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Diverse molecular species of sulfatide with differences in FA lengths, unsaturation degrees, and hydroxylation statuses are expressed in the kidneys. However, the physiological functions of specific sulfatide species in the kidneys are unclear. Here, we evaluated the distribution of specific sulfatide species in the kidneys and their physiological functions. Electron microscopic analysis of kidneys of Cst-deficient mice lacking sulfatide showed vacuolar accumulation in the cytoplasm of intercalated cells in the collecting duct, whereas the proximal and distal tubules were unchanged. Immunohistochemical analysis revealed that vacuolar H+-ATPase-positive vesicles were accumulated in intercalated cells in sulfatide-deficient kidneys. Seventeen sulfatide species were detected in the murine kidney by iMScope MALDI-MS analysis. The distribution of the specific sulfatide species was classified into four patterns. Although most sulfatide species were highly expressed in the outer medullary layer, two unique sulfatide species of m/z 896.6 (predicted ceramide structure: t18:0-C22:0h) and m/z 924.6 (predicted ceramide structure: t18:0-C24:0h) were dispersed along the collecting duct, implying expression in intercalated cells. In addition, the intercalated cell-enriched fraction was purified by fluorescence-activated cell sorting using the anti-vacuolar H+-ATPase subunit 6V0A4, which predominantly contained sulfatide species (m/z 896.6 and 924.6). The Degs2 and Fa2h genes, which are responsible for ceramide hydroxylation, were expressed in the purified intercalated cells. These results suggested that sulfatide molecular species with ceramide composed of phytosphingosine (t18:0) and 2-hydroxy FAs, which were characteristically expressed in intercalated cells, were involved in the excretion of NH3 and protons into the urine.

This review is an effort towards the development of substrate reduction therapy using cerebroside sulfotransferase (CST) as a target protein for the development of inhibitors intended to treat pathophysiological condition resulting from the accumulation of sulfatide, a product from the catalytic action of CST. Accumulation of sulfatides leads to progressive impairment and destruction of the myelin structure, disruption of normal physiological transmission of electrical impulse between nerve cells, axonal loss in the central and peripheral nervous system and cumulatively gives a clinical manifestation of metachromatic leukodystrophy. Thus, there is a need to develop specific and potent CST inhibitors to positively control sulfatide accumulation. Structural similarity and computational studies revealed that LYS85, SER172 and HIS141 are key catalytic residues that determine the catalytic action of CST through the transfer of sulfuryl group from the donor PAPS to the acceptor galactosylceramide. Computational studies revealed catalytic site of CST consists two binding site pocket including PAPS binding pocket and substrate binding pocket. Specific substrate site residues in CST can be targeted to develop specific CST inhibitors. This review also explores the challenges of CST-directed substrate reduction therapy as well as the opportunities available in natural products for inhibitor development., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests associated with the manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Iron chelators, such as deferoxamine, exert an anticancer effect by altering the activity of biomolecules critical for regulation of the cell cycle, cell metabolism, and apoptotic processes. Thus, iron chelators are sometimes used in combination with radio- and/or chemotherapy in the treatment of cancer. The possibility that deferoxamine could induce a program of senescence similar to radio- and/or chemotherapy, fostering adaptation in the treatment of cancer cells, is not fully understood. Using established biochemical techniques, biomarkers linked to lipid composition, and coherent anti-Stokes Raman scattering microscopy, we demonstrated that hepatocellular carcinoma-derived HepG2 cells survive after deferoxamine treatment, acquiring phenotypic traits and representative hallmarks of senescent cells. The results support the view that deferoxamine acts in HepG2 cells to produce oxidative stress-induced senescence by triggering sequential mitochondrial and lysosomal dysfunction accompanied by autophagy blockade. We also focused on the lipidome of senescent cells after deferoxamine treatment. Using mass spectrometry, we found that the deferoxamine-induced senescent cells presented marked remodeling of the phosphoinositol, sulfatide, and cardiolipin profiles, which all play a central role in cell signaling cascades, intracellular membrane trafficking, and mitochondria functions. Detection of alterations in glycosphingolipid sulfate species suggested modifications in ceramide generation, and turnover is frequently described in cancer cell survival and resistance to chemotherapy. Blockade of ceramide generation may explain autophagic default, resistance to apoptosis, and the onset of senescence., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Myelin in the mammalian nervous system has a high concentration of galactolipids [galactosylceramide (GalCer) and sulfatide] with 2-hydroxy fatty acids. We recently reported that fatty acid 2-hydroxylase (FA2H), encoded by the FA2H gene, is the major fatty acid 2-hydroxylase in the mouse brain. In this report, we show that FA2H also plays a major role in the formation of 2-hydroxy galactolipids in the peripheral nervous system. FA2H mRNA and FA2H activity in the neonatal rat sciatic nerve increased rapidly during developmental myelination. The contents of 2-hydroxy fatty acids were ∼5% of total galactolipid fatty acids at 4 days of age and increased to 60% in GalCer and to 35% in sulfatides at 60 days of age. The chain length of galactolipid fatty acids also increased significantly during myelination. FA2H expression in cultured rat Schwann cells was highly increased in response to dibutyryl cyclic AMP, which stimulates Schwann cell differentiation and upregulates myelin genes, such as UDP-galactose:ceramide galactosyltransferase and protein zero. These observations indicate that FA2H is a myelination-associated gene. FA2H-directed RNA interference (RNAi) by short-hairpin RNA expression resulted in a reduction of cellular 2-hydroxy fatty acids and 2-hydroxy GalCer in D6P2T Schwannoma cells, providing direct evidence that FA2H-dependent fatty acid 2-hydroxylation is required for the formation of 2-hydroxy galactolipids in peripheral nerve myelin. Interestingly, FA2H-directed RNAi enhanced the migration of D6P2T cells, suggesting that, in addition to their structural role in myelin, 2-hydroxy lipids may greatly influence the migratory properties of Schwann cells.

A variety of procedures have been developed for determining the sulfate ester content of various biomolecules. Ion chromatography (IC), that is, quantitation of ionic substances by ion conductimetry after separation by anion-exchange chromatography, has been increasingly utilized for the determination of inorganic sulfate in clinical and environmental samples. We adopted suppressed-mode IC to the determination of lipid- or glycolipid-bound sulfate released by acid hydrolysis and found that it has the advantage of increased precision for wide concentration ranges (30 pmol to ~μmol) and lack of interference from other lipids. To minimize deterioration of the separation column, the lipophilic constituents in the acid hydrolysate were removed by a two-phase partition system of chloroform-methanol-water. The inorganic sulfate was quantitatively extracted into the aqueous phase by replacing water with an alkaline buffer.By this method, the concentration of sulfolipids was determined in the kidney of mammals with various body mass. Sulfolipids were more concentrated in the kidney of smaller animals, which have higher maximum urine concentrating activity per gram of body mass, supporting the hypothesis of the function of sulfolipids as an ion barrier on the luminal surface of renal tubules.

Glycosphingolipids (GSLs), present in cell membranes, participate in a variety of biological functions. Although their exact role(s) may not be understood, it has been shown that 1) embryos lacking glucosylceramide synthase activity do not develop normally, 2) GSLs can affect neuritogenesis, and 3) they can function as receptors for some pathogens. To study the role of the saccharide portion of a GSL in any of these functions, it is necessary to either isolate it from the intact GSL or synthesize it. Because syntheses are more complex, modifications were made to the oxidation/elimination procedure previously described for the isolation of the saccharide portion of GM1 and GD1a to enable it to be used with GSLs of varying polarity. The key is to use a mixture of GSLs that differ in polarity. This appears to eliminate problems encountered when purified GSLs such as sulfatide or GT1b are used. —Yowler, B. C., S. A. Stoehr, and C-L. Schengrund. Oxidation and base-catalyzed elimination of the saccharide portion of GSLs having very different polarities. J. Lipid Res. 2001. 42: 659–662.

Diverse molecular species of sulfatide with differences in FA lengths, unsaturation degrees, and hydroxylation statuses are expressed in the kidneys. However, the physiological functions of specific sulfatide species in the kidneys are unclear. Here, we evaluated the distribution of specific sulfatide species in the kidneys and their physiological functions. Electron microscopic analysis of kidneys of Cst-deficient mice lacking sulfatide showed vacuolar accumulation in the cytoplasm of intercalated cells in the collecting duct, whereas the proximal and distal tubules were unchanged. Immunohistochemical analysis revealed that vacuolar H + -ATPase-positive vesicles were accumulated in intercalated cells in sulfatide-deficient kidneys. Seventeen sulfatide species were detected in the murine kidney by iMScope MALDI-MS analysis. The distribution of the specific sulfatide species was classified into four patterns. Although most sulfatide species were highly expressed in the outer medullary layer, two unique sulfatide species of m/z 896.6 (predicted ceramide structure: t18:0-C22:0h) and m/z 924.6 (predicted ceramide structure: t18:0-C24:0h) were dispersed along the collecting duct, implying expression in intercalated cells. In addition, the intercalated cell-enriched fraction was purified by fluorescence-activated cell sorting using the anti-vacuolar H + -ATPase subunit 6V0A4, which predominantly contained sulfatide species (m/z 896.6 and 924.6). The Degs2 and Fa2h genes, which are responsible for ceramide hydroxylation, were expressed in the purified intercalated cells. These results suggested that sulfatide molecular species with ceramide composed of phytosphingosine (t18:0) and 2-hydroxy FAs, which were characteristically expressed in intercalated cells, were involved in the excretion of NH 3 and protons into the urine., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Factor XII (FXII) is a plasma serine protease that initiates the intrinsic pathway of blood coagulation upon contact with anionic substances, such as the sulfated glycolipid sulfatide. Annexins (ANXs) have been implicated in the regulation of the blood coagulation reaction by binding to anionic surfaces composed of phospholipids and sulfated glycoconjugates, but their physiological importance is only partially understood., Objective: To test the hypothesis that ANXs are involved in suppressing the intrinsic pathway initiated by sulfatide, we examined the effect of eight recombinant ANX proteins on the intrinsic coagulation reaction and their sulfatide binding activities., Methods: Recombinant ANXs were prepared in Escherichia coli expression systems and their anticoagulant effects on the intrinsic pathway initiated by sulfatide were examined using plasma clotting assay and chromogenic assay. ANXA4 active sites were identified by alanine scanning and fold deletion in the core domain., Results and Conclusions: We found that ANXA3, ANXA4, and ANXA5 strongly inhibited sulfatide-induced plasma coagulation. Wild-type and mutated ANXA4 were used to clarify the molecular mechanism involved in inhibition. ANXA4 inhibited sulfatide-induced auto-activation of FXII to FXIIa and the conversion of its natural substrate FXI to FXIa but showed no effect on the protease activity of FXIIa or FXIa. Alanine scanning showed that substitution of the Ca 2+ -binding amino acid residue in the fourth fold of the core domain of ANXA4 reduced anticoagulant activity, and deletion of the entire fourth fold of the core domain resulted in complete loss of anticoagulant activity., (© 2020 International Society on Thrombosis and Haemostasis.)

Sulfatide is associated with numerous health problems, affecting different parts of the human body, including the metastasis; however, the underlying mechanisms are yet to be fully elucidated. Sulfatide has been used to potential inhibitor for tumor cell metastasis. In the present study we synthesized oleic acid sulfated chitosan (OlcShCs). It shows structural similarity to sulfatide because of its functional groups (sulfate and fatty acyl chains). Chitosan has smart properties such as biocompatibility, biodegradability and non-toxicity. We have prepared oleic acid sulfated chitosan (OlcShCs) by chitosan modification to mimic sulfatide. Its structure was characterized by FT-IR, H-NMR, and thermogravimetric analysis. After characterization studies its antimicrobial, antifungal and cytotoxic properties were investigated. Oleic acid sulfated chitosan (OlcShCs) was tested for its anti-cancer potential against human cancer cell lines (HeLa (ATCC® CCL-2™)) for 24 h, 48 h and 72 h using the MTT assays. This new material which is soluble at physiological conditions, is a potential candidate for further metastasis inhibition investigations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Besides cerebrcside and sulfatide four other glycolipids were isolated from rabbit sciatic nerve and analyzed by chemical and chromatographic methods. Three of the glycolipids were shown to be fatty acid esters of cerebroside; the fourth was characterized as diacyl glycerol galactoside and its alkyl ether analog. In the ester linkage mainly unsubstituted acids with chain length C16 to C18 were present. Both hydroxy and unsubstituted acids were found in amide linkage. They varied in chain length from C16 to C24 and were typical of cerebrosides. The long-chain base fraction contained sphingosine and dihydrosphingosine as the main components.

Chronic triethyl tin intoxication was induced in young adult rats by oral feeding of triethyl tin sulfate. Progressively severe brain edema developed during the 3-month experimental period. The yield of myelin from the brains of the experimental animals decreased to almost half normal per brain, but the isolated myelin appeared morphologically normal. The analysis of whole brain showed corresponding decreases in proteolipid protein and total lipid, particularly galactolipids. The proportions of the major constituents of isolated myelin (chloroform–methanol-insoluble residue, proteolipid protein, and total lipid) were unchanged despite the low yield. However, the proportion of cholesterol increased from 16 to 21% dry weight, and that of total galactolipid decreased from 21 to 1570, as the yield of myelin decreased. This decrease of total galactolipid was mainly due to the decrease in cerebroside. Total phospholipid remained constant initially but showed a slight decrease toward the end of the experiment, due mostly to decreased ethanolamine phospholipid. There was no preferential loss or preservation of phosphatidalethanolamine. The fatty acid composition of sulfatide showed statistically significant shifts to less long-chain fatty acids and less monoenoic acids, but cerebroside and sphingomyelin did not show significant changes in the fatty acid composition. There was no increase in esterified cholesterol. These findings generally support our hypothesis of nonspecific chemical abnormalities of the myelin sheath undergoing secondary degeneration.In an acute experiment, a single intraperitoneal injection of triethyl tin sulfate produced acute and transient brain edema. There were slight decreases in the yield of myelin, but no detectable changes in the chemical composition.

Long-chain bases were prepared from human aorta sphingomyelin by a combined enzymatic hydrolysis-alkaline hydrolysis procedure and these bases were isolated by thin-layer chromatography. Aldehydes, obtained from the long-chain bases by periodate oxidation, were converted to 1,3-dioxolane derivatives. Dioxolanes were identified and quantified by gas-liquid chromatography before and after catalytic hydrogenation, and before and after separation into saturated, monoene, and diene dioxolane fractions. The monoene dioxolanes were converted to aldehydes by reductive ozonolysis with dimethyl sulfide and these aldehydes were isolated and identified as dioxolane derivatives. The double bond positions in the major diene component were established by reductive ozonolysis and permanganate-periodate oxidation. Sphingenines in the cerebroside-sulfatide and sulfatide fractions of aorta were converted to aldehydes by the reductive ozonolysis of intact sphingolipids and these aldehydes were analyzed as the dioxolanes.Human aorta sphingomyelin contained significant amounts of 4-hexadecasphingenine, 4-heptadecasphingenine, sphinganine, 4-sphingenine, and 4,x14-sphingadienine. Small amounts of hexadecasphinganine, 4-tetradecasphingenine, a sphingadienine isomer, an unknown sphinganine, and two unknown diene long-chain bases were also found in sphingomyelin. The presence of a branched-chain 4-sphingenine was tentatively established and the possible presence of a sphingenine isomer was suggested. The major sphingenines were the same in the sphingomyelin, sulfatide, and cerebroside-sulfatide fractions of human aorta.

A rapid, sensitive spectrophotometric method for the analysis of sulfatides is described. The assay method is based upon the formation of a colored complex between the cationic dye azure A and (anionic) sulfolipids; the complex is extractable by a solution of chloroform-methanol 1:1. With the exception of some of the phospholipids, the reaction is specific for the sulfolipids. Cardiolipin was the most reactive of the nonsulfolipid compounds that were tested. Except for sphingosine and the mono- and dihexose derivatives of sphingosine, a wide variety of lipids did not interfere with the formation of color by standard sulfatides. Sulfur-containing amino acids, sugar sulfates, and sulfated polymers neither produced color nor interfered in its formation by sulfatide. Chloride and nitrate ions produced relatively little color.The method is much more sensitive (lower limit, about 0.002 μmole) than most methods currently employed for the analysis of sulfatides and has a high degree of precision. It is applicable to the analysis of sulfolipids in tissue extracts and gives values similar to those obtained by previously published procedures. The reliability of the method is increased when it is applied to partially purified lipid solutions. Sulfatides added to extracts of rabbit brain tissue were quantitatively accounted for by the assay. In addition, the method can be applied to samples obtained directly from thin-layer plates.

Epsilon toxin (Etx) from Clostridium perfringens is synthesized as a very low-active prototoxin form (proEtx) that becomes active upon proteolytic activation and has the capacity to cross the blood-brain barrier (BBB), thereby producing severe neurological effects. The identity and requirements of host receptors of Etx remain a matter of controversy. In the present study, we analysed the binding of proEtx or Etx to liposomes containing distearoylphosphatidylcholine (DSPC), cholesterol and sulfatide, or alternatively to detergent-solubilized lipids, using surface plasmon resonance (SPR). We also tested the influence of calcium on Etx or proEtx binding. Our findings show that the presence of sulfatide in liposomes increases both Etx and proEtx binding, and Etx binding is enhanced by calcium. These results were corroborated when SPR was conducted with immobilized toxin, since detergent-solubilized sulfatide increases its binding to Etx in the presence of calcium, but not to proEtx. Moreover, binding affinity is also affected, since the treatment of liposomes with sulfatase causes the dissociation rate constants (K D ) in both proEtx and Etx to increase, especially in the case of proEtx in the presence of calcium. In addition, protein-lipid overlay assays corroborated the calcium-induced enhancement of Etx binding to sulfatide, and to lipids extracted from sulfatide-enriched rat brain lipid rafts. In conclusion, the present work highlights the role of sulfatide as an important element in the pathophysiology of Etx and reveals the influence of calcium in the interaction of Etx, but not of proEtx, with the target membrane., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) analysis and imaging of lipids, comprehensive ionization of lipids simultaneously by a universal matrix is a very challenging problem. Ion suppression of readily ionizable lipids to others is common. To overcome this obstacle and enhance the coverage of MALDI MS analysis and imaging of lipids, we developed a novel strategy employing a mixture of matrices, each of which is capable of selective ionization of different lipid classes. Given that MALDI MS with either 9-aminoacridine (9-AA) or N-(1-naphthyl) ethylenediamine dihydrochloride (NEDC) yields weak in-source decay which is critical for analysis of complex biological samples and possesses orthogonal selectivity for ionization of lipid classes, we tested the mixtures of NEDC and 9-AA with different ratios for analysis of standard lipids and mouse brain lipid extracts. We determined 1.35 of NEDC/9-AA as an optimized molar ratio. It was demonstrated that an enhanced coverage with the optimized mixture was obtained, which enabled us to analyze and map all the major classes of phospholipids and sulfatide from either lipid extracts or tissue slides, respectively. We believe that this powerful novel strategy can enhance lipidomics analysis and MALDI MS imaging of lipids in a high-throughput and semi-quantitative fashion., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We compared the lateral structure of giant unilamellar vesicles (GUVs) composed of three pseudo binary mixtures of different glycosphingolipid (GSL), i.e. sulfatide, asialo-GM1 or GM1, with POPC. These sphingolipids possess similar hydrophobic residues but differ in the size and charge of their polar head group. Fluorescence microscopy experiments using LAURDAN and DiIC 18 show coexistence of micron sized domains in a molar fraction range that depends on the nature of the GSLs. In all cases, experiments with LAURDAN show that the membrane lateral structure resembles the coexistence of solid ordered and liquid disordered phases. Notably, the overall extent of hydration measured by LAURDAN between the solid ordered and liquid disordered membrane regions show marked similarities and are independent of the size of the GSL polar head group. In addition, the maximum amount of GSL incorporated in the POPC bilayer exhibits a strong dependence on the size of the GSL polar head group following the order sulfatide>asialo-GM1>GM1. This observation is in full harmony with previous experiments and theoretical predictions for mixtures of these GSL with glycerophospholipids. Finally, compared with previous results reported in GUVs composed of mixtures of POPC with the sphingolipids cerebroside and ceramide, we observed distinctive curvature effects at particular molar fraction regimes in the different mixtures. This suggests a pronounced effect of these GSL on the spontaneous curvature of the bilayer. This observation may be relevant in a biological context, particularly in connection with the highly curved structures found in neural cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Impaired sulfatide catabolism is the primary biochemical insult in patients with the inherited neurodegenerative disease, metachromatic leukodystrophy (MLD), and sulfatide elevation in body fluids is useful in the diagnostic setting. Here we used mass spectrometry to quantify fourteen species of sulfatide, in addition to the deacetylated derivative, lyso-sulfatide, using high pressure liquid chromatography-electrospray ionisation-tandem mass spectrometry in both positive and negative ion mode. A single phase extraction of 0.01 mL of MLD plasma identified all 14 sulfatide species in the positive ion mode but none in the negative ion mode. Interrogation of seven major and seven hydroxylated molecular species, as well as lyso-sulfatide, identified the C18 isoform as the most informative for MLD. The C18 produced a linear response and was below the limit of quantification (<10 pmol mL -1 ) in control plasma with concentrations in MLD plasma ranging from 12 to 196 pmol mL -1 . Serial plasma samples from an MLD patient post-therapeutic bone marrow transplant proved similar to non-disease controls with C18 sulfatide concentrations below the limit of quantification, as did samples from three individuals with an arylsulfatase A pseudodeficiency - a population variant which appears deficient upon enzymatic assay, without manifestation of disease. These findings emphasise the utility of the C18 sulfatide species for the diagnosis of MLD and biochemical monitoring of MLD patients. Extension of this approach to a newborn screening card correctly identified an MLD patient at birth with elevated C18 sulfatide at levels almost double that present in the newborn card from his unaffected sibling, suggesting the methodology may have applicability for newborn screening., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The anatomical progression of neurofibrillary tangle pathology throughout Alzheimer's disease (AD) pathogenesis runs inverse to the pattern of developmental myelination, with the disease preferentially affecting thinly myelinated regions. Myelin is comprised 80% of lipids, and the prototypical myelin lipids, galactosylceramide, and sulfatide are critical for neurological function. We observed severe depletion of galactosylceramide and sulfatide in AD brain tissue, which can be traced metabolically to the loss of their biosynthetic precursor, very long chain ceramide. The synthesis of very long chain ceramides is catalyzed by ceramide synthase 2 (CERS2). We demonstrate a significant reduction in CERS2 activity as early as Braak stage I/II in temporal cortex, and Braak stage III/IV in hippocampus and frontal cortex, indicating that loss of myelin-specific ceramide synthase activity precedes neurofibrillary tangle pathology in cortical regions. These findings open a new vista on AD pathogenesis by demonstrating a defect in myelin lipid biosynthesis at the preclinical stages of the disease. We posit that, over time, this defect contributes significantly to myelin deterioration, synaptic dysfunction, and neurological decline., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Natural killer T cells (NKT) are innate-like cells which are abundant in liver sinusoids and express the cell surface receptors of NK cells (e.g., NK1.1 (mouse) or CD161+/CD56+(human)) as well as an antigen receptor (TCR) characteristic of conventional T cells. NKT cells recognize lipid antigens in the context of CD1d, a non-polymorphic MHC class I-like molecule. Activation of NKT cells has a profound influence on the immune response against tumors and infectious organisms and in autoimmune diseases. NKT cells can be categorized into at least two distinct subsets: iNKT or type I use a semi-invariant TCR, whereas type II NKT TCRs are more diverse. Recent evidence suggests that NKT-cell subsets can play opposing roles early in non-microbial liver inflammation in that type I NKT are proinflammatory whereas type II NKT cells inhibit type I NKT-mediated liver injury., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The association of neuropathy with monoclonal gammopathy has been known for several years, even if the clinical and pathogenetic relevance of this association is not completely defined. This is not a marginal problem since monoclonal gammopathy is present in 1-3% of the population above 50 years in whom it is often asymptomatic, and in at least 8% of patients is associated with a symptomatic neuropathy, representing one of the leading causes of neuropathy in aged people. Monoclonal gammopathy may result from malignant lymphoproliferative diseases including multiple myeloma or solitary plasmocytoma, Waldenström's macroglobulinemia (WM), other IgM-secreting lymphoma or chronic lymphocytic leukemia, and primary systemic amyloidosis (AL). In most instances it is not associated with any of these disorders and is defined monoclonal gammopathy of undetermined significance (MGUS) for its possible, though infrequent, evolution into malignant forms. Several data support the pathogenetic role of the monoclonal gammopathy in the neuropathy particularly when of IgM isotype where IgM reactivity to several neural antigens has been reported. Increased levels of VEGF have been implicated in POEMS syndrome. However, there are as yet no defined therapies for these neuropathies, as their efficacy has not been confirmed in randomized trials., (Copyright © 2013 Elsevier B.V. All rights reserved.)