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. 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.
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.
History
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". 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. 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. Thus, in 1962, Yamakawa completed the corrected chemical structure of sulfatide.Synthesis and degradation
Sulfatide synthesis begins with a reaction between UDP-galactose and 2-hydroxylated or non-hydroxylated ceramide. This reaction is catalyzed by galactosyltransferase, where galactose is transferred to 2-hydroxylated, or non-hydroxylated ceramide, from UDP-galactose. This reaction occurs in the luminal leaflet of the endoplasmic reticulum, and its final product is GalCer, or galactocerebroside, which is then transported to the Golgi apparatus. Here, GalCer reacts with 3’-phosphoadenosine-5’-phosphosulfate to make sulfatide. This reaction is catalyzed by cerebroside sulfotransferase. CST is a homodimeric protein that is found in the Golgi apparatus. It has been demonstrated that mice models lacking CST, CGT, or both are incapable of producing sulfatide indicating that CST and CGT are necessary components of sulfatide synthesis.Sulfatide degradation occurs in the lysosomes. Here, arylsulfatase A hydrolyzes the sulfate group. However, in order for this reaction to be carried out, a sphingolipid activator protein such as saposin B must be present. Saposin B extracts sulfatide from the membrane, which makes it accessible to arylsulfatase A. 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.
Biological functions of sulfatide
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
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%. 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. Thus, lacking sulfatide can lead to muscle weakness, tremors, and ataxia.Elevated levels of sulfatide are also associated with Metachromatic Leukodystrophy, which leads to the progressive loss of myelin as a result of sulfatide accumulation in the Schwann cells, oligodendrocytes, astrocytes, macrophages and neurons. Elevated levels of sulfatide have also been linked to epilepsy and audiogenic seizures, while elevated levels of anti-sulfatide antibodies in the serum have been associated with multiple sclerosis and Parkinson's.
Differentiating myelin sheath
As stated above, sulfatide is predominantly found in the oligodendrocytes and the Schwann cells in the nervous system. When oligodendrocytes are differentiating, sulfatide is first evident in immature oligodendrocytes. However, research suggests that sulfatide has a greater role than simply being a structural component of the membrane. This is because sulfatide is upregulated, i.e.there is an increase in sulfatide, prior to the myelin sheath being wrapped around the axon, and experiments in cerebroside sulfotransferase deficient mice have shown that sulfatide operates as a negative regulator of oligodendrocyte differentiation. 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. 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. 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. Sulfatide binding to laminin also causes c-src/fyn kinase activation and initiation of basement membrane formation.Sulfatide and myelin and lymphocyte protein
Sulfatide also associates with myelin and lymphocyte protein. Research has shown that MAL may be involved in vesicular transport of sulfatide and other myelin proteins and lipids to the myelinating membrane. MAL is also believed to form membrane microdomains in which lipids, such as sulfatide, are stabilized into lipid rafts, allowing stabilization of the glial-axon junctions.Glial-axon junctions and signaling
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 -deficient mice. These mice had vacuolar degeneration, uncompacted myelin, and moderate demyelination of the spinal cord. 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. 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. 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.Sulfatide is also important for glial-axon junctions in the peripheral nervous system. In peripheral nerves that are cerebroside sulfotransferase deficient, the nodes of Ranvier form enlarged axonal protrusions filled with enlarged vesicles, and neurofascin 155 and Caspr clusters are diminished or absent. In order to form a paranodal junction, Caspr and contactin form a complex with neurofascin 155. It has been shown that sulfatide may be involved 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. 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 in astrocytes and neurons, which is also indicative of its importance in glial-axon junctions.