5—Cont’d hydrogen bonds bound to BoNT/A. The hydrogen bonds between the
protein (blue) and GT1b (black) are shown as dotted red lines, and the GT1b internal
hydrogen bonds are shown as dotted black lines. Distances of key hydrogen bonds
are displayed in Å. Sia7 that is disordered in the complex is shaded gray. Panel (A):
Reproduced from Benoit, R. M.; Frey, D.; Hilbert, M.; Kevenaar, J. T.; Wieser, M. M.;
Stirnimann, C. U.; McMillan, D.; Ceska, T.; Lebon, F.; Jaussi, R.; Steinmetz, M. O.;
Schertler, G. F.; Hoogenraad, C. C.; Capitani, G.; Kammerer, R. A. Structural Basis for Recog-
nition of Synaptic Vesicle Protein 2C by Botulinum Neurotoxin A. Nature 2014, 505,
108–111, with permission. Panel (B): Reproduced from Stenmark, P.; Dupuy, J.;
Imamura, A.; Kiso, M.; Stevens, R. C. Crystal Structure of Botulinum Neurotoxin Type A in
Complex With the Cell Surface Co-receptor GT1b—Insight Into the Toxin-Neuron Interac-
tion. PLoS Pathog. 2008, 4, e1000129.
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Fig. 6 See legend on next page.

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the sialic acid carboxylate and glycerol side chain (Fig. 6B), along with a
tryptophan (W22) adjacent to the N-acetyl methyl group (not shown), is
consistent with MAG’s high specificity for each major molecular compo-
nent of sialic acid—the carboxylate, the N-acyl group, and the glycerol side
chain. Since the Siglec family of sialic acid-binding proteins has evolved to
engage sialic acids with differential specificity for its linkage and glycan
structure,89 the finding that a major side chain of the major sialoglycans
on nerve cells is targeted by MAG argues that the binding pocket evolved
to bind GD1a and GT1b. The finding that MAG is highly conserved among
mammals (>95% amino acid identical between rodents and humans)95 and
that major brain gangliosides (including GD1a and GT1b) are quantitatively
and qualitatively similar among mammals96 led to the hypothesis that MAG
and GD1a/GT1b bind to each other to support myelination. This was found
to be the case based on evidence from mouse and human genetics.
Mice engineered to lack the enzyme that adds the first glucose to cer-
amide, glucosylceramide (GlcCer) synthase (Ucgc gene) are early embryonic
lethal.97 To test the roles of glycosphingolipids in the nervous system,
conditional Ucgc knockouts were created behind either the pan-neural
promoter nestin,98,99 the Purkinje neuron promoter Pcp2,100 or the oligo-
dendrocyte promoter Cnp.101 Mice deficient in neuronal GlcCer-based
glycosphingolipids (nestin-driven) were born and appeared normal, but
within days displayed severe ataxia with peripheral nerve axon degeneration
and dysmyelination and central nerve axonal pruning. Mice with a less
penetrant loss of brain GlcCer-based glycosphingolipids (75% decrease)
displayed progressive neuropathy with dysreflexia by three months of age.
Mice lacking these glycosphingolipids in their Purkinje neurons displayed
Purkinje axon degeneration with abnormalities at their myelin nodes of
Ranvier. In contrast, mice with loss of Ugcg in myelinating cells did not
have remarkable changes in brain gangliosides or a phenotype. Together,
Fig. 6 Structural characterization of MAG–ganglioside binding and a model for

myelin–axon engagement. (A) MAG crystal structure (deglycosylated, blue) and MAG-
binding trisaccharide (Neu5Acα2-3Galβ1-3GalNAc, orange). (B) Protein–ligand interac-
tions with hydrogen bonds are indicated by dashes and van der Waals’ contacts by
curved blue lines. (C) Model for MAG-mediated myelin–axon engagement and signaling.
Dimerization of MAG restricts the distance between the innermost myelin sheath and
axon membrane to 10 nm. Reproduced from Pronker, M. F.; Lemstra, S.; Snijder, J.;
Heck, A. J.; Thies-Weesie, D. M.; Pasterkamp, R. J.; Janssen, B. J. Structural Basis of
Myelin-Associated Glycoprotein Adhesion and Signalling. Nat. Commun. 2016, 7, 13584.
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these data are consistent with the interpretation that gangliosides are not
required for nerve cell differentiation or nervous system anatomic develop-
ment, but their expression on nerve cells is required to maintain healthy
intracellular interactions essential to nervous system stability and function,
especially axon–myelin interactions. However, the phenotypic outcomes
of these genetic disruptions may be related to reduced expression of GlcCer
or other glycosphingolipids, not solely to ganglioside loss. Additional
mutations in the ganglioside biosynthetic pathway in mice provided addi-
tional insights.
Mice engineered with a disrupted GM3 synthase gene (St3gal5) lacked
downstream gangliosides, but were remarkably normal in their nervous
system phenotype.46 Notably, they expressed the same total brain ganglio-
side concentration, but as the normally minor ganglioside species GM1b
(cis-GM1) and GD1α (see Figs. 1 and 2), both of which carry the MAG-
binding glycan terminus Neu5Acα2-3Galβ1-3GalNAc. In fact, GD1α
had been identified as a high-affinity MAG ligand.102 The phenotype of
these GM3-knockout mice included enhanced insulin sensitivity (see above)
and deafness, but not dysmyelination or ataxia. This contrasts with mutations
of the same gene in humans, as will be described later. To further restrict
ganglioside biosynthesis a double-null mouse was created by disrupting
St3gal5 and B4galnt1 (see Fig. 2).103 These mice, which lacked GM3 and
all ganglio-series gangliosides, had reduced brain ganglioside expression
with low concentrations of sialylated glycosphingolipids and increased
LacCer expression. What little sialylated glycosphingolipid was found in
the brain was carried on a neolacto-series rather than a ganglio-series glycan
core. These “ganglioside-null” mice were born with an intact nervous
system, indicating the lack of a requirement for gangliosides in gross nervous
system development. However, they were short-lived, had small brains,
severe disruption of spinal and cerebellar white matter tracks, axon degen-
eration, malformed nodes of Ranvier, and severe hind limb weakness.
These findings are consistent with a role for gangliosides in axon–myelin
interactions as well as other nervous system functions.
More direct support for a role of gangliosides in MAG-mediated axon–
myelin interactions came from single-knockout B4galnt1-null mice.104,105
These mice lacked the optimal MAG-binding sequence Neu5Acα2-
3Galβ1-3GalNAc on all gangliosides, instead building up gangliosides behind
the block (GM3, GD3, see Fig. 2) to the same total brain ganglioside concen-
tration. Although these mice were born at Mendelian frequency and appeared
generally normal at a young age, they suffered progressive peripheral axonal
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degeneration, dysmyelination in the peripheral and central nervous systems,

and progressive motor neuropathy.105,106 A comparison of mice engineered
to lack MAG (Mag-null) with those lacking the MAG-binding ganglioside gly-
can (B4galnt1-null) and double-null mice (Mag/B4galnt1) revealed remarkably
similar phenotypes,107 including quantitatively similar central and peripheral
axon degeneration, decreased axon caliber due to reduced neurofilament spac-
ing, progressive motor deficits, and (paradoxically) hyperactivity. These deficits
can be traced to loss of axonal protective axon–myelin signaling.108,109
The conclusions reached from studying gene mutations in mice are
supported by observations in human congenital disorders of ganglioside bio-
synthesis.110 Linkage analyses in several families discovered 12 mutations in
the B4GALNT1 gene that were responsible for hereditary spastic paraplegia,
a progressive loss of limb motor function, in 42 reported individuals
(Table 3).111–113 The age of onset of gait difficulties ranged from 2 to
19 years. Progression was typically slow, with about a quarter of the affected
individuals bedridden or confined to a wheelchair, but only decades after the
disease was first noted. Most had muscle wasting associated with peripheral
neuropathy predominantly of the axonal type, as in B4galnt1-null mice. Fur-
ther evidence that this may relate to MAG–ganglioside binding comes from
a case study of siblings diagnosed with progressive axonal sensorimotor poly-
neuropathy115 due to a single amino acid mutation in MAG (R118), its sialic
acid-binding site.33,116 This finding is consistent with other studies that dis-
covered other mutations in MAG that result in hereditary spastic paraple-
gia.117,118 Together, these data support the conclusion that MAG on the
innermost wrap of myelin binds to gangliosides GD1a and GT1b on axons
to support effective myelination and optimize axonal survival. Other phe-
notypes in humans and mice with disrupted ganglioside biosynthesis point
to other roles for gangliosides in brain function and health.
7. INTELLECTUAL DISABILITY AND SEIZURES IN

HUMANS AND MICE WITH ALTERED GANGLIOSIDE
BIOSYNTHETIC GENES
In addition to lower-limb spasticity and gait disorders, all individuals
with B4GALNT1 mutations suffered mild to severe intellectual impairment
(IQ 50–70, see http://aaidd.org).110 Intellectual disability (ID) did not cor-
relate with onset of motor deficits. Some individuals that suffered gait
disorders late in life displayed ID in childhood,112 whereas some with
early-onset gate disorders had only mild ID.113 Cognitive dysfunction is
Table 3 Human Congenital Mutations in B4galnt1a
Seizures
No. of Onset Developmental Cognitive Affected/
Mutation Affected References (Years) Motor Deficits Delay Deficits Observed Other Features
B4GALNT1
c.852G > C 2 111,112 6–11 Progressive None reported ID 2/12 Sensory
(p.K284N) weakness, spasticity polyneuropathy,
pes cavus,
c.1514G > A 4
emotional lability,
(p.R505H)
psychiatric illness
c.1458dupA 6
(p.L487TfsX77)
c. 395delC 3 113 2–19 Spasticity, Mild–moderate Mild–moderate 0/21 Sensory
(p.P132QfsX7) hyperreflexia, ID polyneuropathy,
dysarthria, pes cavus,
c.898C > T 4
extrapyramidal signs strabismus
(p.R300C)
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c.682C > T 5
(p.R228X)
c.263dupG 1
(p.L89PfsX13)
c.358C > T 4
(p.Q120X)
Continued
Table 3 Human Congenital Mutations in B4galnt1—cont’d
Seizures
No. of Onset Developmental Cognitive Affected/
Mutation Affected References (Years) Motor Deficits Delay Deficits Observed Other Features
c.1298A > C 3
(p.D433A)
c.917_922dup 1
(p.T307_Val308dup);
c1315_1317delTTC
(p.F439del)
c.838-2A > G 4 114 <3–7 Delayed milestones, None reported Mild–severe ID, 0/9 Autistic features,
spasticity, dysarthria low verbal skills paranoia, social
c.1458_1459insA 5
phobia, emotionally
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(p.L487fs)
labile
a
Reproduced from Li and Schnaar,110 with permission.
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phenocopied, at least in part, in B4galnt1-null mice.119 Compared to wild-

type littermates these mice displayed measurable deficits in memory tasks
as well as alterations in electrically induced long-term potentiation (LTP),
an electrophysiological correlate of learning and memory.120
A few human subjects (5/42) with B4GALNT1 mutations suffered from
seizures, a phenotype also sporadically observed in B4galnt1-null mice.
Whether seizure susceptibility and ID are related to dysmyelination or another
functional role of gangliosides is as yet unclear. Notably, all human subjects
with a mutation in another enzyme in the same ganglioside biosynthetic
pathway, GM3 synthase (coded by ST3GAL5), were profoundly intellec-
tually impaired, and nearly all suffered from intractable infantile seizures.110
Linkage analysis in a family with several individuals suffering from a
hereditary infantile-onset severe seizure disorder revealed a nonsense mutation
in ST3GAL5.121 Subsequently, several pedigrees with the same mutation
(R288X) in a total of 49 affected individuals were reported (Table 4).121–123
Subjects with this mutation uniformly suffered severe drug-resistant seizures
starting in the first year of life with ongoing choreoathetosis. Motor and
cognitive development was markedly delayed with microcephaly, hypotonia,
failure to thrive, and profound ID. Subjects were nonambulatory, nonverbal,
blind,124 and deaf.127 Magnetic resonance imaging revealed delayed brain
maturation, atrophy, and hypomyelination upon aging.122,127 Another five
subjects with different (missense) ST3GAL5 mutations had serious motor
and cognitive deficits, although only one suffered seizures, and none were
blind (Table 4).125,126 Together, these findings indicate that disruption of
brain ganglioside biosynthesis in humans results in severe motor and cognitive
deficits in all subjects.
Unlike mutations of B4GALNT1, which phenocopied between mice
and humans, mutations in ST3GAL5 had markedly different outcomes.
St3gal5-null mice were not seizure prone and appeared to develop nor-
mally.46,128 In mice, disruption of St3gal5 led to loss of all major brain
gangliosides, but this loss was quantitatively matched by increased expression
of the usually minor 0-series gangliosides GM1b and GD1α behind the
biosynthetic block (see Fig. 2). It is speculated that functions served by
major brain gangliosides in mice were compensated by GM1b and
GD1α, a concept supported by MAG binding to both of these structures.102
In the absence of nervous system tissue from affected human subjects, it is
unknown whether humans with ST3GAL5 mutations express comparable
levels of 0-series gangliosides.
A closer phenotypic match with human subjects with ST3GAL5 muta-
tions is represented by “GM3 only” double-mutant mice,129 engineered
Table 4 Human Congenital Mutations in St3gal5a
No. of Onset Cognitive Seizures Affected/
Mutation Affected References (Years) Motor Deficits Developmental Delay Deficits Observed Other Features
ST3GAL5
c.862C > T 49 121–124 <1 Severely delayed, Profound stagnation, ID, nonverbal 46/46 Microcephaly,
(p.R288X) choreoathetosis, regression blind, deaf
nonambulatory
c.1063G > A 3 125 2 Choreoathetosis, Severely delayed ID, nonverbal 1/3 Microcephaly,
(p.E355K) spasticity, landmarks normal vision
nonambulatory
c.584G > C 2 126 <1 Choreoathetosis, Profound stagnation, ID, nonverbal 0/2 Microcephaly,
(p.C195S); nonambulatory regression normal vision
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c.601G > A
(p.G201R)
a
Reproduced from Li and Schnaar,110 with permission.
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to lack both St8sia1 (GD3 synthase) and B4galnt1 (GM2/GD2 synthase).

These mice are biosynthetically “stuck” at GM3, which is overexpressed
in the brain to a level equal to the total ganglioside concentration in
wild-type mice. These double-null mice suffer lethal audiogenic seizures
leading to early death, primarily within the first month of life.
One trait that is phenocopied between mice and humans with
ST3GAL5 mutations is hearing loss.128 In the mouse model, hair-cell defor-
mities and selective degeneration of the organ of Corti were reported.
Human subjects with ST3GAL5 mutations have neonatal onset hearing
impairment. Consistent with the mouse model, tympanometry of these sub-
jects as young children revealed outer hair-cell impairment as well as signif-
icant dysfunction of inner hair cells, central auditory pathways, or both.127
The mechanisms by which loss of major brain gangliosides leads to intel-
lectual disability and seizures are undetermined, but do not appear to track
with dysmyelination. Data implicating gangliosides in regulation of excit-
atory neurotransmission, including via lateral association with excitatory
glutamate receptors, suggest roles for gangliosides in learning and memory
independent of their roles in myelin stabilization.130
8. GANGLIOSIDES IN HUMAN DISEASE

As cell-surface molecular determinants on all mammalian cells that
function in membrane protein regulation and molecular recognition, gangli-
osides are implicated in a variety of human disease processes. As detailed
earlier, gangliosides or altered ganglioside metabolism is responsible for or
contribute to rare hereditary paraplegia and intellectual disability,110
Alzheimer’s disease,58 Parkinson’s disease,131 axon stabilization,132 insulin sen-
sitivity and diabetes,22,40 and bacterial toxin susceptibility.34 In other studies
beyond the scope of this review, genetic disruption of ganglioside catabolic
genes results in severe lysosomal storage diseases,24 and ganglioside-targeted
autoimmunity is responsible for certain forms of Guillain–Barre syndrome,
a common cause of acute flaccid paralysis.133 In addition, the function of
gangliosides in regulating growth factors and receptor tyrosine kinases results
in their involvement in cancer progression.31 Ganglioside expression is quan-
titatively and/or qualitatively altered in many cancers,134 leading to their
effective targeting for cancer immunotherapy.135,136 The prominence of gan-
gliosides as cell-surface molecular determinants and their varied roles in phys-
iology and pathology will provide opportunities for additional therapeutic
intervention as details of their expression and function continue to emerge.
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ACKNOWLEDGMENTS
The author thanks the many authors of the recently published book “Gangliosides in
Health and Disease”137 for providing a wealth of information about ganglioside biology.
The author’s efforts are supported in part by a grant from the National Institute of Mental
Health, National Institutes of Health, U. S. A. (MH107695).
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The Biology of Gangliosides

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The Biology of Gangliosides

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ARTICLE IN PRESS

The Biology of Gangliosides

1. GANGLIOSIDE STRUCTURES, DISTRIBUTION,

Advances in Carbohydrate Chemistry and Biochemistry # 2018 Elsevier Inc. 1

glycan Galβ1-3GalNAcβ1-4Galβ1-4Glcβ1-10 Cer, other gangliosides consist

Fig. 1 See legend on next page.

Table 1 Concentration of Gangliosides in Some Human Organsa

Gangliosides are biosynthesized stepwise starting with addition of glu-

2. GANGLIOSIDE FUNCTIONS: cis REGULATION

specific ganglioside-binding proteins either in the extracellular environment

3. GANGLIOSIDES REGULATE RECEPTOR TYROSINE

interactions of gangliosides with membrane proteins and indicate that

4. GANGLIOSIDES IMPACT HUMAN PROTEINOPATHIES

Fig. 3 See legend on opposite page.

Fig. 3 (A, B) Aβ fibrillogenesis of two different Aβ peptides is induced by GM1 lipo-

5. GANGLIOSIDES ARE CELL-SURFACE RECEPTORS

to entry of their toxic A subunits, which ADP-ribosylate the Gαs subunit

wild-type mice are relatively resistant to cholera toxin-induced diarrhea,

6. GANGLIOSIDES ARE CELL-SURFACE RECEPTORS

Fig. 6 See legend on next page.

Fig. 6 Structural characterization of MAG–ganglioside binding and a model for

degeneration, dysmyelination in the peripheral and central nervous systems,

7. INTELLECTUAL DISABILITY AND SEIZURES IN

phenocopied, at least in part, in B4galnt1-null mice.119 Compared to wild-

to lack both St8sia1 (GD3 synthase) and B4galnt1 (GM2/GD2 synthase).

8. GANGLIOSIDES IN HUMAN DISEASE

Sialoadhesin, Myelin-Associated Glycoprotein and CD22 Define a New Family of

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