User:7753spoom/sandbox/Sulfatide

Sulfatide also known as 3-O-sulfogalactosylceramide, SM4, or sulfated galactocerebrosides is a class of sulfolipids, specifically a class of sulfoglycolipids synthesized primarily starting in the endoplasmic reticulum and ending in the Golgi apparatus where ceramide is converted to galactocerebroside and later sulfated to make sulfatide. Of all of the myelin galactolipids, one fifth is sulfatide. Sulfatide is primarily found on the extracellular leaflet of the myelin plasma membrane produced by the oligodendrocytes in the central nervous system and in the Schwann cells in the peripheral nervous system. However, sulfatide is also present on the extracellular leaflet of the plasma membrane of many cells in a eukaryotic organism.

Since sulfatide is a multifunctional molecule, it can be used in multiple biological areas. Aside from being a membrane component, sulfatide functions in protein trafficking, cell aggregation and adhesion, neural plasticity, memory, and axon-myelin interactions. Sulfatide also plays a role in several physiological processes and systems including the nervous system, the immune system, insulin secretion, blood clotting, viral infection, and bacterial infection. As a result, sulfatide is associated with, able to bind to, and/or present in kidney tissues, cancer cells/ tissues, the surface of red blood cells and platelets, CD1 a-d cells in the immune system, many bacteria cells, several viruses, myelin, neurons, and astrocytes.

An abnormal metabolism or an expression change of sulfatide has also been associated with various types of pathology including metachromatic leukodystrophy, which leads to the progressive loss of myelin as a result of sulfatide accumulation. Sulfatide is also associated with Alzheimer’s disease, diabetes mellitus, cancer metastases, and viruses including HIV-1, influenza A virus, hepatitis C and Vaccinia virus. Over expression of sulfatide has also been linked to epilepsy and audiogenic seizures as well as other pathological states in the nervous system.

Past and ongoing research continues to elucidate the many biological functions of sulfatide and their many implications as well as the pathology that has been associated with sulfatide. Most research utilizes mice models but heterologous expression systems are utilized as well.

History
Sulfatide was the first sulfoglycolipid to be isolated in the human brain. It was named sulfatide in 1884 by Johann Ludwig Wilhelm Thudichum. In 1962, Tamio Yamakawa completed the structure of sulfatide.

Sulfatide synthesis
Sulfatide synthesis starts with a reaction between UDP-galactose and 2-hydroxylated or non-hydroxylated ceramide. This reaction is catalyzed by galactosyltranferase (CGT) and galactose is transferred to 2-hydroxylated, or non-hydroxylated ceramide, from UDP-galactose. This reaction occurs in the luminal leaflet of the endoplasmic reticulum and its final product is GalCer, or galactocerebroside, which is then transported to the Golgi apparatus. Here, GalCer reacts with 3’-phosphoadenosine-5’-phosphosulfate (PAPS) to make sulfatide. The reaction is catalyzed by cerebroside sulfotransferase (CST). CST is a homodimeric protein that is found in the Golgi apparatus. It has been demonstrated that mice models lacking CST, CGT, or both are incapable of producing sulfatide indicating that CST and CGT are necessary components of sulfatide synthesis. Sulfatide degradation occurs is lysosomes. Here, arylsulfatase A hydrolyzes the sulfate group. However, in order for this reaction to be carried out a sphingolipid activator protein like saposin B must be present. Saposin B extracts sulfatide from the membrane, which makes it accessible to arylsulfatase A to hydrolyze the sulfate group. Accumulation of sulfatide can cause Metachromatic Leukodystrophy, a lysosomal storage disease and may be caused because of a defect in arylsulfatase A leading to an inability to degrade sulfatide.

Biological Functions of Sulfatide
Sulfatide functions in many biological systems including the nervous system, the immune system, and in haemostasis/ thrombosis. Sulfatide has also been shown to play a minor role in the kidneys.

Nervous system
Sulfatide is a major component and is found in high levels in the myelin sheath in both the peripheral nervous system and the central nervous system. Myelin is typically composed of about 70 -75% lipids, and sulfatide comprises 4-7% of this 70-75%. When lacking sulfatide, myelin sheath is still produced around the axons; however, the lateral loops and part of the node of Ranvier are disorganized, so the myelin sheath does not function properly. Thus, lacking sulfatide can lead to muscle weakness, tremors, and ataxia.

Elevated levels of sulfatide are also associated with Metachromatic Leukodystrophy, which leads to the progressive loss of myelin as a result of sulfatide accumulation in the Schwann cells, oligodendrocytes, astrocytes, macrophages and neurons. Elevated levels of sulfatide have also been linked to epilepsy and audiogenic seizures, while elevated levels of anti-sulfatide antibodies in the serum has been associated with Multiple Sclerosis and Parkinson’s.

Differentiating myelin sheath
As stated above, sulfatide is predominantly found in the oligodendrocytes and the Schwann cells in the nervous system. When oligodendrocytes are differentiating, sulfatide is first evident in immature oligodendrocytes. However, research suggests that sulfatide has a greater role than simply being a structural component of the membrane. This is because sulfatide is up-regulated prior to the myelin sheath being wrapped around the axon, and experiments in CST deficient mice have shown that sulfatide operates as a negative regulator for oligodendrocyte differentiation. Further research has demonstrated that when sulfatide is deficient there is a two to threefold increase in oligodendrocyte differentiation. Myelination also appears to be stimulated by sulfatide in the Schwann Cells. First, sulfatide binds to tenascin- R or laminin in the extracellular matrix, which then binds to signaling molecules such as F3 and integrins in the glial membrane. This causes signaling through c-src/fyn kinase. Specifically, the laminin α6β1-integrin forms a complex with fyn kinase and with focal adhesion kinase that enables signaling, which causes myelination to begin. Sulfatide binding to laminin causes c-src/fyn kinase activation and initiation of basement membrane formation.

Sulfatide and MAL
Sulfatide also associates with myelin and lymphocyte protein (MAL). Research has shown MAL may be involved in vesicular transport of sulfatide and other myelin proteins and lipids to the myelinating membrane. MAL is also believed to form membrane micro domains in which lipids are stabilized allowing stabilization of the axial-glial junctions.

Glial-Axon signaling
Sulfatide has also been demonstrated to play a role in myelin maintenance and glial-axon signaling, which was indicated by older CST-deficient mice. These mice had vacuolar degeneration, un-compacted myelin, and moderated demyelination of the spinal cord. This occurs because improper glial-axon signaling and contact causes improper placement and maintenance of sodium and potassium channel clusters in the axons at the nodes of Ranvier. As a result, the maintenance of Nv1.6 clusters is impaired as there is a decrease in the number of clusters of the channels, and Kv1.2 channels are moved from the paranodal position to the juxtaparanodal position; this is also associated with the loss of neurofascin 155 and Caspr clusters, which are important components of the glial-axon junction.

Sulfatide is also important for axon-glial junctions in the peripheral nervous system. In peripheral nerves that are CST deficient, the nodes of Ranvier from enlarged axonal protrusions filled with enlarge vesicles, and neurofascin 155 and Caspr cluster are diminished or absent. In order to form a paranodal junction, Caspr and contactin form a complex with neurofascin 155. It has been shown that sulfatide may be involved to recruit and form neurofascin 155 in lipid rafts; neurofascin 155 cluster then bring Caspr and contactin into the membrane to form the complex, which allows the formation of stable axon-glial junctions. Consequently, sulfatide plays an important role in maintaining the paranodal axon-glial junction, which allows proper axon-glial interaction and signaling. Sulfatide has also been shown to be an inhibitor of myelin associated [axon outgrowth]] and small amounts are found in astrocytes and neurons, which is also indicative of its importance in axon-glial junctions.

Abnormal Sulfatide Expression
Abnormal expression of sulfatide is linked to several neurological disorders. As stated before, one of the major neurological disorders is Metachromatic Leukodystrophy, which is caused by elevated levels of sulfatide, leading to the progressive loss of myelin as a result of sulfatide accumulation. High levels of sulfatide in the gray matter in the cerebellum and in the superior frontal lobe have been associated with Parkinson’s disease. Additionally, accumulation of sulfatide in neurons causes audiogenic seizures, which have been shown to be lethal in mouse models. On the other hand, reduced levels of sulfatide in the cerebral gray and white matter have been associated with Alzheimer’s disease.

Immune system
Different types of cells that present antigens on their surfaces include:
 * macrophages
 * dendritic cells
 * Hepatocytes
 * B cells
 * tumor cells
 * thymocytes

Each of these is expressed in cluster of differentiation 1 molecules (CD1). There are 5 subtypes of CD1 molecules that range from a through e. The a through d subtypes are capable of binding to sulfatide. CD1 a-c subtypes present lipid antigens to T cells, while CD1d cells present lipids, glycolipids, and lipoproteins to Natural Killer T-cells. CD1 a through c cell subtypes initiate T helper type 1 and type 2 responses, and they facilitate sulfatide loading onto the surface of the cells. There are two types of cell subtypes that interact with CD1d cells: Type 1 Natural Killer T- cells and Type 2 Natural Killer T- cells. Type 2 Natural Killer T-cells are able to recognize sulfatide/ CD1d tetramers, and as a result, they are activated by different tissues specific forms of sulfatide. Type 2 Natural Killer T-cells that react with sulfatide help aid in protection from autoimmune disease and ischemic reperfusion. They are capable of such protection because the Type 1 Natural Killer T-cells can be regulated by Type 2 Natural Killer T-cells that react with sulfatide by altering how the dendritic cells function.

Sulfatide also acts as an L-selectin and P- selectin ligand, but it does not act as an E- selectin ligand. Selectins are adhesion molecules that facilitate the capture of circulating leukocytes. Sulfatide is also expressed on the surface of many types of cancer cells and tissues. Accordingly, sulfatide may function as a ligand for P –selectin, which facilitates cancer metastasis. Additionally, when L-selectin and sulfatide bind, this leads to up regulation of the chemokine co-receptor’s (CXCR4) expression, specifically on the surfaced of leukocytes.

Sulfatide may also function as a receptor for chemokins which are small chemostatic cytokines and they provide directional signals for leukocyte movement. Chemokins are implicated in: Sulfatide is also capable of binding to scavenger proteins found on macrophages. Such binding, facilitates a macrophage’s ability to take up apoptotic cells.
 * angiogenesis
 * HIV-1 infection
 * tumor metastasis
 * hematopoiesis
 * graft rejection
 * embryonic development

Autoimmunity also affects sulfatide levels. When an enhanced antibody response against myelin lipids occurs, including sulfatide in patients with Multiple Sclerosis, the demyelination process is increased significantly. When sulfatide and gangliosides are present, the proliferation of NK T cells that produce cytokines is activated. However, when CD1d deficient-mice are tested for their response to sulfatide, the same response is not seen which indicates that in myelin, sulfatide is an immunodominant glycolipid. Locally, the disruption of myelin due to the infiltration of T cells and macrophages results in the phagocytosis of myelin by microglia or macrophages, indicating that the T cells are presented with myelin lipids by CD1 molecules at sites of inflammation.

Hemostasis/thrombosis
Sulfatide has roles in both blood coagulation and anticoagulation. Sulfatide has anticoagulation activity when it binds to fibrinogen, which prevents fibrinogen from converting to fibrin. Sulfatide also has a direct inhibitory effect on thrombosis. On the other hand, sulfatide also helps to improve blood coagulation and thrombosis: first, sulfatide is believed to aid in thrombosis through its participation with coagulation factor XII; second, sulfatide binding to annexin V accelerates coagulation; third, sulfatide and P-selectin interactions expressed on platelets help to ensure stable platelet adhesion and aggregation. However, most of these conclusions have been drawn using exogenous forms of sulfatide. Consequently, additional research and experimentation on endogenous sulfatide is necessary to fully understand the role of sulfatide in coagulation and thrombosis. Sulfatide is also in serum lipoproteins which are believe to be associated with the cause and development of cardiovascular disease.

Kidney
Sulfatide can also be found in the kidney. Although sulfatide is not necessary for the kidneys to maintain their function and structure, it does play an active role in different aspects of the kidney. For example, sulfatide is a ligand for L-selectin, which is a receptor that can be found in the kidneys. Specifically, L- selectin is a lymphoid receptor, and the binding between L-selectin and sulfatide in the kidney’s interstitium plays a major role in monocyte permeation and infiltration into the kidney. Additionally, sulfatide is also found in the glandular stomach epithelium and in the apical membranes of the distal kidney tubuli where MAL is expressed. MAL forms complexes with sulfatide and other glycosphingolipids, and these complexes have been shown to play a role in apical sorting and stabilization of sphingoglycolipid enriched areas.

Role in pathological cells and tissue
Sulfatide has been shown to play a role or have some association with several diseases and infections. These include diabetes mellitus, cancer and tumors, metachromatic leukodystrophy, various bacterial infections, and viruses including HIV-1, Hepatitis C, Influenza A Virus, and Vaccinia Virus.

Metachromatic leukodystrophy
Metachromatic leukodystrophy, also known as MLD, is a recessive lysosomal storage disorder. It is believed to be caused by a deficiency in arylsulfatase A. Arylsulfatase A is a lysosomal sulfatase that is able to hydrolyze the 3-O-sulfogalactosylceramide and 3-O-sulfolactosylceramide. Both 3-O-sulfolactosylceramide and 3-O-sulfogalactosylceramide can be located mainly in the central nervous system as well as in the peripheral nervous system. When lacking the lysosomal enzyme or mutations in the gene coding for SapB occur, this can lead to the accumulation of lysosomal sulfatide, which then develops into metachromatic leukodystrophy.

Sulfatides play an important role with myelin. Myelin acts as an insulating sheath that surrounds many nerve fibers and increases the speed at which impulses are conducted and it also contributes to the conduction of nerve impulses in both the central nervous system and the peripheral nervous system. When sulfatide is not distributed properly, it can affect the normal physiological conduction of electrical impulses between nerve cells. This then results in demyelination because of the buildup of sulfatide and is the main cause of Metachromatic Leukodystrophy.

However, how sulfatide buildup causes demyelination and neural degeneration is still mostly unknown. Metachromatic Leukodystrophy results in neurological manifestations that are centered on the impairment of the central nervous system and the peripheral nervous system including the following: seizures, progressive coordination and speech problems, and behavioral disturbances. Treatment is still being studied and evaluated, but mice studies indicate that treatments including gene therapy, cell based therapies using oligodendrocyte progenitors cells, enzyme replacement therapy, or adeno-associated viral and lentiviral mediated gene therapy may prove to be effective in reducing the effects of MLD.

Diabetes mellitus
Sulfatide has several isoforms including C16:0, which is found mainly in the secretory granules and toward the surface of the membrane β cells. Secretory granules and β cells are found in the islet of Langerhans and in rat β TC3 cells. Research has shown that in the pancreases of a type II diabetic mouse models, there is a deficiency of C16:0. Additional research has shown that C16:0 plays an important role in assisting to increase insulin crystal preservations, and as the β cells in the pancreas secrete insulin, sulfatide aids in the monomerization of insulin. Consequently sulfatide is needed in order to maintain normal insulin secretion, which sulfatide is capable of mediating through stimulation of calcium dependent exocytosis and ATP sensitive potassium ion channels. Sulfatide can also stimulate proinsulin folding as well, as it can serve as a molecular chaperone for insulin.

In the diagnosis of type I diabetes, elevated anti-sulfatide antibodies in serum arise. Such anti-sulfatide bodies prevent insulin secretion and exocytosis. However, research has shown that when non-obese diabetic mice are treated with sulfatide, it reduces the possible occurrence of diabetes from 85% in control animals to 35% in experimental animal. Sulfatide is also commonly known to possess anti-inflammatory properties. As a result of these anti-inflammatory properties, which aid in the blockage of L-selectin, sulfatide has been shown to prevent type I diabetes and inhibit insulitis in non-obese diabetic mice. Sulfatide also prevents apoptosis in insulin secreting cells by preventing the effects of lL-1β, lFN-1β, and TNF-α that promote apoptosis.

Sulfatide may also be involved in not just type I diabetes but also type II diabetes. Specifically, sulfatide is capable of inhibiting TNF-α secretion. When there are low serum levels of sulfatide as well as elevated production of TNF-α in patients that have type II diabetes it is commonly associated with insulin resistance. However, sulfatide may mediate suppression of type II diabetes through the activation of potassium protein channels.

Cancer and tumor
Elevated sulfatide is common in many tissues in the human body including, numerous cancer tissues and cells. These include:
 * primary colorectal cancer tissues
 * primary lung adenocarcinoma tissues
 * malignant and benign ovarian cancer tissues
 * renal carcinoma tissues
 * serous papillary ovarian carcinoma tissues
 * gastric cancer tissues
 * renal carcinoma (SMKT-R3 cell line)

Sulfatide levels in these cancer lines/tissues may vary. For example, the levels of sulfatide are much lower in undifferentiated small cell carcinoma tissues and primary lung squamous cell carcinoma tissues in humans than in primary lung adenocarcinoma tissue in humans. In human ovarian cancers, sulfatide levels are much higher in malignant ovarian cancers than in benign ovarian cancers. Other cancers such as Wilms’ tumor show no expression of sulfatide. Therefore, it appears that such increased levels of sulfatide are not universal in every form of cancer, and more experimentation must be done to confirm that elevated levels of sulfatide is not just an artifact of the cultured cancer cell lines.

However, experimentation of renal cancer cell lines has given some insight into the mechanism for the elevated levels of sulfatide expression in cancer cells. Specifically, Cerebroside sulfotransferase (CST) is elevated as it passes along a signaling pathway which involves:
 * hepatocyte growth factor
 * epidermal growth factor
 * tyrosine kinases
 * TNF-α
 * protein kinase C
 * Ras

This path, in turn, results in the accumulation of sulfatide in renal cancer cell lines. Additionally, sulfatide can accumulate on the surface of cancer cells. This indicates that this sulfatide may serve as a specific ligand for P-selectin. This would, in turn, contribute to increased metastasis of the cancer. However, more research is needed to elucidate the relationship between elevated levels of the expression of sulfatide and initiation and metastasis mechanisms of cancer, but sulfatide may be a useful serum biomarker for early tumor detection.

Viral infection
Experimentation on sulfatide has shown that it has involvement in several viral infections including HIV-1, Influenza A virus, Hepatitis C, and the Vaccinia virus.

HIV-1
Sulfatide shows involvement in the HIV-1 infection. gp120-gp41 are specific types of envelope glycoprotein complexes that are found on HIV-1. These glycoprotein complexes can interact with CD4, a viral receptor molecule, which induces a change in the conformation of gp120. This change in conformation allows the gp120 complex to interact with the chemokine co-receptor and the insertion of the fusion peptide, gp41, into the membrane of the host cell. This allows the HIV-1 virus to enter into the cells. Gp120 can also bind to glycolipids like sulfatide and GalCer. Sulfatide binds strongly to the V3 loop of gp120, which, does not interact with CD4. Consequently, sulfatide acts as an alternate virus receptor in CD4- cells and it participates in transmembrane signaling. However, sulfatide has little function in HIV infection of CD4+ cells.

The binding of gp120 to GalCer has the ability to start the fusion of HIV-1, but the binding of gp120 to sulfatide does not. Sulfatide is not a functional receptor. However, experiments have shown that sulfatide and GalCer compete for the ability to bind to gp120, and sulfatide has been shown to have the strongest binding affinity for recombinant gp120 of all the glycolipids tested. Therefore, this suggests that when sulfatide is attached to HIV-1 it cannot interact with the chemokine coreceptor because of the instability of the complex between gp120 and sulfatide, which therefore prevents the initiation of the fusion process. This indicates that sulfatide can prevent HIV-1 infection by mediating gp120 binding, which, in turn, prevents the fusion process. Consequently, it has been demonstrated that sulfatide treatments may lead to the inhibition of HIV-1 replication.

Additionally, HIV-1 infected patients often suffer from myelin degeneration in the CNS. These patients have elevated levels of sulfatide in the CFS and anti sulfatide antibodies in the serum. Elevated levels of sulfatide antibodies can cause demyelination. This is caused by the binding of the sulfatide antibodies to the surface of the myelin sheath and/or the surface of Schwann Cells, which then activates a complete cascade of demyelination. Also, advance stage AIDS patients can develop Guillain-Barré syndrome (GBS). Guillain-Barré syndrome is classified as an acute autoimmune polyneuropathy, which specifically affects the peripheral nervous system of the infected patient. Experimentation has shown that anti sulfatide autoimmune antibodies may contribute to the development of GBS in AIDS patients as well as the development of peripheral nervous system injury in HIV-1 infected patients.

Hepatitis C
Several patients with hepatitis C virus (HCV) associated with mixed cryoglobulinemia (MC) have elevated levels of anti-sulfatide antibodies in their blood plasma. Mixed cryoglobulinemia (MC) is an immune disease, which typically presents with immune complex mediated vasculitis of the small vessels. It is believed there is a relationship between HCV and MC; however, the exact role of HCV in relation to the cause of MC has not yet been fully understood or discovered. Nevertheless, sphingolipid synthesis in the host, has been demonstrated to be necessary for HCV replication, which indicates that sulfatide may be involved in the replication of HCV.

Influenza A
Influenza A virus (IAV) binds strongly to sulfatide. However, sulfatide receptors have no sialic acid, which has been shown to play a necessary role as a virus receptor that facilitates the binding of the influenza A virus. Sulfatide has also been shown to inhibit influenza A virus sialidase activity. However, this is only under acidic conditions not neutral conditions. To fully understand the role of sulfatide in the cycle of IAV infection, sulfatide was expressed in Madin-Darby canine kidney cells, which can support IAV replication and in COS-7 Cells, which do not have the ability to express sulfatide and support IAV replication sufficiently. These cells were used to make two cloned cells with the ability to express sulfatide.

These cells were then infected with the IAV virus, and the sulfatide enhanced cells infected with IAV showed improved IAV replication in the progeny virus, 300-5000 times the parent virus. However, the sulfatide enriched cells had a small reduction in initial infection compared to the parent cells. The opposite was shown in sulfatide knockdown cells with reduction in progeny virus concentration vs. parent virus and an increase in initial infection. Overall, such experiments demonstrated that sulfide rich cells enhance IAV replication and that sulfatide on the cell’s surface may play a role in the replication of IAV.

Further experimentation has demonstrated that sulfatide enriched cells in which sulfatide binds to hemagglutinin enhances IAV replication by increasing the progeny virus particle formation, which is done through the promotion of nuclear export of IAV formed viral ribonucleoprotein from the nucleus to the cytoplasm. Experimentation has also demonstrated that if binding is inhibited between sulfatide and hemagglutinin that viral particle formation and replication would be inhibited again suggesting that the binding between sulfatide and hemagglutinin facilitate IAV replication.

Vaccinia virus
Vaccinia virus is closely related to variola virus, which is known to causes the smallpox disease. The vaccinia virus has been shown to be able to bind to sulfatide through the L5 and A27 membrane proteins on the virus. It has been demonstrated in mouse models that sulfatide prevents the attachment of vaccinia virus to the cell’s surface, while also preventing death in the lethal mouse models. This suggests that sulfatide may be one receptor for the vaccinia virus.

Bacterial infection

 * Sulfatide binds to many bacteria including:
 * enterotoxigenic Escherichia coli TOP10 strain
 * Campylobacter jejuni
 * Mycoplasma hyopneumoniae
 * Haemophilus influenzae
 * Actinobacillus pleuropneumoniae
 * Helicobacter pylori
 * Moraxella catarrhalis
 * Bordetella pertussis
 * 987P-fimbriated enterotoxigenic Escherichia coli
 * Lactobacillus reuteri (JCM1081 and TM105 strains)
 * Mycoplasma hominis
 * Mycoplasma pneumonia
 * Pseudomonas aeruginosa
 * Haemophilus ducreyi

Sulfatide acts as a glycolipid receptor that functions to aid in the adherence of these bacterial to the mucosal surface. Mycoplasma hyopneumoniae and Actinobacillus pleuropneumoniae are pathogens that cause respiratory disease in swine. Haemophilus influenza, Bordetella pertussis, Mycoplasma pneumonia, Moraxella catarrhalis, and Pseudomonas aeruginosa cause respiratory disease in humans. Accordingly, sulfatide is located in the tracheas of both human and swine, and through the use of sulfatide present in the trachea, these several bacteria are capable of adherence to the respiratory tract. Hsp-70 on the outside of H. influenzae, has also been shown to aid in the ability of this bacteria to bind to sulfatide.

Helicobacter pylori, enterotoxigenic E. coli TOP10 strain, 987P-fimbriated enterotoxigenic E. coli, and Lactobacillus reuteri are different strains of bacteria that are found to adhere to the gastrointestinal tract’s mucosal surface. Here, sulfatide is present within the tract and is loaded from outside the tract, aiding the bacteria in adherence to the mucosa.

STb is an enterotoxin type B that is heat stable; additionally, it is secreted by the enterotoxigenic E. coli strain, and it causes diarrheal diseases in humans and many other species of animals. STb also binds strongly to sulfatide as demonstrated by its binding to sulfatide present on the mucosal surface of a pig’s jejunum. Additional experimentation suggests that sulfatide is a functional STb receptor.

Sulfatide may also play a role in Mycobacterium tuberculosis, which is the agent that causes tuberculosis in humans. Experimentation suggests that sulfatide may be involved in Mycobacterium tuberculosis infection, and it may be an element of the cell wall of the bacteria Mycobacterium tuberculosis.

Role in Alzheimer's disease
In Alzheimer’s disease, sulfatide in the brain tissue decreases tremendously, starting in the early stages. In the mild stages of Alzheimer’s disease, the loss of sulfatide can be up to 50% in white matter and up to 90% in gray matter in the brain. Sulfatides in the cerebral spinal fluid is also lower in subjects with Alzheimer’s disease. .The characteristic loss of neuronal function via loss of neurons and synapses occur yet, and the deficit is lipid class specific to sulfatides. When comparing sulfatide depletion to other neurodegenerative diseases, Alzheimer’s disease is the only case in which sulfatide is so dramatically depleted; in dementia no marked sulfatide depletion is observed, in Parkinson's disease sulfatide levels are dramatically elevated, and Multiple sclerosis patients only had moderate sulfatide depletion. Additionally, the loss of sulfatide has been observed to only happen at the very beginning of the disease, at more severe stages minimal additional sulfatide loss occurs.

Sulfatides in brain tissue has been studied by looking at apolipoprotein E (apoE), specifically the ε4 allele. The ε4 allele of apolipoprotein E is the only known genetic risk factor to majorly indicate late onset AD. ApoE ε4 has been associated with a higher risk of Alzheimer’s disease. ApoE is a protein that is involved in the transport of many lipids, including cholesterol, and thus, regulates how much sulfatide is in the central nervous system and mediates the homeostasis of the system. It has been found that higher levels of apoE are positively correlated with more sulfatide depletion. ApoE associated proteins take sulfatide from the myelin sheath and degrades sulfatide into various compounds, such as sulfate. When apoE is increased, the amount of sulfatide that is taken from the myelin sheath is also increased; hence, there is more sulfatide depletion.

Sulfatides also are involved in the amyloid-β peptide clearance. Amyloid-β peptides are one of the hallmarks of Alzheimer’s disease. When they are not degraded properly, these peptides accumulate and create plaques, which are highly associated with Alzheimer’s disease. Amyloid-β peptide clearance is important so this accumulation does not occur. Sulfatide facilitates amyloid-β peptide removal through an endocytotic pathway, so when there are high levels of sulfatide, there are lower amounts of amyloid-β peptides. Since subjects with Alzheimer’s disease have lower sulfatide levels, the clearance of amyloid-β peptides is lower, which allows the peptides to accumulate and create plaques in the brain.

Relationship to vitamin K
Vitamin K has been found to be associated with sulfatide concentrations in the brain. Not only in animals, but also in bacteria, vitamin K has been observed to influence sulfatide concentrations in the brain. Vitamin K in the nervous system is responsible for the activation of enzymes that are essential for the biosynthesis of brain phospholipids, such as sulfatides. When warfarin, a vitamin K antagonist, was added to an animal model system, sulfatide synthesis was impaired. However, when vitamin K was added back into the system, sulfatide synthesis proceeded normally.