Sulfatide

The structural formula of a sulfatide

Sulfatide,also known as3-O-sulfogalactosylceramide,SM4,orsulfated galactocerebroside,is a class ofsulfolipids,specifically a class of sulfoglycolipids, which areglycolipidsthat contain asulfategroup.Sulfatide is synthesized primarily starting in theendoplasmic reticulumand ending in theGolgi apparatuswhereceramideis converted togalactocerebrosideand later sulfated to make sulfatide. Of all of thegalactolipidsthat are found in themyelin sheath,one fifth of them are sulfatide. Sulfatide is primarily found on the extracellular leaflet of themyelinplasma membraneproduced by theoligodendrocytesin thecentral nervous systemand in theSchwann cellsin theperipheral nervous system.However, sulfatide is also present on the extracellular leaflet of the plasma membrane of many cells ineukaryoticorganisms.

Since sulfatide is a multifunctional molecule, it can be used in multiple biological areas. Aside from being a membrane component, sulfatide functions inprotein trafficking,cell aggregation and adhesion,neural plasticity,memory,and glial-axon interactions. Sulfatide also plays a role in several physiological processes and systems, including thenervous system,theimmune system,insulinsecretion,blood clotting,viral infection,andbacterial infection.As a result, sulfatide is associated with, able to bind to, and/or is present inkidneytissues,cancercells/ tissues, the surface ofred blood cellsandplatelets,CD1a-d cells in the immune system, manybacteriacells, severalviruses,myelin,neurons,andastrocytes.

An abnormalmetabolismor change in the expression of sulfatide has also been associated with various pathologies, including neuropathologies, such asmetachromatic leukodystrophy,Alzheimer's disease,andParkinson's disease.Sulfatide is also associated withdiabetes mellitus,cancermetastasis,and viruses, includingHIV-1,Influenza A virus,Hepatitis CandVaccinia virus.Additionally, overexpression of sulfatide has been linked toepilepsyand audiogenic seizures as well as otherpathological statesin thenervous system.

Past and ongoing research continues to elucidate the many biological functions of sulfatide and their many implications as well as thepathologythat has been associated with sulfatide. Most research utilizesmice models,butheterologous expressionsystems are utilized as well, including, but not limited to,Madin-Darby canine kidney cellsandCOS-7Cells.

History

Sulfatide was the first sulfoglycolipid to be isolated in the humanbrain.It was named sulfatide in 1884 byJohann Ludwig Wilhelm Thudichumwhen he published "A Treatist of the Chemical Constitution of the Brain".Originally, in 1933, it was first reported by Blix that sulfatide containedamideboundfatty acidand 4-sphingenine and that thesulfateof sulfatide was thought to be attached to the C6 position ofgalactose.This was again supported in 1955 by Thannhauser and Schmidt; however, throughgas-liquid chromatography,Tamio Yamakawafound thatsulfatewas actually attached to the C3 position ofgalactose,not the C6 position.Thus, in 1962, Yamakawa completed the correctedchemical structureof sulfatide.

Synthesis and degradation

Synthesis of sulfatide

Sulfatide synthesis begins with a reaction betweenUDP-galactoseand 2-hydroxylated or non-hydroxylatedceramide.This reaction is catalyzed bygalactosyltransferase(CGT), wheregalactoseis transferred to 2-hydroxylated, or non-hydroxylated ceramide, from UDP-galactose.This reaction occurs in the luminal leaflet of theendoplasmic reticulum,and its final product is GalCer, or galactocerebroside, which is then transported to theGolgi apparatus.Here, GalCer reacts with3’-phosphoadenosine-5’-phosphosulfate(PAPS) to make sulfatide. This reaction is catalyzed by cerebroside sulfotransferase (CST).CST is ahomodimericprotein that is found in theGolgi apparatus.It has been demonstrated thatmice modelslacking CST, CGT, or both are incapable of producing sulfatide indicating that CST and CGT are necessary components of sulfatide synthesis.

Sulfatide degradation occurs in thelysosomes.Here,arylsulfatase Ahydrolyzes thesulfategroup.However, in order for this reaction to be carried out, asphingolipid activator proteinsuch as saposin B must be present.Saposin B extracts sulfatide from the membrane, which makes it accessible to arylsulfatase A.Arylsulfatase A can thenhydrolyzethe sulfate group. Accumulation of sulfatide can causemetachromatic leukodystrophy,alysosomal storage diseaseand may be caused because of a defect in arylsulfatase A, leading to an inability to degrade sulfatide.

Biological functions of sulfatide

Sulfatide participates in many biological systems and functions, including thenervous system,theimmune system,and inhaemostasis/thrombosis.Sulfatide has also been shown to play a minor role in thekidneys.

Nervous system

Transmission electron micrographof a myelinated axon

Sulfatide is a major component in thenervous systemand is found in high levels in themyelin sheathin both theperipheral nervous systemand thecentral nervous system.Myelinis 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 theaxons;however, when lacking sulfatide the lateral loops and part of thenodes of Ranvierare disorganized, so the myelin sheath does not function properly.Thus, lacking sulfatide can lead to muscle weakness,tremors,andataxia.

Elevated levels of sulfatide are also associated withMetachromatic Leukodystrophy,which leads to the progressive loss of myelin as a result of sulfatide accumulation in theSchwann cells,oligodendrocytes,astrocytes,macrophagesandneurons.Elevated levels of sulfatide have also been linked toepilepsyand audiogenic seizures (seizures induced by sound), while elevated levels of anti-sulfatide antibodies in theserumhave been associated withmultiple sclerosisandParkinson's.

Differentiating myelin sheath

As stated above, sulfatide is predominantly found in theoligodendrocytesand theSchwann cellsin thenervous system.When oligodendrocytes aredifferentiating,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 isupregulated,i.e.there is an increase in sulfatide, prior to themyelin sheathbeing wrapped around theaxon,and experiments in cerebroside sulfotransferase (CST) deficient mice have shown that sulfatide operates as a negative regulator (inhibitor) ofoligodendrocytedifferentiation.Accordingly, further research has demonstrated that when sulfatide is deficient, there is a two to threefold increase inoligodendrocytedifferentiation,evidence providing support that sulfatide operates as a negative regulator or inhibitor of oligodendrocytedifferentiation.Myelinationalso appears to be stimulated by sulfatide in theSchwann Cells.Such stimulation is thought to occur through the following interactions. First, sulfatide binds totenascin-Rorlamininin theextracellular matrix,which goes on to bind signaling molecules such as F3 andintegrinsin theglialmembrane.This causes signaling throughc-src/fynkinase. Specifically, thelamininα6β1-integrinforms a complex withfynkinase andfocal adhesion kinasethat enables signaling, which, in turn, causesmyelinationto begin.Sulfatide binding tolamininalso causesc-src/fynkinase activation and initiation of basement membrane formation.

Sulfatide and myelin and lymphocyte protein

Sulfatide also associates withmyelin and lymphocyte protein(MAL). Research has shown thatMALmay be involved invesicular transportof sulfatide and othermyelinproteinsandlipidsto the myelinating membrane.MALis also believed to form membrane microdomains (small regions on the membrane with distinct structure and function) in whichlipids,such as sulfatide, are stabilized intolipid rafts,allowing stabilization of the glial-axon junctions.

Glial-axon junctions and signaling

Sulfatide has also been shown to play a role inmyelinmaintenance and glial-axon signaling, which was indicated by research in older cerebroside sulfotransferase (CST)-deficient mice.These mice hadvacuolardegeneration, uncompacted myelin, and moderatedemyelinationof thespinal cord.This occurs because improper glial-axon signaling and contact and disruption of paranodal glial-axon junctions causes improper placement and maintenance ofsodiumandpotassiumchannel clusters in theaxonsat thenodes of Ranvier.As a result, the maintenance ofNav1.6sodium clusters is impaired as there is a decrease in the number of clusters ofsodium channelsat thenodes of Ranvier.Additionally,Kv1.2channels are moved from the paranodal position to the juxtaparanodal position causing impairment of these channels; this is also associated with the loss ofneurofascin155 andCasprclusters, which are important components of the glial-axon junction.

Sulfatide is also important for glial-axon junctions in theperipheral nervous system.Inperipheral nervesthat are cerebroside sulfotransferase (CST) deficient, thenodes of Ranvierform enlarged axonal protrusions filled with enlargedvesicles,andneurofascin155 andCasprclusters are diminished or absent.In order to form a paranodal junction,Casprandcontactinform a complex withneurofascin155.It has been shown that sulfatide may be involved in the recruitment and formation ofneurofascin155 inlipid rafts;neurofascin 155 protein clusters then bringCasprandcontactininto the membrane to form the complex, which allows the formation of stable glial-axon junctions.Consequently, sulfatide plays an important role in maintaining the paranodal glial-axon junctions, which allows for proper glial-axon interaction and signaling.Sulfatide has also been shown to be an inhibitor of myelin-associated axon outgrowth, and small amounts of sulfatide have been found inastrocytesandneurons,which is also indicative of its importance in glial-axon junctions.

Abnormal sulfatide expression

Abnormal expression of sulfatide is linked to severalneurological disorders.As stated before, one of the major neurological disorders isMetachromatic Leukodystrophy,which is caused by elevated levels of sulfatide, leading to the progressive loss ofmyelinas a result of sulfatide accumulation.High levels of sulfatide in thegray matterin thecerebellumand in the superiorfrontal lobehave been associated withParkinson's disease.Additionally, accumulation of sulfatide in neurons causesaudiogenicseizures,which have been shown to be lethal inmouse models.On the other hand, reduced levels of sulfatide in thecerebralgray andwhite matterhave been associated withAlzheimer's disease.

Immune system

Different types of cells that presentantigenson their surfaces include:

• Macrophages
• Dendritic cells
• Hepatocytes
• B cells
• Tumour cells
• Thymocytes

CD1DProtein

Each of these different cell types are expressed incluster of differentiation 1 molecules(CD1).There are 5 subtypes ofCD1molecules that range from a through e. The a through d subtypes are capable of binding to sulfatide.CD1a,CD1b, and CD1c subtypes present lipid antigens toT cells,whileCD1dcells presentlipids,glycolipids,andlipoproteinstoNatural 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 withCD1dcells: Type 1 Natural killer T cells and Type 2 Natural killer T cells.Type 2 Natural killer T cells are able to recognize sulfatide/CD1dtetramers, 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 fromautoimmune diseaseand 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 thedendritic cellsfunction.

Sulfatide also acts as anL-selectinandP-selectinligand,but it does not act as an E- selectin ligand.Selectins are adhesion molecules that facilitate the capture of circulatingleukocytes.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 cancermetastasis.Additionally, whenL-selectinand sulfatide bind,upregulationof thechemokineco-receptor's (CXCR4) expression is observed, specifically on the surfaced ofleukocytes.

Sulfatide may also function as a receptor forchemokines,which are small chemostaticcytokines,and they provide directional signals forleukocytemovement.Chemokinesare implicated in:

• Angiogenesis
• HIV-1 infection
• Tumourmetastasis
• Haematopoiesis
• Graft rejection
• Embryonic development

Sulfatide is also capable of binding to scavenger proteins found onmacrophages.Such binding facilitates a macrophage's ability to take upapoptoticcells.

Autoimmunityalso affects sulfatide levels. When an enhancedantibodyresponse againstmyelinlipids occurs, including sulfatide in patients withmultiple sclerosis,thedemyelinationprocess is increased significantly.When sulfatide andgangliosidesare present, the proliferation or production ofNatural Killer-T cellsthat producecytokinesare activated. However, whenCD1ddeficient-mice are tested for their response to sulfatide, the same response is not seen, which indicates that in myelin, sulfatide is aglycolipidthat possessesimmunodominance.

Locally, the disruption of myelin due to the infiltration ofT cellsand macrophages, results in thephagocytosisof myelin bymicrogliaormacrophages,suggesting that the T cells are presented with myelin lipids byCD1molecules at sites of inflammation.

Hemostasis/thrombosis

Sulfatide has roles in both bloodcoagulationand anticoagulation. Sulfatide has anticoagulation activity when it binds tofibrinogen,which prevents fibrinogen from converting tofibrin.Sulfatide also has a direct inhibitory effect onthrombosis.On the other hand, sulfatide also helps to improve bloodcoagulationandthrombosis:first, sulfatide is believed to aid in thrombosis through its participation withcoagulation factor XII;second, sulfatide binding toannexin Vaccelerates coagulation; third, sulfatide andP-selectininteractions expressed on platelets, help to ensure stableplateletadhesion 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 incoagulationandthrombosis.Sulfatide is also present inserumlipoproteins,which are believed to be associated with the cause and development ofcardiovascular disease.

Kidney

Sulfatide can also be found in thekidney.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 aligandforL-selectin,which is a receptor that can be found in the kidneys. Specifically, L-selectin is alymphoidreceptor, and the binding between L-selectin and sulfatide in the kidney's interstitium plays a major role inmonocytepermeation and infiltration into the kidney.Additionally, sulfatide is also found in the glandular stomachepitheliumand in the apical membranes of the distal kidney tubuli whereMyelin and lymphocyte protein(MAL) is expressed.MALforms complexes with sulfatide and otherglycosphingolipids,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. This includesdiabetes mellitus,cancerand tumors,metachromatic leukodystrophy,variousbacterial infections,andviruses,includingHIV-1,Hepatitis C,Influenza A virus,andVaccinia virus.

Metachromatic leukodystrophy

arylsulfatase A

Metachromatic leukodystrophy,also known as MLD, is arecessivelysosomal storage disorder.It is believed to be caused by a deficiency inarylsulfatase A.Arylsulfatase A is alysosomalsulfatasethat 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 thecentral nervous systemas well as in theperipheral nervous system.When lacking the lysosomal enzyme ormutationsin the gene coding for saposin B occur, this can lead to the accumulation oflysosomal sulfatide,which then develops intometachromatic leukodystrophy.

Sulfatide plays an important role in themyelin.Myelinacts as an insulating sheath that surrounds manynerve fibersand increases the speed at which impulses are conducted. When sulfatide is not distributed properly, it can affect the normal physiological conduction of electrical impulses betweennerve cells.This then results indemyelinationbecause of the buildup of sulfatide and is the main cause ofMetachromatic Leukodystrophy.

However, how sulfatide buildup causes demyelination and neural degeneration is still mostly unknown.Metachromatic Leukodystrophyresults 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, includinggene therapy,cell-based therapies usingoligodendrocyteprogenitors cells,enzyme replacement therapy,oradeno-associated viralandlentiviralmediated gene therapy may prove to be effective in reducing the effects ofMetachromatic Leukodystrophy.

Diabetes mellitus

Sulfatide has several isoforms, including C16:0, which is found primarily in thesecretory granulesand toward the surface of the membrane ofβ cells.Secretory granulesandβ cellsare found in theislet of Langerhansand in rat β TC3 cells.Research has shown that in thepancreasesofType II diabeticmouse models,there is a deficiency of C16:0. Additional research has shown that C16:0 plays an important role in assisting to improveinsulincrystal preservation, and as theβ cellsin the pancreas secrete insulin, sulfatide aids in the monomerization of insulin, which is the breakdown of insulin into its basics components ormonomers.Consequently, sulfatide is needed in order to maintain normalinsulinsecretion, which sulfatide is capable of mediating through stimulation ofcalciumdependentexocytosisandadenosine triphosphate (ATP)-sensitivepotassium ion channels.Sulfatide can also stimulateproinsulinfolding as well, as it can serve as amolecular chaperonefor insulin.

In the diagnosis ofType I diabetes,elevated anti-sulfatide antibodies inserumarise. Such anti-sulfatide antibodies prevent insulinsecretionandexocytosis.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.Sulfatide is also commonly known to possessanti-inflammatoryproperties. As a result of these anti-inflammatory properties, which aid in the blockage ofL-selectin,sulfatide has been shown to prevent type I diabetes and inhibitinsulitisin non-obese diabetic mice.Sulfatide also preventsapoptosisin insulin secreting cells by preventing the effects ofinterleukin-1 beta(lL-1β),interferon beta 1b(lFN-1β), andtumor necrosis factor Alpha(TNF-α) that promoteapoptosis.

Sulfatide may also be involved in not justtype I diabetes,but alsotype II diabetes.Specifically, sulfatide is capable of inhibitingTNF-αsecretion. When there are lowserumlevels of sulfatide, as well as elevated production ofTNF-αin patients that have type II diabetes, it is commonly associated withinsulin 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 numerouscancertissues and cells.These include:

Primary Lungadenocarcinoma

• Primarycolorectal cancertissues
• Primarylung adenocarcinomatissues
• Malignant and benignovarian cancertissues
• Renal carcinomatissues
• Serous papillary ovarian carcinoma tissues
• Gastric cancertissues
• Renal carcinoma (SMKT-R3 cell line)

Sulfatide levels in these cancer lines and tissues may vary. For example, the levels of sulfatide are much lower in undifferentiated small cellcarcinomatissues and primary lungsquamous cell carcinomatissues in humans than in primary lungadenocarcinomatissue in humans.In humanovarian cancers,sulfatide levels are much higher inmalignantovarian cancers than inbenignovarian cancers.Other cancers such asWilms' tumorshow 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 justartifactsof cultured cancer cell lines.

P-selectin

However, experimentation usingrenal cancercell 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 asignaling pathwaywhich involves:

• Hepatocyte growth factor
• Epidermal growth factor
• Tyrosine kinases
• TNF-α
• Protein kinase C
• Ras

This path results in the accumulation of sulfatide inrenal cancercell lines.Additionally, sulfatide can accumulate on the surface of cancer cells. This indicates that sulfatide may serve as a specificligandforP-selectin.This would contribute to increasedmetastasisof the cancer.However, more research is needed to elucidate the relationship between the elevated levels of sulfatide expression and the initiation and metastasis mechanisms of cancer,but sulfatide may be a usefulserumbiomarkerfor early tumor detection.

Viral infection

Experimentation with sulfatide has shown that it has involvement in several viral infections, includingHIV-1,Influenza A virus,Hepatitis C,and theVaccinia virus.

HIV-1

V3 loopfragment of theHIV-1envelopegp120complex

Sulfatide shows involvement inHIV-1infection.gp120-gp41are specific types of envelopeglycoproteincomplexes that are found on HIV-1.These glycoprotein complexes can interact withCD4,a viral receptor molecule, which induces a change in the conformation of gp120. This change in conformation allows the gp120 complex to interact with thechemokineco-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 cell.Gp120 can also bind toglycolipidslike sulfatide and galactocerebroside (GalCer). Sulfatide binds strongly to theV3 loopof 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-1 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 strongestbinding affinityfor recombinant gp120 of all the glycolipids tested.Therefore, this suggests that when sulfatide is attached to HIV-1, it cannot interact with thechemokineco-receptor 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 preventHIV-1infection 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 thecentral nervous system.These patients have elevated levels of sulfatide in thecerebrospinal fluid(CSF) and anti-sulfatide antibodies in theserum.Elevated levels of anti-sulfatide antibodies can causedemyelination.This is caused by the binding of the anti-sulfatide antibodies to the surface of themyelin sheathand/or the surface ofSchwann Cells,which then activates a complete cascade of demyelination.Also, advanced stageAIDSpatients can developGuillain–Barré syndrome(GBS). Guillain–Barré syndrome is classified as an acuteautoimmunepolyneuropathy,which specifically affects theperipheral nervous systemof the infected patient.Experimentation has shown that anti-sulfatide autoimmune antibodies may contribute to the development of Guillain–Barré syndrome inAIDSpatients as well as the development ofperipheral nervous systeminjury in HIV-1 infected patients.

Hepatitis C

Several patients withHepatitis Cvirus (HCV) associated with mixedcryoglobulinemia(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 mediatedvasculitisof 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,sphingolipidsynthesis in the host, has been demonstrated to be necessary for HCVreplication,which indicates that sulfatide may be involved in thereplicationof HCV.

Influenza A

Influenza A virus(IAV) binds strongly to sulfatide.However, sulfatide receptors have nosialic 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, research have expressed sulfatide in Madin-Darby canine kidney cells, which can express sulfatide and support IAVreplicationand inCOS-7cells, which do not have the ability to express sulfatide and do not support IAV replication sufficiently. Consequently, the COS-7 cells weretransfectedwith 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.

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.The opposite is shown in sulfatideknockdownMadin-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.

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

Vaccinia virus

Vaccinia virusis closely related tovariola virus,which is known to cause thesmallpoxdisease. Thevaccinia virushas been shown to be able to bind to sulfatide through the L5 and A27 membrane proteins on the virus.It has been demonstrated inmouse modelsthat sulfatide prevents the attachment of vaccinia virus to the cell's surface, while also preventing death inmouse modelsthat are typically lethal. This suggests that sulfatide may be one receptor for the vaccinia virus.

Bacterial infection

Sulfatide binds to many bacteria, including:

• EnterotoxigenicEscherichia coliTOP10 strain
• Campylobacter jejuni
• Mycoplasma hyopneumoniae
• Haemophilus influenzae
• Actinobacillus pleuropneumoniae
• Helicobacter pylori
• Moraxella catarrhalis
• Bordetella pertussis
• 987P-fimbriated enterotoxigenicEscherichia coli
• Lactobacillus reuteri(JCM1081 and TM105 strains)
• Mycoplasma hominis
• Mycoplasma pneumoniae
• Pseudomonas aeruginosa
• Haemophilus ducreyi

Sulfatide acts as aglycolipidreceptor that functions to aid in the adherence of thesebacteriato themucosalsurface.Mycoplasma hyopneumoniaeandActinobacillus pleuropneumoniaearepathogensthat causerespiratory diseaseinswine.Haemophilus influenzae,Bordetella pertussis,Mycoplasma pneumoniae,Moraxella catarrhalis,andPseudomonas aeruginosacause respiratory disease in humans. Accordingly, sulfatide is located in thetracheasof both human and swine, and through the use of sulfatide present in the trachea, these several bacteria are capable of adherence to therespiratory tract.Hsp-70on the outside ofH. influenzae,has also been shown to aid in the ability of this bacteria to bind to sulfatide.

Helicobacter pylori,enterotoxigenicE. coliTOP10 strain, 987P-fimbriated enterotoxigenicE. coli(a strain ofE. coli), andLactobacillus reuteriare different strains of bacteria that are found to adhere to thegastrointestinal 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 anenterotoxintype B that is heat stable; additionally, it is secreted by the enterotoxigenicE. 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'sjejunum.Additional experimentation suggests that sulfatide is a functional STb receptor.

Sulfatide may also play a role inMycobacterium tuberculosis,which is the agent that causestuberculosisin humans. Experimentation suggests that sulfatide may be involved inMycobacterium tuberculosisinfection, and it may be an element of the cell wall of the bacteriumMycobacterium tuberculosis.

Clinical significance

Role in Alzheimer's disease

Main article:Alzheimer's disease

InAlzheimer's disease,sulfatide in the brain tissue decreases tremendously, starting in the early stages of the disease.In the mild stages of Alzheimer's disease, the loss of sulfatide can be up to 50% in thewhite matterand up to 90% in thegray matterin the brain.Sulfatide concentration in thecerebral spinal fluidis also lower in subjects with Alzheimer's disease.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.When comparing sulfatide depletion to otherneurodegenerative diseases,Alzheimer's disease is the only case in which sulfatide is so dramatically depleted; indementiano marked sulfatide depletion is observed, while inParkinson's disease,sulfatide levels are dramatically elevated, andmultiple sclerosispatients only have a moderate sulfatide depletion.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.

apolipoprotein E

Sulfatides in brain tissue has been studied by looking atapolipoprotein 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. Possessing theapoEε4 allele has been associated with a higher risk of developing Alzheimer's disease.ApoE is a protein that is involved in the transport of manylipids,includingcholesterol,and thus, regulates how much sulfatide is in thecentral nervous systemand mediates thehomeostasisof the system.It has been found that higher levels of apoE are positively correlated with greater sulfatide depletion.ApoE-associated proteins take sulfatide from themyelin sheathand then degrade sulfatide into various compounds, such assulfate.When apoE is increased, the amount of sulfatide that is taken from the myelin sheath is also increased; hence, there is more sulfatide depletion.

Sulfatide is also involved in the clearance ofamyloid-βpeptide. 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.Amyloid-β peptide clearance is important so that this accumulation does not occur.Sulfatide facilitates amyloid-β peptide removal through anendocytoticpathway, 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 Khas 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.Vitamin K in thenervous systemis responsible for the activation ofenzymesthat are essential for thebiosynthesisof brainphospholipids,such as sulfatide.Whenwarfarin,a vitamin Kantagonist,is added to an animal model system, sulfatide synthesis is impaired.However, when vitamin K is added back into the system, sulfatide synthesis proceeds normally, suggesting that Vitamin K is necessary for sulfatide synthesis.

External links

• Sulfatidesat the U.S. National Library of MedicineMedical Subject Headings(MeSH)