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Sulfatide
Sulfatide
Sulfatide
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The structural formula of a sulfatide

Sulfatide, also known as 3-O-sulfogalactosylceramide, SM4, or sulfated galactocerebroside, is a class of sulfolipids, specifically a class of sulfoglycolipids, which are glycolipids that contain a sulfate group.[1] Sulfatide is 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 galactolipids that are found in the myelin sheath, one fifth of them are 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 eukaryotic organisms.[2]

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 glial-axon 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 is 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 change in the expression of sulfatide has also been associated with various pathologies, including neuropathologies, such as metachromatic leukodystrophy, Alzheimer's disease, and Parkinson's disease. Sulfatide is also associated with diabetes mellitus, cancer metastasis, and viruses, including HIV-1, Influenza A virus, Hepatitis C and Vaccinia virus. Additionally, overexpression of sulfatide has 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, including, but not limited to, Madin-Darby canine kidney cells and COS-7 Cells.[2][3]

History

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Sulfatide was the first sulfoglycolipid to be isolated in the human brain. It was named sulfatide in 1884 by Johann Ludwig Wilhelm Thudichum when he published "A Treatist of the Chemical Constitution of the Brain".[1] Originally, in 1933, it was first reported by Blix that sulfatide contained amide bound fatty acid and 4-sphingenine and that the sulfate of sulfatide was thought to be attached to the C6 position of galactose.[3][4] This was again supported in 1955 by Thannhauser and Schmidt; however, through gas-liquid chromatography, Tamio Yamakawa found that sulfate was actually attached to the C3 position of galactose, not the C6 position.[4] Thus, in 1962, Yamakawa completed the corrected chemical structure of sulfatide.[5]

Synthesis and degradation

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Synthesis of sulfatide

Sulfatide synthesis begins with a reaction between UDP-galactose and 2-hydroxylated or non-hydroxylated ceramide. This reaction is catalyzed by galactosyltransferase (CGT), where galactose is transferred to 2-hydroxylated, or non-hydroxylated ceramide, from UDP-galactose.[1] 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.[1][2] Here, GalCer reacts with 3’-phosphoadenosine-5’-phosphosulfate (PAPS) to make sulfatide. This reaction is catalyzed by cerebroside sulfotransferase (CST).[1] CST is a homodimeric protein that is found in the Golgi apparatus.[1] 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.[2]

Sulfatide degradation occurs in the lysosomes. Here, arylsulfatase A hydrolyzes the sulfate group.[1] However, in order for this reaction to be carried out, a sphingolipid activator protein such as saposin B must be present.[2] Saposin B extracts sulfatide from the membrane, which makes it accessible to arylsulfatase A.[1] Arylsulfatase A can then 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.[2][3]

Biological functions of sulfatide

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Sulfatide participates in many biological systems and functions, 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

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Transmission electron micrograph of a myelinated axon

Sulfatide is a major component in the nervous system 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%.[2] When lacking sulfatide, myelin sheath is still produced around the axons; however, when lacking sulfatide the lateral loops and part of the nodes of Ranvier are disorganized, so the myelin sheath does not function properly.[5] Thus, lacking sulfatide can lead to muscle weakness, tremors, and ataxia.[5]

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.[1][2] Elevated levels of sulfatide have also been linked to epilepsy and audiogenic seizures (seizures induced by sound), while elevated levels of anti-sulfatide antibodies in the serum have been associated with multiple sclerosis and Parkinson's.[2]

Differentiating myelin sheath

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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.[1] However, research suggests that sulfatide has a greater role than simply being a structural component of the membrane.[1] This is because sulfatide is upregulated, i.e.there is an increase in sulfatide, prior to the myelin sheath being wrapped around the axon, and experiments in cerebroside sulfotransferase (CST) deficient mice have shown that sulfatide operates as a negative regulator (inhibitor) of oligodendrocyte differentiation.[1] Accordingly, further research has demonstrated that when sulfatide is deficient, there is a two to threefold increase in oligodendrocyte differentiation, evidence providing support that sulfatide operates as a negative regulator or inhibitor of oligodendrocyte differentiation.[1] Myelination also appears to be stimulated by sulfatide in the Schwann Cells. Such stimulation is thought to occur through the following interactions. First, sulfatide binds to tenascin-R or laminin in the extracellular matrix, which goes on to bind signaling molecules such as F3 and integrins in the glial membrane.[1] This causes signaling through c-src/fyn kinase. Specifically, the laminin α6β1-integrin forms a complex with fyn kinase and focal adhesion kinase that enables signaling, which, in turn, causes myelination to begin.[1] Sulfatide binding to laminin also causes c-src/fyn kinase activation and initiation of basement membrane formation.[1]

Sulfatide and myelin and lymphocyte protein

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Sulfatide also associates with myelin and lymphocyte protein (MAL). Research has shown that MAL may be involved in vesicular transport of sulfatide and other myelin proteins and lipids to the myelinating membrane.[3] MAL is also believed to form membrane microdomains (small regions on the membrane with distinct structure and function) in which lipids, such as sulfatide, are stabilized into lipid rafts, allowing stabilization of the glial-axon junctions.[1]

Glial-axon junctions and signaling

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Sulfatide has also been shown to play a role in myelin maintenance and glial-axon signaling, which was indicated by research in older cerebroside sulfotransferase (CST)-deficient mice.[3] These mice had vacuolar degeneration, uncompacted myelin, and moderate demyelination of the spinal cord.[1][3] This occurs because improper glial-axon signaling and contact and disruption of paranodal glial-axon junctions causes improper placement and maintenance of sodium and potassium channel clusters in the axons at the nodes of Ranvier.[3] As a result, the maintenance of Nav1.6 sodium clusters is impaired as there is a decrease in the number of clusters of sodium channels at the nodes of Ranvier.[1] Additionally, Kv1.2 channels are moved from the paranodal position to the juxtaparanodal position causing impairment of these channels; this is also associated with the loss of neurofascin 155 and Caspr clusters, which are important components of the glial-axon junction.[1]

Sulfatide is also important for glial-axon junctions in the peripheral nervous system. In peripheral nerves that are cerebroside sulfotransferase (CST) deficient, the nodes of Ranvier form enlarged axonal protrusions filled with enlarged vesicles, and neurofascin 155 and Caspr clusters are diminished or absent.[1] In order to form a paranodal junction, Caspr and contactin form a complex with neurofascin 155.[1] It has been shown that sulfatide may be involved in the recruitment and formation of neurofascin 155 in lipid rafts; neurofascin 155 protein clusters then bring Caspr and contactin into the membrane to form the complex, which allows the formation of stable glial-axon junctions.[1] Consequently, sulfatide plays an important role in maintaining the paranodal glial-axon junctions, which allows for proper glial-axon interaction and signaling.[1][3] Sulfatide has also been shown to be an inhibitor of myelin-associated axon outgrowth, and small amounts of sulfatide have been found in astrocytes and neurons, which is also indicative of its importance in glial-axon junctions.[3]

Abnormal sulfatide expression

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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.[2][3] High levels of sulfatide in the gray matter in the cerebellum and in the superior frontal lobe have been associated with Parkinson's disease.[2] Additionally, accumulation of sulfatide in neurons causes audiogenic seizures, which have been shown to be lethal in mouse models.[2] On the other hand, reduced levels of sulfatide in the cerebral gray and white matter have been associated with Alzheimer's disease.[2][6]

Immune system

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Different types of cells that present antigens on their surfaces include:[3]

CD1D Protein

Each of these different cell types are expressed in cluster of differentiation 1 molecules (CD1).[3] There are 5 subtypes of CD1 molecules that range from a through e. The a through d subtypes are capable of binding to sulfatide.[2] CD1a, CD1b, and CD1c 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.[3] 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.[2] 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.[3] 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.[3]

Sulfatide also acts as an L-selectin and P-selectin ligand, but it does not act as an E- selectin ligand.[3] 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.[3] Additionally, when L-selectin and sulfatide bind, upregulation of the chemokine co-receptor's (CXCR4) expression is observed, specifically on the surfaced of leukocytes.[3]

Sulfatide may also function as a receptor for chemokines, which are small chemostatic cytokines, and they provide directional signals for leukocyte movement.[3] Chemokines are implicated in:[3]

Sulfatide is also capable of binding to scavenger proteins found on macrophages. Such binding facilitates a macrophage's ability to take up apoptotic cells.[3]

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.[7] When sulfatide and gangliosides are present, the proliferation or production of Natural Killer-T cells that produce cytokines are 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 a glycolipid that possesses immunodominance.[7]

Locally, the disruption of myelin due to the infiltration of T cells and macrophages, results in the phagocytosis of myelin by microglia or macrophages, suggesting that the T cells are presented with myelin lipids by CD1 molecules at sites of inflammation.[7]

Hemostasis/thrombosis

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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.[3][8] 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.[3][8] 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.[8] Sulfatide is also present in serum lipoproteins, which are believed to be associated with the cause and development of cardiovascular disease.[2]

Kidney

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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.[3] 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.[3][5] Additionally, sulfatide is also found in the glandular stomach epithelium and in the apical membranes of the distal kidney tubuli where Myelin and lymphocyte protein (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.[1][3]

Role in pathological cells and tissue

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Sulfatide has been shown to play a role or have some association with several diseases and infections. This includes 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

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arylsulfatase A

Metachromatic leukodystrophy, also known as MLD, is a recessive lysosomal storage disorder. It is believed to be caused by a deficiency in arylsulfatase A.[1][9] 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.[1] When lacking the lysosomal enzyme or mutations in the gene coding for saposin B occur, this can lead to the accumulation of lysosomal sulfatide, which then develops into metachromatic leukodystrophy.[1][3]

Sulfatide plays an important role in the myelin. Myelin acts as an insulating sheath that surrounds many nerve fibers and increases the speed at which impulses are conducted. When sulfatide is not distributed properly, it can affect the normal physiological conduction of electrical impulses between nerve cells.[1] This then results in demyelination because of the buildup of sulfatide and is the main cause of Metachromatic Leukodystrophy.[1][3]

However, how sulfatide buildup causes demyelination and neural degeneration is still mostly unknown.[1] 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.[10] 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 Metachromatic Leukodystrophy.[1]

Diabetes mellitus

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Sulfatide has several isoforms, including C16:0, which is found primarily in the secretory granules and toward the surface of the membrane of β cells. Secretory granules and β cells are found in the islet of Langerhans and in rat β TC3 cells.[3] Research has shown that in the pancreases of 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 improve insulin crystal preservation, and as the β cells in the pancreas secrete insulin, sulfatide aids in the monomerization of insulin, which is the breakdown of insulin into its basics components or monomers.[3] Consequently, sulfatide is needed in order to maintain normal insulin secretion, which sulfatide is capable of mediating through stimulation of calcium dependent exocytosis and adenosine triphosphate (ATP)-sensitive potassium ion channels.[3] Sulfatide can also stimulate proinsulin folding as well, as it can serve as a molecular chaperone for insulin.[3]

In the diagnosis of Type I diabetes, elevated anti-sulfatide antibodies in serum arise. Such anti-sulfatide antibodies prevent insulin secretion and exocytosis.[3] 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 animals.[3] 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.[3] Sulfatide also prevents apoptosis in insulin secreting cells by preventing the effects of interleukin-1 beta (lL-1β), interferon beta 1b (lFN-1β), and tumor necrosis factor alpha (TNF-α) that promote apoptosis.[3]

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.[3] However, sulfatide may mediate suppression of type II diabetes through the activation of potassium protein channels.[3]

Cancer and tumor

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Elevated sulfatide is common in many tissues in the human body, including numerous cancer tissues and cells.[2][3] These include:

Primary Lung adenocarcinoma

Sulfatide levels in these cancer lines and 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.[3] In human ovarian cancers, sulfatide levels are much higher in malignant ovarian cancers than in benign ovarian cancers.[2][3] 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 are not just artifacts of cultured cancer cell lines.[3]

P-selectin

However, experimentation using renal cancer cell lines has given some insight into the mechanism for the elevated levels of sulfatide expression in cancer cells.[3] Specifically, cerebroside sulfotransferase (CST) is elevated as it passes along a signaling pathway which involves:[3]

This path results in the accumulation of sulfatide in renal cancer cell lines.[3] Additionally, sulfatide can accumulate on the surface of cancer cells. This indicates that sulfatide may serve as a specific ligand for P-selectin. This would contribute to increased metastasis of the cancer.[3] However, more research is needed to elucidate the relationship between the elevated levels of sulfatide expression and the initiation and metastasis mechanisms of cancer,[3] but sulfatide may be a useful serum biomarker for early tumor detection.[2]

Viral infection

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Experimentation with 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

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V3 loop fragment of the HIV-1 envelope gp120 complex

Sulfatide shows involvement in HIV-1 infection.[2] gp120-gp41 are specific types of envelope glycoprotein complexes that are found on HIV-1.[3] 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.[3] This allows the HIV-1 virus to enter into the cell.[3] Gp120 can also bind to glycolipids like sulfatide and galactocerebroside (GalCer). Sulfatide binds strongly to the V3 loop of gp120, which does not interact with CD4.[3] Consequently, sulfatide acts as an alternate virus receptor in CD4- cells, and it participates in transmembrane signaling. However, sulfatide has little function in HIV-1 infection of CD4+ cells.[3]

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.[3] 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.[3] Therefore, this suggests that when sulfatide is attached to HIV-1, it cannot interact with the chemokine co-receptor because of the instability of the complex between gp120 and sulfatide, which therefore prevents the initiation of the fusion process.[3] 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.[3]

Additionally, HIV-1-infected patients often suffer from myelin degeneration in the central nervous system. These patients have elevated levels of sulfatide in the cerebrospinal fluid (CSF) and anti-sulfatide antibodies in the serum.[3] Elevated levels of anti-sulfatide antibodies can cause demyelination. This is caused by the binding of the anti-sulfatide antibodies to the surface of the myelin sheath and/or the surface of Schwann Cells, which then activates a complete cascade of demyelination.[3] Also, advanced 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.[3] Experimentation has shown that anti-sulfatide autoimmune antibodies may contribute to the development of Guillain–Barré syndrome in AIDS patients as well as the development of peripheral nervous system injury in HIV-1 infected patients.[3]

Hepatitis C

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Several patients with Hepatitis C virus (HCV) associated with mixed cryoglobulinemia (MC) have elevated levels of anti-sulfatide antibodies in their blood plasma.[3] Mixed cryoglobulinemia (MC) is an immune disease, which typically presents with immune complex mediated vasculitis of the small vessels.[3] 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.[3]

Influenza A

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Influenza A virus (IAV) binds strongly to sulfatide.[2] 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.[3] Sulfatide has also been shown to inhibit influenza A virus sialidase activity. However, this is only under acidic conditions not neutral conditions.[3] To fully understand the role of sulfatide in the cycle of IAV infection, research have expressed sulfatide in Madin-Darby canine kidney cells, which can express sulfatide and support IAV replication and in COS-7 cells, which do not have the ability to express sulfatide and do not support IAV replication sufficiently. Consequently, the COS-7 cells were transfected with galactosyltransferase and cerebroside sulfotransferase genes from the Madin-Darby canine kidney cells and used to make two cell clones with the ability to express sulfatide .[3]

These cells were then infected with the IAV virus, and research has shown that the sulfatide enhanced cells infected with IAV show increased IAV replication in the progeny virus, 500–3,000 times the parent virus. However, the sulfatide enriched cells also have a small reduction in initial infection compared to the parent cells.[2][3] The opposite is shown in sulfatide knockdown Madin-Darby canine kidney cells, exhibiting a reduction in progeny virus concentration vs. parent virus concentration and an increase in initial infection. Overall, such experiments demonstrate that sulfide rich cells enhance IAV replication and that sulfatide on the cell's surface may play a role in the replication of IAV.[2][3]

Further experimentation has demonstrated that sulfatide enriched cells, in which sulfatide binds to hemagglutinin, enhances IAV replication by increasing the progeny virus particle formation; this is done through the promotion of nuclear export of IAV formed viral ribonucleoproteins from the nucleus to the cytoplasm.[3] 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 facilitates IAV replication.[3]

Vaccinia virus

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Vaccinia virus is closely related to variola virus, which is known to cause 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.[3] 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 mouse models that are typically lethal. This suggests that sulfatide may be one receptor for the vaccinia virus.[2][3]

Bacterial infection

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Sulfatide binds to many bacteria, including:[3]

Sulfatide acts as a glycolipid receptor that functions to aid in the adherence of these bacteria to the mucosal surface.[3] Mycoplasma hyopneumoniae and Actinobacillus pleuropneumoniae are pathogens that cause respiratory disease in swine. Haemophilus influenzae, Bordetella pertussis, Mycoplasma pneumoniae, 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.[3]

Helicobacter pylori, enterotoxigenic E. coli TOP10 strain, 987P-fimbriated enterotoxigenic E. coli (a strain of E. coli), and Lactobacillus reuteri are different strains of bacteria that are found to adhere to the gastrointestinal tract's mucosal surface.[3] Here, sulfatide is present within the tract and is loaded from outside the tract, aiding the bacteria in adherence to the mucosa.[3]

STb is an enterotoxin type B that is heat stable; additionally, it is secreted by the enterotoxigenic E. coli strain, and it causes diarrhoeal 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.[3]

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 bacterium Mycobacterium tuberculosis.[3]

Clinical significance

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Role in Alzheimer's disease

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Main article: Alzheimer's disease

In Alzheimer's disease, sulfatide in the brain tissue decreases tremendously, starting in the early stages of the disease.[6] In the mild stages of Alzheimer's disease, the loss of sulfatide can be up to 50% in the white matter and up to 90% in the gray matter in the brain.[6] Sulfatide concentration in the cerebral spinal fluid is also lower in subjects with Alzheimer's disease.[6] The characteristic loss of neuronal function associated with Alzheimer's disease occurs via the loss of neurons and synapses, and the deficit is lipid class specific to sulfatides.[11] 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, while in Parkinson's disease, sulfatide levels are dramatically elevated, and multiple sclerosis patients only have a moderate sulfatide depletion.[11] Additionally, the loss of sulfatide has been observed to only occur at the very beginning of the disease while at more severe stages, minimal additional sulfatide loss occurs.[11]

apolipoprotein E

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 significantly indicate late onset Alzheimer's disease.[11] Possessing the apoE ε4 allele has been associated with a higher risk of developing Alzheimer's disease.[11] 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.[6] It has been found that higher levels of apoE are positively correlated with greater sulfatide depletion.[6] ApoE-associated proteins take sulfatide from the myelin sheath and then degrade 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.[6]

Sulfatide is also involved in the clearance of amyloid-β peptide. 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 clumps of amyloid-β peptide pieces, and they are highly associated with Alzheimer's disease.[6] Amyloid-β peptide clearance is important so that this accumulation does not occur.[6] 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.[6] 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.[6]

Relationship to vitamin K

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Vitamin K has been found to be associated with sulfatide. Not only in animals, but also in bacteria, vitamin K has been observed to influence sulfatide concentrations in the brain.[12][13] Vitamin K in the nervous system is responsible for the activation of enzymes that are essential for the biosynthesis of brain phospholipids, such as sulfatide.[12] When warfarin, a vitamin K antagonist, is added to an animal model system, sulfatide synthesis is impaired.[12] However, when vitamin K is added back into the system, sulfatide synthesis proceeds normally, suggesting that Vitamin K is necessary for sulfatide synthesis.[12][13][14]

References

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Sulfatide

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Sulfatide, chemically known as 3-O-sulfogalactosylceramide (SM4), is a sulfated glycosphingolipid that serves as a major component of the sheath in both the central and peripheral nervous systems of mammals. This molecule consists of a backbone—a base linked to a —covalently bound to a residue that is sulfated at the 3-position of the ring. Sulfatides account for approximately 4–6% of total and exhibit structural diversity through variations in the chain length (typically C16–C26), , and . Beyond the , sulfatides are present in various tissues, including the kidneys (particularly renal tubular cells), , , , and plasma lipoproteins, as well as on the surface of certain tumor cells. In these locations, sulfatides perform multifaceted roles, such as facilitating protein trafficking, and aggregation, neuronal plasticity, modulation, and insulin secretion from pancreatic β-cells. For instance, they promote platelet adhesion and aggregation by interacting with P-selectin, while also exhibiting effects through binding to fibrinogen and contributing to processes. Sulfatides are biosynthesized in the Golgi apparatus of and Schwann cells through sulfation of galactosylceramide by the enzyme cerebroside sulfotransferase (CST), encoded by the GAL3ST1 gene. Dysregulation of sulfatide levels has been implicated in several diseases; accumulation occurs in due to arylsulfatase A dysfunction, leading to sulfatide storage and demyelination, while altered levels are associated with , , , and certain cancers. These also participate in host-pathogen interactions and cell survival signaling, underscoring their broad physiological significance.

Chemical Structure and Properties

Molecular Composition

Sulfatide, also known as 3-O-sulfogalactosylceramide or GalCer-I³S, is a sulfated glycosphingolipid characterized by a group esterified at the 3-position of the residue. Its core structure comprises a lipid backbone, consisting of a sphingoid base—typically (2S,3R,4E)-sphing-4-enine (d18:1, an 18-carbon chain with a trans between carbons 4 and 5)—linked via an amide bond to a fatty acyl chain, to which a β-D- unit is attached at the primary hydroxyl group (C1) of the sphingoid base through a β-glycosidic linkage. The moiety imparts a negative charge to the hydrophilic headgroup, distinguishing sulfatide from its unsulfated precursor, galactosylceramide. Structural variants of sulfatide arise primarily from heterogeneity in the portion, particularly the length and saturation of the fatty acyl chain, which typically ranges from C16 to C26 carbons. Common isoforms include those with saturated fatty acids such as palmitoyl (C16:0), stearoyl (C18:0), or lignoceroyl (C24:0), as well as unsaturated forms like C24:1, and hydroxylated variants such as 2-hydroxy lignoceroyl (2-OH-C24:0). The sphingoid base is predominantly d18:1, though minor with different chain lengths or saturation may occur in specific tissues. These variations influence the physical properties and distribution of sulfatide isoforms within cellular membranes. In , sulfatide specifically denotes the class with the described ceramide-based structure, while the term is sometimes contrasted with seminolipid, a structurally distinct sulfoglycolipid found in testicular tissue that features a 3-O-sulfated attached to a 1-alkyl-2-acyl-sn-glycerol backbone rather than . A representative molecular formula for a common sulfatide isoform, such as the d18:1/18:0 variant (with and ), is C₄₂H₈₁NO₁₁S (free acid form; as the sodium salt, C₄₂H₈₀NO₁₁SNa).

Physicochemical Characteristics

Sulfatide exhibits an amphipathic , featuring a polar head group composed of sulfated and a hydrophobic tail consisting of and a chain, which facilitates its integration into bilayers with the head group oriented toward the aqueous environment and the tail embedded in the hydrophobic core. This dual nature enables sulfatide to contribute to organization by promoting lateral segregation into distinct domains. Due to the sulfate ester group on the galactose moiety, sulfatide is anionic at physiological , with a pKa value of approximately -1.8 for the , ensuring it remains fully deprotonated and negatively charged under neutral conditions. This charge property mediates electrostatic interactions with positively charged proteins and cations, such as calcium, which can stabilize sulfatide-enriched domains in membranes. For its lyso , the sulfate pKa is around 1.9, confirming the strong acidity of the group. Sulfatide is insoluble in owing to its hydrophobic portion but readily soluble in organic solvents, including :: mixtures (65:25:4) at concentrations up to 5 mg/mL, , and DMSO. This solubility profile is typical of glycosphingolipids and supports its extraction and study in non-aqueous environments. While direct (CMC) data for intact sulfatide is limited due to its tendency to form bilayers rather than micelles, the lyso-sulfatide variant has a CMC exceeding 300 μM, indicating low micellization propensity at physiological concentrations. In environments, sulfatide preferentially partitions into liquid-ordered phases, particularly those enriched with and , thereby contributing to the formation and stabilization of rafts. At physiological levels (around 5 mol%), it co-localizes with other like galactosylceramide in these ordered domains, enhancing heterogeneity without requiring sterols in simpler mixtures. Sulfatide demonstrates stability against under physiological conditions, resisting spontaneous breakdown in neutral pH environments due to the robust linkage. However, it is susceptible to enzymatic degradation by sulfatases, such as arylsulfatase A, which specifically hydrolyzes the group in lysosomal compartments. This selective sensitivity underscores its role in regulated membrane dynamics.

Biosynthesis and Metabolism

Biosynthetic Pathways

Sulfatide biosynthesis begins with the formation of its precursor, galactosylceramide (GalCer), which is synthesized in the and Golgi apparatus through the action of UDP-galactose:ceramide galactosyltransferase (CGT), an that transfers from UDP- to . The subsequent sulfation step occurs in the Golgi apparatus, where cerebroside sulfotransferase (CST), also known as galactosylceramide sulfotransferase, catalyzes the transfer of a group from (PAPS) to the 3-position of the residue in GalCer, yielding sulfatide. The CST is encoded by the GAL3ST1 gene, located on human 22q12.2. Sulfatide production is primarily localized to specific cell types, including in the , Schwann cells in the peripheral nervous system, and epithelial cells in the , where it supports membrane functions in these tissues. Its synthesis is developmentally regulated, with expression peaking during the myelination phase in and Schwann cells to facilitate sheath formation. Regulation of sulfatide biosynthesis involves transcriptional control by factors such as , which promotes the expression of genes in the pathway, including those for CGT and CST, in myelinating glial cells. Additionally, sulfatide levels exert feedback inhibition on the pathway, particularly by suppressing GalCer synthesis upon accumulation. In the , sulfatide constitutes approximately 4-5% of total lipids, underscoring its significance in myelin composition. CST deficiency disrupts this pathway, though detailed pathological effects are addressed elsewhere.

Degradation Mechanisms

Sulfatide degradation primarily occurs through lysosomal , initiating with the action of arylsulfatase A (ASA, EC 3.1.6.8), which removes the sulfate group from the 3-O position to produce galactosylceramide (GalCer). This enzymatic step is essential for breaking down sulfatide, a sulfated glycosphingolipid abundant in . Following desulfation, GalCer is hydrolyzed by galactosylceramidase (also known as β-galactosylceramidase or GALC, EC 3.2.1.46), cleaving the β- residue to yield and . then serves as a precursor for further recycling or degradation. This sequential pathway ensures the of sulfatide into reusable components, maintaining in cells. The lysosomal degradation process relies on accessory proteins for efficiency, particularly saposin B, a sphingolipid activator protein derived from prosaposin. Saposin B binds to , solubilizing it within the intralysosomal membrane environment and presenting it to ASA for . Without saposin B, ASA activity toward sulfatide is severely impaired, highlighting the coordinated nature of this catabolic mechanism. The primary site of degradation is the late endosomal-lysosomal compartment, where acidic conditions facilitate enzymatic function; in sheaths, sulfatide turnover is slow, with a exceeding 6 months, reflecting its structural stability. Although lysosomal dominates, limited extralysosomal degradation pathways exist, particularly in certain cell types. Studies in lymphoblastoid cell lines have identified a non-lysosomal route for sulfatide breakdown, independent of ASA and unaffected by lysosomal inhibitors like , suggesting involvement of neutral pH activities potentially at the plasma membrane. This alternative pathway may contribute to basal sulfatide clearance in scenarios of lysosomal dysfunction, though its physiological significance remains under investigation. Degradation is tightly regulated, with ASA exhibiting optimal activity at pH 4.5–5.0, aligning with the acidic milieu of lysosomes. Genetic variants in the gene can reduce enzymatic efficiency, altering degradation kinetics even in non-pathological contexts. These factors underscore the pathway's sensitivity to cellular environment and genetic background, influencing sulfatide levels across tissues.

Biological Functions

Role in the Nervous System

Sulfatide, a sulfated glycosphingolipid, plays a pivotal role in the (CNS) primarily as a key component of sheaths produced by . Constituting approximately 4-5% of total CNS lipids by weight, sulfatide contributes to the structural integrity and compaction of . It interacts directly with major proteins, including myelin basic protein (MBP) and proteolipid protein (PLP), to stabilize the multilayered architecture. Specifically, sulfatide facilitates interactions between adjacent extracellular domains of PLP molecules, promoting the tight compaction essential for efficient nerve conduction. These interactions help maintain the periodic structure of lamellae, ensuring the sheath's mechanical stability and insulating properties.80093-8.pdf) Sulfatide further supports myelin formation through its association with the and lymphocyte protein (MAL), a raft-associated proteolipid involved in trafficking. Binding between sulfatide and MAL enhances the transport and incorporation of and proteins into myelin membranes, aiding in the assembly of specialized myelin domains. Additionally, sulfatide mediates intercellular at glial-axon junctions, particularly at paranodes, via interactions with axonal molecules such as neurofascin-155 (NF155). The negatively charged groups of sulfatide enable electrostatic binding to positively charged regions on NF155, stabilizing axo-glial contacts and preventing myelin slippage along the . This is crucial for delineating axonal domains and maintaining the overall organization of myelinated fibers. In neural signaling, sulfatide modulates the distribution and function of ion channels at specialized axonal regions. It is essential for clustering voltage-gated potassium channels, such as Kv1.1, at juxtaparanodes, and sodium channels at nodes of Ranvier, ensuring proper and repolarization after action potentials. By stabilizing these channel clusters, sulfatide indirectly supports efficient release at synaptic terminals, as disruptions in nodal architecture can impair impulse propagation. During development, sulfatide expression initiates in differentiating and escalates progressively, reaching peak levels in mature adult to coincide with full myelination. This temporal pattern underscores its role in orchestrating oligodendrocyte maturation and myelin biogenesis.

Role in the Immune System

Sulfatide plays a key role in modulating T-cell responses through its presentation by CD1d molecules on antigen-presenting cells (APCs), such as dendritic cells and macrophages, to type II natural killer T (NKT) cells. These type II NKT cells, distinguished from invariant type I NKT cells by their diverse T-cell receptor repertoire, recognize sulfatide-loaded CD1d complexes, leading to activation that promotes immunoregulatory pathways. This interaction influences the Th1/Th2 balance by favoring Th2 cytokine production, such as IL-4 and IL-13, while suppressing proinflammatory Th1 responses, thereby helping to maintain immune homeostasis and prevent excessive inflammation. For instance, sulfatide-activated type II NKT cells inhibit the function of type I NKT cells, reducing their IFN-γ secretion and overall proinflammatory activity. In macrophages, sulfatide exhibits regulatory effects on phagocytic and inflammatory functions, though its impact varies by context. The C16:0 isoform of sulfatide inhibits the production of cytokines, including TNF-α, IL-1, IL-6, and IL-10, thereby attenuating inflammatory responses in conditions like . This suppression occurs through interference with signaling pathways, such as hindering TLR4 localization in lipid rafts, which reduces downstream activation of and MAPK pathways, leading to decreased TNF-α and IL-6 upon LPS stimulation. Regarding , sulfatide enhances the uptake of apoptotic cells by binding to scavenger receptors on macrophages, promoting phagosome-lysosome fusion and increasing of anti-inflammatory cytokines like TGF-β1. These effects are mediated in part by interactions involving residues, which facilitate sulfatide's binding to cellular receptors and modulate immune . Sulfatide also contributes to B-cell and responses via its expression on and interaction with the and (MAL) protein. Subsets of B cells express CD1d and can present sulfatide to type II NKT cells, enhancing B-cell activation and production through NKT cell-derived help, such as IL-4 that promotes class switching. In , sulfatide associates with MAL to stabilize membrane microdomains and facilitate glycosphingolipid trafficking, supporting T- and B-cell migration and immune synapse formation. This MAL-mediated trafficking ensures proper localization of sulfatide in lipid rafts, aiding efficient and responses. Sulfatide exerts anti-inflammatory effects, particularly by suppressing TLR4 signaling in immune cells like dendritic cells and macrophages. By preventing TLR4 co-localization with rafts, sulfatide blocks LPS-induced activation, reducing translocation and release, including TNF-α. This mechanism mitigates excessive inflammation in response to endotoxins, as demonstrated by decreased secretion and ROS production in stimulated cells. Sulfatide is notably enriched in immune tissues such as the and , where it constitutes a significant portion of glycolipids, supporting its role in local immune regulation; for example, sulfatide-reactive NKT cells comprise 0.3–0.7% of splenocytes and 0.3–0.5% of thymocytes.

Role in Hemostasis and Thrombosis

Sulfatides, sulfated glycosphingolipids present on the surface of endothelial cells and platelets, play a dual role in modulating platelet activation during . Upon endothelial activation, P-selectin is translocated to the cell surface, where it binds to sulfatides exposed on circulating platelets, facilitating initial platelet rolling and firm adhesion to the vascular wall. This interaction stabilizes early platelet aggregates and triggers intracellular signaling pathways that amplify platelet activation, contributing to formation at sites of vascular injury. The binding affinity of P-selectin for sulfatides is mediated by the negatively charged sulfate groups on the galactosyl head of sulfatide, which mimic ligands and promote shear-resistant adhesion under flow conditions.90570-O) In the coagulation cascade, sulfatide's sulfate moieties interact with key clotting factors, including factors V and VIII, to support the assembly of the prothrombinase complex on surfaces. These interactions enhance the localization and activation of factor Xa, accelerating the conversion of prothrombin to and thereby amplifying generation. Sulfatides also bind (vWF) via its A1 domain, indirectly stabilizing and facilitating its cofactor function in the intrinsic tenase complex. This membrane-associated mechanism underscores sulfatide's procoagulant properties, leveraging its anionic nature to bridge factors and platelet surfaces. At higher concentrations, sulfatides exhibit effects by binding fibrinogen and disrupting , akin to the inhibitory actions of sulfated like . This concentration-dependent inhibition prolongs clotting times and reduces clot stability, providing a regulatory balance to prevent excessive . Such dual functionality helps maintain hemostatic equilibrium, with physiological levels favoring clot promotion and supraphysiological levels shifting toward anticoagulation. Sulfatides are abundantly expressed in platelet membranes, where they modulate the Ib-IX-V (GPIb-IX-V) complex, a critical receptor for vWF-mediated . By binding to the A1 domain of vWF, sulfatides can inhibit GPIb-IX-V-dependent platelet tethering under high shear, fine-tuning platelet recruitment to prevent unwarranted aggregation.35039-7/fulltext) This regulatory interaction ensures controlled platelet activation without compromising primary . Studies in sulfatide-deficient animal models, such as cerebroside sulfotransferase (CST)-knockout mice, reveal mild bleeding tendencies characterized by prolonged lag phases in collagen-induced platelet aggregation and subtly extended tail bleeding times compared to wild-type controls. These findings indicate that sulfatide deficiency impairs efficient stabilization, though compensatory mechanisms often maintain overall without overt hemorrhage.

Role in Renal Physiology

Sulfatide is abundantly expressed in the , with distinct regional patterns that highlight its localization in key segments of the . Immunohistochemical studies in reveal high levels in the of proximal tubules, distal tubules of Henle's loop, the (including the ), and cortical and medullary collecting ducts, while expression is absent in the glomerular region. In murine models, specific sulfatide species, such as those composed of phytosphingosine (t18:0) and 2-hydroxy fatty acids (e.g., t18:0-C16:0h at m/z 888.6), are predominantly localized to intercalated cells of the collecting ducts, where their synthesis is regulated by cerebroside sulfotransferase (CST). CST deficiency leads to complete loss of sulfatides and morphological abnormalities, such as vacuolar accumulation in intercalated cell , underscoring the enzyme's regulatory in maintaining sulfatide levels in these structures. In proximal tubules, sulfatide modulates megalin-mediated by contributing to the composition in the apical membrane, facilitating the of filtered proteins and peptides. As a major sulfated in renal , sulfatide supports the structural integrity of the , where megalin and its co-receptor cubilin drive endocytic uptake essential for tubular and prevention of under normal conditions. Additionally, sulfatide influences Na⁺-K⁺-ATPase activity on the basolateral membrane of proximal tubular cells, promoting ion transport and fluid critical for maintaining renal . Sulfatide plays a homeostatic role in renal cells by protecting against , as evidenced by its levels being preserved in conditions where oxidative damage is mitigated, such as through that reduces systemic oxidative burden and restores sulfatide in renal tissues. This protective function helps maintain cellular resilience in the renal during physiological challenges, including ion balance and acid-base regulation in the distal .

Roles in Pathology

Genetic and Neurodegenerative Disorders

Sulfatide plays a central role in genetic disorders involving lysosomal storage dysfunction, particularly (MLD), an autosomal recessive condition caused by mutations in the ARSA gene on 22q13.33, which encodes the arylsulfatase A (ASA). Deficiency in ASA impairs the desulfation of sulfatide to galactosylceramide, leading to lysosomal accumulation of sulfatide and its deacylated derivative, lysosulfatide, primarily in and Schwann cells. This buildup destabilizes sheaths, triggering progressive demyelination in the central and peripheral nervous systems, which manifests as motor impairment, , , and cognitive decline. MLD presents in three main forms based on age of onset: late-infantile (most common, 50-60% of cases, symptoms starting before age 3), juvenile (20-30%, onset between ages 4 and puberty), and adult (15-20%, later onset with milder progression), with severity correlating to residual ASA activity influenced by specific ARSA mutations, such as null alleles in infantile cases. Over 260 unique ARSA mutations have been identified, underscoring the genetic heterogeneity. An overlap exists with Krabbe disease, another lysosomal storage disorder caused by galactocerebrosidase (GALC) deficiency due to mutations in the GALC gene, where sulfatide metabolism is secondarily disrupted. GALC normally hydrolyzes galactosylceramide (the product of sulfatide desulfation by ASA) to ceramide and galactose; its absence leads to accumulation of galactosylceramide and psychosine, indirectly impairing downstream sulfatide degradation and contributing to shared demyelinating pathology, including globoid cell formation and oligodendrocyte loss. This secondary effect exacerbates myelin pathology in Krabbe disease, highlighting interconnected glycosphingolipid pathways in these leukodystrophies. In (MS), an autoimmune , sulfatide expression is abnormally reduced within demyelinated plaques, correlating with impaired remyelination and disease progression. Studies of postmortem MS brain tissue and experimental demyelination models show marked depletion of sulfatide isoforms (e.g., C22-C26 chains) in chronic lesions, which disrupts differentiation and axon- interactions essential for repair. This reduction contributes to remyelination failure, as evidenced by slower myelin recovery in sulfatide-deficient conditions, promoting persistent axonal vulnerability and neurological decline. Advancements in for MLD leverage sulfatide biomarkers for early detection, with 16:1-OH-sulfatide emerging as a highly precise first-tier in dried blood spots. In a 2024 multicenter study across four screening programs, 16:1-OH-sulfatide measurement achieved a false-positive rate of 0.048% (reducible to near zero with second-tier ASA assay) while detecting all 40 confirmed MLD cases, outperforming the traditional 16:0-sulfatide marker by minimizing non-specific elevations. This approach enables presymptomatic intervention, potentially halting demyelination through therapies like . Sulfatide deficiency also induces reactive and disruption, as demonstrated in recent mouse models mimicking adult-onset loss. A 2024 study using conditional sulfotransferase (CST; Gal3st1)-deficient mice revealed that sulfatide depletion triggers activation, marked by upregulated GFAP, , and ApoE expression, independent of Trem2 signaling, alongside transcriptomic shifts toward reactive (e.g., Cd109). Concurrently, lipid dyshomeostasis— including elevated and reduced —occurs in the and , leading to structural disruption and without overt demyelination, underscoring sulfatide's role in glial- integrity.

Metabolic and Fibrotic Diseases

Sulfatide plays a critical role in pancreatic β-cell function, where its reduction in diabetes mellitus impairs insulin secretion and contributes to hyperglycemia. In β-cells, sulfatide facilitates proinsulin folding, stabilizes insulin crystals at acidic pH within secretory granules, and promotes insulin monomerization and exocytosis upon granule fusion with the plasma membrane during glucose-stimulated secretion. Studies in animal models and human islets demonstrate that sulfatide deficiency disrupts ATP-sensitive potassium channel modulation and calcium-dependent exocytosis, leading to diminished first-phase insulin release, a hallmark of early type 2 diabetes progression. Furthermore, islet sulfatide content is notably decreased in type 2 diabetic patients compared to healthy controls, exacerbating β-cell stress and dysfunction. In , a severe renal manifestation of systemic , serum sulfatide levels serve as a potential for disease classification and activity. A 2025 clinical study of patients with biopsy-proven found significantly lower serum sulfatide concentrations compared to healthy controls, with levels inversely correlating to the renal activity index and histological evidence of active lesions such as endocapillary proliferation and wire-loop formations. This reduction may reflect systemic dysregulation of sulfatide metabolism amid autoimmune inflammation. Concurrently, loss in glomerular structures is a prominent pathological feature, contributing to and glomerular barrier dysfunction through foot process effacement and detachment from the basement membrane. Sulfatide exhibits protective effects against by modulating immune responses that inhibit activation, key mediators of deposition. In models of chronic , sulfatide activates type II natural killer T cells, which suppress pro-fibrogenic type I NKT cell activity and reduce cytokine-driven transdifferentiation into myofibroblasts. Recent investigations highlight direct anti-fibrotic properties of sulfatide isoforms, such as C16:0, which inhibit proliferation and synthesis in hepatic contexts, positioning sulfatide as a potential therapeutic agent for fibrotic liver diseases. These effects were evidenced in 2024-2025 preclinical studies demonstrating reduced scores in sulfatide-treated models of toxin-induced . In non-alcoholic fatty liver disease (NAFLD), now termed metabolic dysfunction-associated steatotic liver disease (MASLD), sulfatide deficiency correlates with accelerated steatosis progression toward inflammation and fibrosis. Lipoprotein-bound sulfatides, primarily on high-density lipoproteins in healthy states, shift to low-density lipoproteins in MASLD patients, impairing their immunomodulatory role and promoting hepatic lipid accumulation. Proteomic and lipidomic analyses reveal that reduced arylsulfatase A activity, which degrades sulfatides, elevates sulfatide levels in advanced steatosis but overall systemic deficiency exacerbates steatohepatitis by dysregulating NKT cell responses and stellate cell activation. A 2024 lipid panel incorporating sulfatide metrics achieved high accuracy (AUROC 0.775) in detecting early fibrosis transition from steatosis, underscoring its biomarker utility.00404-2) Diabetic nephropathy involves sulfatide alterations that exacerbate through glomerular barrier disruption, linking metabolic dysregulation to renal pathology. Loss of sulfatide in podocytes and glomerular , akin to its normal role in maintaining selectivity, heightens permeability to under hyperglycemic conditions, promoting and disease advancement. This deficiency parallels broader glycosphingolipid imbalances in , where reduced sulfatide contributes to injury and basement membrane thickening, as observed in experimental diabetic models. Clinical correlations show that early interventions targeting analogs indirectly support sulfatide-related barrier integrity, slowing progression.

Oncological Implications

Sulfatide expression is upregulated in various tumor cells, including those in gliomas and (HCC), where it facilitates cancer cell invasion through interactions with . In gliomas, polar lipid remodeling leads to increased sulfatide levels, which correlate with therapeutic responses involving elevation and topoisomerase-1 inhibition. In HCC, sulfatide, synthesized by galactose-3-O-sulfotransferase 1 (also known as cerebroside sulfotransferase or CST), binds directly to αVβ3, promoting its clustering, phosphorylation, and activation independent of ligands, thereby enhancing , migration, and metastatic potential. This integrin-mediated mechanism supports tumor progression by enabling anchorage-independent growth and invasion in aggressive cancers. Sulfatide contributes to immune evasion in cancer by modulating interactions that suppress anti-tumor immunity. In clear cell renal cell carcinoma (ccRCC), a hypoxia-inducible axis involving HIF1 and GAL3ST1 (CST) elevates sulfatide levels on tumor cells, enhancing platelet binding that shields cells from immune surveillance and promotes metastatic dissemination. Additionally, sulfatide activates type II natural killer T (NKT) cells, which exert immunosuppressive effects by inhibiting type I NKT cell responses, conventional T cell activation, and overall tumor immunosurveillance in preclinical models. These mechanisms highlight sulfatide's role in dampening innate and adaptive immune responses against tumors. Sulfatide promotes indirectly through its activation of on endothelial and tumor cells. In HCC, sulfatide-induced activation of integrin αVβ3 drives tumor by facilitating vascular remodeling and endothelial cell interactions essential for neovascularization. This process supports nutrient supply and tumor expansion in hypoxic environments. Elevated sulfatide levels in serum and other body fluids show diagnostic potential for cancer detection and staging. In (RCC), lipidomic profiling reveals significantly altered sulfatide profiles in plasma and urine compared to healthy controls, with specific species like ST24:0 and ST24:1 decreased in patient samples, enabling non-invasive monitoring of tumor presence and progression. Similarly, in intrahepatic (iCCA), a high tumor ratio of unsaturated to saturated sulfatides correlates with reduced disease-free survival, suggesting utility in prognostic staging. Therapeutic targeting of sulfatide holds promise for inhibiting cancer in preclinical models. Inhibition of CST (GAL3ST1) reduces sulfatide production, suppressing epithelial-mesenchymal transition, migration, and invasion in cells, with knockdown models showing decreased tumor growth and metastatic potential. Upstream inhibition of the sulfatide pathway via UGT8 blockade with diminishes sulfatide levels, reducing αVβ5 activation, , and lung in basal-like xenografts. These findings indicate that CST or pathway inhibitors could serve as anti-metastatic agents by disrupting sulfatide-dependent oncogenic signaling.

Infectious Disease Associations

Sulfatide interacts with several viruses to facilitate host cell entry and replication. In human immunodeficiency virus type 1 (HIV-1) infection, the envelope glycoprotein gp120 binds directly to sulfatide on the surface of neural and peripheral cells, serving as an alternative receptor that promotes viral attachment and entry independent of CD4. This interaction contributes to HIV-1 for myelin-rich tissues, potentially exacerbating neuropathies associated with the virus. Similarly, for vaccinia virus, sulfatide acts as an alternate receptor that supports viral attachment, a critical step preceding envelope fusion with host membranes during entry. Sulfatide plays a key role in enhancing influenza virus replication through binding to the hemagglutinin (HA) glycoprotein. For influenza A virus, membrane-associated sulfatide is required for efficient viral replication by promoting the translocation of newly synthesized nucleoprotein from the nucleus to the cytoplasm, facilitating virion assembly. This HA-sulfatide interaction initiates replication without serving as the primary receptor. Recent studies on influenza B virus, including data from 2025, confirm that sulfatide binds HA and significantly boosts viral replication when overexpressed in host cells, paralleling its proviral effects in influenza A. In bacterial infections, sulfatide from enables pathogen evasion and invasion of host . Mycobacterial sulfatides inhibit macrophage priming and phagosome-lysosome fusion, allowing intracellular survival and proliferation within these immune cells. This mechanism underscores sulfatide's role in pathogenesis by suppressing host antimicrobial responses. Sulfatide also contributes to host defense against certain viruses, particularly through inhibitory effects on . Soluble or excessive sulfatide binds particles, preventing by competitively inhibiting viral attachment to receptors and suppressing sialidase activity essential for uncoating and release. In neural tissues, where sulfatide is abundant in , it can paradoxically aid viral persistence; for instance, HIV-1 reservoirs in the correlate with sulfatide release from damaged , sustaining low-level replication despite antiretroviral therapy.

Clinical and Research Significance

Association with Alzheimer's Disease

Sulfatide levels are significantly reduced in the brains and of individuals with (AD), serving as an early lipidomic signature that precedes the formation of . This deficiency has been observed in preclinical and stages, with lipidomic analyses showing dramatic losses in myelin-enriched sulfatides as a hallmark of early AD pathology. Recent studies from 2023 and 2024 confirm that these reductions occur independently of classical AD , highlighting sulfatide depletion as a potential initiator of disease progression. A bidirectional relationship exists between sulfatide and precursor protein (APP) processing, where the APP intracellular domain (AICD) inhibits expression of cerebroside sulfotransferase (CST), the enzyme responsible for sulfatide synthesis, thereby exacerbating sulfatide deficiency. This inhibition creates a feedback loop: reduced sulfatides promote amyloidogenic APP cleavage, increasing AICD production and further suppressing CST, which perpetuates pathology in both cellular and animal models. In models of sulfatide deficiency, such as CST conditional knockouts, ventricular enlargement and loss occur without , neurofibrillary tangles, or substantial neuronal death, as evidenced by histological and MRI assessments in 2023-2024 studies. These changes reflect disrupted , with up to 12-fold increases in ventricular volume observed by 20 months of age. Sulfatide loss contributes to through , driving dysfunction that destabilizes the myelin sheath and correlates with increased -associated pathology severity in spinal cords and models. This dysfunction promotes hyperphosphorylation, , and microglial activation, linking alterations to broader progression. Therapeutically, sulfatide supplementation in models reduces β- and γ-secretase activity, decreases amyloid-β production by up to 66%, and inhibits aggregation, thereby restoring cognitive functions impaired by deficiency. These findings suggest sulfatide as a promising target for interventions that could mitigate symptoms via lipid restoration.

Potential

Sulfatide, particularly the isoform 16:1-OH-sulfatide, serves as a key in for (MLD), a lysosomal storage disorder characterized by sulfatide accumulation due to arylsulfatase A deficiency. Analysis of 16:1-OH-sulfatide in dried blood spots (DBS) enables first-tier screening with improved precision, outperforming the earlier marker 16:0-sulfatide by reducing false positives while maintaining sensitivity for early detection. A 2024 study demonstrated that this approach lowers the first-tier referral rate to approximately 0.05%, facilitating timely intervention before neurological symptoms manifest. This method's integration into routine programs, such as the pilot in (first-tier rate 0.21%, reduced to 0.02% post-second-tier as of February 2025), underscores its potential for population-wide MLD identification. In neurodegenerative conditions like (AD), sulfatide levels in (CSF) and plasma offer diagnostic value for early detection, with reduced concentrations signaling preclinical stages. depletion, observed up to 40% lower in individuals with incipient AD compared to controls, correlates with loss and cognitive decline, positioning it as an indicator of dysmyelination. Ratios of sulfatide between and plasma further enhance specificity, distinguishing early neurodegeneration from normal aging in cohorts with . Though some studies indicate limited diagnostic utility due to unaltered levels in certain groups, shows promise across demyelinating disorders, while plasma assays require standardization for broader clinical adoption. Serum sulfatide measurements show promise as a prognostic marker in lupus nephritis (LN), an autoimmune renal complication. Levels are markedly decreased in LN patients versus healthy controls (6.90 ± 2.22 nmol/mL vs. 8.34 ± 1.68 nmol/mL, P = 0.007), with strong negative correlations to disease activity indices, including active glomerular lesions (6.38 ± 1.81 nmol/mL vs. 8.23 ± 2.55 nmol/mL, P = 0.006) and the National Institutes of Health Activity Index scores (r = -0.51, P < 0.001). A 2025 Frontiers in Immunology study involving 64 LN patients suggests its role in non-invasive monitoring of flares and therapeutic responses, complementing traditional assays like anti-dsDNA antibodies by reflecting sulfatide's involvement in immune-mediated renal damage. For oncological applications, urinary sulfatide profiling aids in monitoring (RCC), a urological , through detection of altered glycosphingolipid . Specific sulfatide , such as C16:0 and C24:1 isoforms, are elevated in of patients with RCC, potentially reflecting tumor metabolism. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantifies these via targeted extraction from , though challenges persist, including sulfatide instability during prolonged storage and specificity issues from isobaric interferences in complex matrices, necessitating internal standards and high-resolution variants for accurate isoform differentiation.

Relationship to Vitamin K

Sulfatide biosynthesis relies on sulfation catalyzed by sulfotransferase (CST), and this process intersects with -dependent regulation of sulfotransferases. Studies in models have demonstrated that stimulates sulfotransferase activity in the , thereby promoting sulfatide synthesis and turnover. Administration of to normal increases both sulfotransferase and arylsulfatase activities, enhancing the overall of sulfatides. This regulatory overlap highlights vitamin K's role in maintaining sulfatide levels through shared enzymatic pathways involved in sulfation. In , sulfatide contributes to by facilitating interactions with clotting factors, such as , on platelet surfaces, while enables the γ- of procoagulant factors II, VII, IX, and X, as well as proteins C and S. Although direct biochemical enhancement of carboxylation by sulfatide remains unexplored, their complementary functions in the cascade suggest a synergistic contribution to balanced hemostatic responses, particularly in vascular and neural tissues where sulfatides are abundant. Vitamin K deficiency or antagonism correlates with reduced sulfatide levels, mimicking pathological states. For instance, , a used in therapy, inhibits sulfotransferase activity and decreases brain sulfatide concentrations by up to 42% in mice after two weeks of treatment. This effect is reversible upon supplementation, which restores enzyme activity and boosts sulfatide synthesis by 33-52%. Such correlations indicate that disruptions in status can indirectly impair sulfatide-mediated processes, including those in . Recent research post-2023 continues to elucidate 's influence on sulfatide metabolism, with evidence suggesting its broader cofactor-like role in pathways beyond traditional recycling in the liver. In demyelination models, supplementation enhances sulfatide production during remyelination, supporting repair independently of effects. These findings underscore evolving insights into 's non-canonical functions in neural .

References

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  2. https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2022.1080161/full
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