i(3)so3-galactosylceramide and Demyelinating-Diseases

Rapid conduction of nerve impulses requires coating of axons by myelin sheaths, which are lipid-rich and multilamellar membrane stacks. The lipid composition of myelin varies significantly from other biological membranes. Studies in mutant mice targeting various lipid biosynthesis pathways have shown that myelinating glia have a remarkable capacity to compensate the lack of individual lipids. However, compensation fails when it comes to maintaining long-term stability of myelin. Here, we summarize how lipids function in myelin biogenesis, axon-glia communication and in supporting long-term maintenance of myelin. We postulate that change in myelin lipid composition might be relevant for our understanding of aging and demyelinating diseases. This article is part of a Special Issue titled Brain Lipids.

Topics: Action Potentials; Aging; Animals; Brain; Cholesterol; Demyelinating Diseases; Galactosylceramides; Gangliosides; Humans; Lipid Metabolism; Mice; Myelin Sheath; Nerve Tissue Proteins; Phosphatidylinositols; Plasmalogens; Sulfoglycosphingolipids

Treatment of immune-mediated neuropathies first requires an accurate diagnosis. The diagnosis is often based on clinical, electrophysiological, and immunological features of the syndrome. The selection of appropriate therapies is then based on the spectrum of response of a syndrome to medications and an assessment of possible side effects. In neuropathies with associated serum immunoglobulin M autoantibodies, such as anti-myelin-associated glycoprotein and motor syndromes, the choices of therapy are often limited to cytotoxic agents and, in some cases, intravenous immunoglobulin. In neuropathies with immunoglobulin G antibodies in both serum and cerebrospinal fluid, such as sensory neuronopathies associated with anti-Hu antibodies, there is no well-documented response to any immunotherapy. The general principles regarding therapy of immune neuropathies will be discussed with a focus on diagnosis and treatment options of the demyelinating and immunoglobulin M antibody-associated neuropathies.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Autoantibodies; Cyclophosphamide; Demyelinating Diseases; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Immunosuppressive Agents; Myelin-Associated Glycoprotein; Neuromuscular Diseases; Polyneuropathies; Rituximab; Sulfoglycosphingolipids

Topics: Autoantibodies; Demyelinating Diseases; Diagnosis, Differential; Glycosphingolipids; Humans; Peripheral Nervous System Diseases; Prognosis; Sulfoglycosphingolipids

Myelin is a multilayered membrane that tightly wraps neuronal axons, enabling efficient, high-speed signal propagation. The axon and myelin sheath form tight contacts, mediated by specific plasma membrane proteins and lipids, and disruption of these contacts causes devastating demyelinating diseases. Using two cell-based models of demyelinating sphingolipidoses, we demonstrate that altered lipid metabolism changes the abundance of specific plasma membrane proteins. These altered membrane proteins have known roles in cell adhesion and signaling, with several implicated in neurological diseases. The cell surface abundance of the adhesion molecule neurofascin (NFASC), a protein critical for the maintenance of myelin-axon contacts, changes following disruption to sphingolipid metabolism. This provides a direct molecular link between altered lipid abundance and myelin stability. We show that the NFASC isoform NF155, but not NF186, interacts directly and specifically with the sphingolipid sulfatide via multiple binding sites and that this interaction requires the full-length extracellular domain of NF155. We demonstrate that NF155 adopts an S-shaped conformation and preferentially binds sulfatide-containing membranes in

Topics: Carrier Proteins; Cell Adhesion Molecules; Demyelinating Diseases; Glycosphingolipids; Humans; Myelin Sheath; Nerve Growth Factors; Sulfoglycosphingolipids

Metachromatic leukodystrophy (MLD) is a severe demyelinating, autosomal recessive genetic leukodystrophy. The disease is underpinned by mutations in the arylsulfatase A gene (ARSA), resulting in deficient activity of the arylsulfatase A lysosomal enzyme and consequential accumulation of galactosylceramide-3-O-sulfate (sulfatide) in the brain. Using an ex vivo murine-derived organotypic cerebellar slice culture model, we demonstrate that sulfatide induces demyelination in a concentration-dependent manner. Interestingly, our novel data demonstrate that sulfatide-induced demyelination is underpinned by PARP-1 activation, oligodendrocyte loss, pro-inflammatory cytokine expression, astrogliosis, and microgliosis. Moreover, such sulfatide-induced effects can be attenuated by the treatment with the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Olaparib (IC50∼100 nM) suggesting that this small molecule may be neuroprotective and limit toxin-induced demyelination. Our data support the idea that sulfatide is a key driver of demyelination and neuroinflammation in MLD and suggest that PARP-1 inhibitors have therapeutic utility in the sphere of rare demyelinating disease.

Topics: Animals; Cerebroside-Sulfatase; Demyelinating Diseases; Leukodystrophy, Metachromatic; Mice; Neuroinflammatory Diseases; Poly(ADP-ribose) Polymerase Inhibitors; Sulfoglycosphingolipids

Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs.. To study the diagnostic utility of CSF ST levels in SSVD.. This was a mono-center, cross-sectional study of SSVD (n = 16), Alzheimer's disease (n = 40), mixed dementia (n = 27), and healthy controls (n = 33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass spectrometry (LC-MS/MS).. CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (r = 0.64, p < 0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (r = 0.30, p < 0.05), but it did not correlate with CSF NFL level.. Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio.

Topics: Aged; Alzheimer Disease; Chromatography, Liquid; Cross-Sectional Studies; Dementia, Vascular; Demyelinating Diseases; Diagnosis, Differential; Diagnostic Techniques, Neurological; Female; Humans; Magnetic Resonance Imaging; Male; Neurofilament Proteins; Procedures and Techniques Utilization; Reproducibility of Results; Sulfoglycosphingolipids; White Matter

Myelin is composed primarily of lipids and diseases affecting myelin are associated with alterations in its lipid composition. However, correlation of the spatial (in situ) distribution of lipids with the disease-associated compositional and morphological changes is not well defined. Herein we applied high resolution matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS), immunohistochemistry (IHC), and liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) to evaluate brain lipid alterations in the dysmyelinating shiverer (Shi) mouse and cuprizone (Cz) mouse model of reversible demyelination. MALDI-IMS revealed a decrease in the spatial distribution of sulfatide (SHexCer) species, SHexCer (d42:2), and a phosphatidylcholine (PC) species, PC (36:1), in white matter regions like corpus callosum (CC) both in the Shi mouse and Cz mouse model. Changes in these lipid species were restored albeit not entirely upon spontaneous remyelination after demyelination in the Cz mouse model. Lipid distribution changes correlated with the local morphological changes as confirmed by IHC. LC-ESI-MS analyses of CC extracts confirmed the MALDI-IMS derived reductions in SHexCer and PC species. These findings highlight the role of SHexCer and PC in preserving the normal myelin architecture and our experimental approaches provide a morphological basis to define lipid abnormalities relevant to myelin diseases.

Topics: Animals; Ceramides; Corpus Callosum; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Immunohistochemistry; Lipid Metabolism; Male; Mice; Mice, Transgenic; Myelin Sheath; Phosphatidylcholines; Spectrometry, Mass, Electrospray Ionization; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sulfoglycosphingolipids; White Matter

Sulfatide is a major glycosphingolipid in myelin and a target for autoantibodies in autoimmune neuropathies. However neuropathy disease models have not been widely established, in part because currently available monoclonal antibodies to sulfatide may not represent the diversity of anti-sulfatide antibody binding patterns found in neuropathy patients. We sought to address this issue by generating and characterising a panel of new anti-sulfatide monoclonal antibodies. These antibodies have sulfatide reactivity distinct from existing antibodies in assays and in binding to peripheral nerve tissues and can be used to provide insights into the pathophysiological roles of anti-sulfatide antibodies in demyelinating neuropathies.

Topics: Animals; Autoantibodies; Cell Line, Tumor; Cell Membrane; Cells, Cultured; Demyelinating Diseases; Mice; Mice, Inbred DBA; Mice, Knockout; Neuroglia; Protein Binding; Sulfoglycosphingolipids

Demyelination and axonal degeneration are the hallmarks of established white matter lesions (WML). The neurochemistry of ongoing WML is only partially known. We explored cerebrospinal fluid (CSF) substances as markers of brain tissue damage in relation to progression of WML rated on magnetic resonance imaging.. CSF from elderly individuals with WML was analyzed for amyloid markers, total τ, hyperphosphorylated τ, neurofilament protein light subunit, sulfatide and CSF/serum-albumin ratio. After 3 years, a follow-up magnetic resonance imaging was performed. Progression of WML was rated using the Rotterdam Progression Scale (RPS).. 37 subjects (age 73.6 ± 4.6 years) were included. Subjects with more pronounced progression (RPS > 2; n = 15) had lower mean sulfatide concentration at baseline as compared to subjects with no or minimal progression (RPS 0-2; n = 22) according to univariate analyses (p = 0.009). Sulfatide was the only biomarker that predicted the RPS score according to regression analysis, explaining 18.9% of the total variance (r = 0.38, p = 0.015).. The correlation of CSF sulfatide levels and RPS scores may reflect a remyelination response to the demyelination process associated with WML. Furthermore, the results strengthen the notion that WML pathology is different from that of Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Dementia, Vascular; Demyelinating Diseases; Disease Progression; Female; Humans; Image Processing, Computer-Assisted; Leukoaraiosis; Linear Models; Magnetic Resonance Imaging; Male; Nerve Degeneration; Netherlands; Neuropsychological Tests; Predictive Value of Tests; Socioeconomic Factors; Sulfoglycosphingolipids; tau Proteins

Metachromatic leukodystrophy (MLD) is a rare metabolic disorder leading to demyelination and rapid neurologic deterioration. As therapeutic options evolve, it seems essential to understand and quantify progression of the natural disease. The aim of this study was to assess cerebral volumetric changes in children with MLD in comparison to normal controls and in relation to disease course.. Eighteen patients with late-infantile MLD and 42 typically developing children in the same age range (20-59 months) were analyzed in a cross-sectional study. Patients underwent detailed genetic, biochemical, electrophysiologic, and clinical characterization. Cerebral gray matter (GM) and white matter (WM) volumes were assessed by multispectral segmentation of T1- and T2-weighted MRI. In addition, the demyelinated WM (demyelination load) was automatically quantified in T2-weighted images of the patients, and analyzed in relation to the clinical course.. WM volumes of patients did not differ from controls, although their growth curves were slightly different. GM volumes of patients, however, were on average 10.7% (confidence interval 6.0%-14.9%, p < 0.001) below those of normally developing children. The demyelination load (corrected for total WM volume) increased with disease duration (p < 0.003) and motor deterioration (p < 0.001).. GM volume in patients with MLD is reduced when compared with healthy controls, already at young age. This supports the notion that, beside demyelination, neuronal dysfunction caused by neuronal storage plays an additional role in the disease process. The demyelination load may be a useful noninvasive imaging marker for disease progression and may serve as reference for therapeutic intervention.

Topics: Adolescent; Adult; Aging; Cerebral Cortex; Child; Confidence Intervals; Cross-Sectional Studies; Demyelinating Diseases; Disease Progression; Female; Humans; Image Processing, Computer-Assisted; Leukodystrophy, Metachromatic; Magnetic Resonance Imaging; Male; Middle Aged; Movement Disorders; Myelin Sheath; Neural Conduction; Regression Analysis; Sulfoglycosphingolipids; Young Adult

A girl with Hurler disease (MPS IH) underwent allogeneic stem cell transplantation at 13 months of age with her one HLA-B antigen mismatch mother as donor. The procedure was complicated by cerebral hemorrhage and a ventricular-peritoneal shunt device was inserted. Mild GVH reactions were rapidly reversed. One year after transplantation ventriculitis was suspected and the shunt was replaced by a ventricular drainage catheter. Antibiotics had no effect and graft-versus-host disease (GVHD) was diagnosed. All symptoms were reversed by prednisolone and cyclosporine. Increased albumin and pleocytosis in the cerebrospinal fluid (CSF) normalized concomitantly. Electron microscopy of the CSF sediment showed debris consisting of numerous complex aggregates of thin lamellae and electron dense fragments with a tight lamellar texture. Biochemical analysis of the CSF sediment proved that the debris contained galactosylceramide and sulfatide. The electron microscopic and biochemical findings were interpreted to represent stripping of central myelin as a result of subacute GVHD in the central nervous system and its desquamation from the brain parenchyma into the ventricular CSF through the post-hemorrhage defect. From reversal of the GVHD at 2 years of age until follow-up at 10 years of age the clinical condition remained stable with no recurrence or deterioration.

Topics: Bone Marrow Transplantation; Brain; Brain Diseases; Cerebral Hemorrhage; Cerebrospinal Fluid; Child; Demyelinating Diseases; Female; Follow-Up Studies; Galactosylceramides; Graft vs Host Disease; Humans; Immunosuppressive Agents; Microscopy, Electron; Mucopolysaccharidosis I; Myelin Sheath; Sulfoglycosphingolipids; Ventriculoperitoneal Shunt

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ASA). This results in accumulation of sulfated glycosphingolipids, mainly 3-O-sulfogalactosylceramide (sulfatide), in the nervous system and various other organs. In patients, lipid storage causes a progressive loss of myelin leading to various neurological symptoms. The sulfatide storage pattern in ASA-deficient [ASA(-/-)] mice is comparable to humans, but regrettably, the mice do not mimic the myelin pathology. We reasoned that increasing sulfatide storage in this animal model might provoke demyelination. Therefore, we generated transgenic ASA(-/-) [tg/ASA(-/-)] mice overexpressing the sulfatide-synthesizing enzyme galactose-3-O-sulfotransferase-1 in myelinating cells. Indeed, these tg/ASA(-/-) mice displayed a significant increase in sulfatide storage in brain and peripheral nerves. Mice older than 1 year developed severe neurological symptoms. Nerve conduction velocity was significantly reduced in tg/ASA(-/-) mice because of a peripheral neuropathy characterized by hypomyelinated and demyelinated axons. Inhomogeneous myelin thickness in the corpus callosum, increased frequency of hypomyelinated and demyelinated axons in corpus callosum and optic nerve, and substantially reduced myelin basic protein levels are in accordance with loss of myelin in the CNS. Thus, increasing sulfatide storage in ASA(-/-) mice leads to neurological symptoms and morphological alterations that are reminiscent of human MLD. The approach described here may also be applicable to improve other mouse models of lysosomal as well as nonlysosomal disorders.

Topics: Age Factors; Animals; Cerebroside-Sulfatase; Demyelinating Diseases; Disease Models, Animal; Electromyography; Hindlimb Suspension; Humans; Leukodystrophy, Metachromatic; Lipids; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Motor Activity; Myelin Basic Protein; Myelin Sheath; Neural Conduction; Peripheral Nerves; Rotarod Performance Test; Sciatic Nerve; Spinal Cord; Sulfoglycosphingolipids

Antiglycolipid antibodies cause a distinctive form of dysmyelination in vivo characterized by marked widening of the myelin period. Such "expanded" or "wide-spaced" myelin occurs in peripheral nerves in certain paraproteinemias and in the CNS in multiple sclerosis. We have used an in vitro system to reproduce this pathology under controlled conditions to assess the role of antibody specificity and class and the need for cofactors in generating this kind of lesion in peripheral myelin. Schwann cell myelin formed in vitro around dorsal root ganglion cell axons was exposed for 3-14 days to hybridoma cells that produce specific monoclonal antibodies. Typical wide-spaced myelin developed after exposure to either O4, which produces an IgM antisulfatide antibody, or O1, which produces an IgM antigalactocerebroside antibody. In both cases, the effect was apparent by three days in paranodal as well as internodal myelin, especially in the outer lamellae. This change did not depend on the presence of complement or macrophages in the cultures. Exposure to anti-GalC hybridoma cells, which produce an IgG3 antiglycolipid antibody, did not produce wide-spaced myelin, nor did exposure to hybridoma cells that secrete IgM antibodies directed against a non-myelin antigen. The location and rapidity of the pathologic changes seen after O4 or O1 are consistent with penetration of the antibodies through the external mesaxon of already formed myelin and then between compact lamellae, progressively spreading them apart in the centripetal direction. This in vitro model shows that either of two specific monoclonal IgM antiglycolipid antibodies can alone reproduce a well known form of myelin pathology under defined conditions.

Topics: Animals; Antibodies, Monoclonal; Cells, Cultured; Coculture Techniques; Demyelinating Diseases; Galactosylceramides; Ganglia, Spinal; Hybridomas; Immunoglobulin M; Microscopy, Electron; Myelin Sheath; Rats; Rats, Sprague-Dawley; Rats, Wistar; Schwann Cells; Sulfoglycosphingolipids; Time Factors

We showed previously that spinal cord implants of hybridoma cells (O1) that secrete an IgM antigalactocerebroside cause focal multiple-sclerosis-like plaques of demyelination followed by remyelination to form "shadow plaques" (Rosenbluth et al., 1999). The antibody in that case was directed against a glycolipid present in mature oligodendrocytes and myelin but not in precursor cells. We now report the effects of implanting a different hybridoma (O4) that secretes IgM antibodies directed against sulfatide, a constituent not only of mature myelin and oligodendrocytes but also of late precursor cells, in order to determine whether this hybridoma too would generate focal demyelination and would, in addition, block remyelination. Our results show that focal plaques of demyelination indeed appear after O4 implantation, and that remyelination does occur, but only in cases where the hybridoma cells have degenerated, probably through host rejection. The occurrence of remyelination suggests that oligodendrocyte precursor cells are capable of migrating in rapidly from adjacent areas or that early precursors, not yet expressing sulfatide, remain undamaged within the lesions. In cases where intact hybridoma cells persist at lesion sites, remyelination does not occur. Failure of remyelination in this model thus appears to result from the continuing presence of antimyelin antibodies rather than from depletion of oligodendrocyte precursors.

Topics: Animals; Animals, Newborn; Autoantibodies; Axons; Cell Movement; Demyelinating Diseases; Disease Models, Animal; Female; Graft Survival; Hybridomas; Immunoglobulin M; Male; Mice; Microscopy, Electron; Myelin Sheath; Oligodendroglia; Rats; Rats, Wistar; Regeneration; Spinal Cord; Stem Cells; Sulfoglycosphingolipids; Tumor Cells, Cultured

To analyse the diagnostic and prognostic value of periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH) magnetic resonance imaging (MRI) changes and their relation to symptoms and cerebrospinal fluid (CSF) markers of demyelination (sulphatide) and axonal degeneration [neurofilament triplet protein (NFL)] in a large series of patients with normal pressure hydrocephalus (NPH) and Binswanger disease (BD).. PVH and DWMH were determined by a semi-automatic segmentation method on T2-weighted images in 29 patients with NPH and 17 patients with BD. CSF analyses, psychometric testing and quantification of balance, gait and continence were performed in all patients and also postoperatively in NPH patients.. No MRI variable could identify NPH or BD patients. Abundant PVH and DWMH preoperatively correlated with improvement in gait, balance and psychometric performance after shunt surgery (P < 0.05). CSF sulphatide correlated positively with the amount of DWMH (P < 0.05) while NFL was correlated to both PVH and DWMH (P < 0.05). Abundant PVH correlated with poor psychometric performance while DWMH correlated with gait disturbance (P < 0.05). Postoperative reduction in PVH correlated with improvement in gait, balance and psychometric performance.. In spite of a refined quantification method, NPH and BD patients exhibited similar MRI changes. MRI had a predictive value in NPH patients. DWMH might relate to demyelination and PVH to neuronal axonal dysfunction. NPH and BD share the major part of symptoms and MRI changes, indicating a common pathophysiological pattern, and we raise the question of how to treat BD patients.

Topics: Aged; Aged, 80 and over; Axons; Dementia, Vascular; Demyelinating Diseases; Female; Humans; Hydrocephalus, Normal Pressure; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Predictive Value of Tests; Sulfoglycosphingolipids

The accumulation of sulfatide (sulfatogalactosyl cerebroside) and changes in the sulfatide species present have been examined in the cerebellum of day 6-32 aged rats and in multiple sclerosis (MS) tissue samples. Negative ion electrospray mass spectrometry with daughter and parent ion analyses were used to distinguish the fatty acyl character in the amide linkage of sulfatide; measurement was done by selected ion and multiple reaction monitoring of individually identified sulfatide molecules. Sulfatide accumulation in rat cerebellum shows that 18:0- and hydroxylated 18:0-sulfatide are the first sulfatide molecules detectable. Very long fatty acyl chain sulfatide molecules (>20:0) are present at day 7 and the ratio of non-hydroxylated compared to hydroxylated sulfatide rises as the amount of non-hydroxylated sulfatide increases. 24:1-sulfatide accumulates at a ratio of about 3:1 over 24:0-sulfatide during active myelination. Analyses of the sulfatide in human tissue have shown differences between MS plaque tissues, normal appearing adjacent white matter and control tissues. The findings show that total sulfatide is reduced by 60% in the plaque matter and decreased 25% in adjacent normal appearing white matter. There are significant increases (P=0.05) in the amount of hydroxylation of sulfatide, demonstrated by an increase in the percentage of hydroxylated h24:0-sulfatide (hydroxy-lignoceroyl sulfatide).

Topics: Aged; Aged, 80 and over; Aging; Animals; Brain Chemistry; Cerebellum; Demyelinating Diseases; Female; Humans; Male; Mass Spectrometry; Middle Aged; Multiple Sclerosis; Myelin Proteins; Rats; Rats, Sprague-Dawley; Sulfoglycosphingolipids

The common association between monoclonal gammopathy and peripheral neuropathy was studied in seven patients with demyelinating polyneuropathy and IgM paraproteinaemia. Plasma samples from these individuals were thoroughly tested for antiperipheral nerve myelin (PNM) antibodies and then screened for glycoprotein and glycolipid reactivity by western immunoblotting and thin-layer chromatography (TLC) immunostaining. Three of the seven samples showed strong IgM anti-PNM and antisulfatide (GalS) antibody reactivity. Two of these three plasma samples showed extraordinarily high antisulfatide IgM antibody titres, ranging from 1 x 104 to 1 x 106 arbitrary units/L. These same samples also showed intense myelin staining of sciatic nerve sections (paraffin and cryostat) and teased nerve fibres. No axonal immunoreactivity was observed. These results suggest that high titre IgM antisulfatide antibodies may play a pathogenetic role in the immune demyelination associated with IgM paraproteinaemia.

Topics: Adult; Aged; Antibodies; Blotting, Western; Chromatography, Thin Layer; Demyelinating Diseases; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Glycolipids; Humans; Immunoglobulin M; Male; Middle Aged; Myelin Sheath; Nerve Fibers; Paraproteinemias; Peripheral Nervous System Diseases; Sciatic Nerve; Sulfoglycosphingolipids

HIV-positive plasma samples from patients with and without neuropathy and with high titre anti-GalS antibodies showed strong binding to the myelin membrane of both fixed and unfixed human sciatic nerve specimens. This staining pattern was also seen with a plasma sample from a patient with IgM paraproteinaemic inflammatory demyelinating neuropathy with anti-GalS IgM antibody. Teased nerve fibres incubated with these anti-GalS antibodies from both HIV and non-HIV plasma samples showed immunofluorescence at the paranodal regions and Schmidt-Lanterman incisures. These data support a potential role for these antibodies in the aetiology of HIV-associated immune mediated neuropathies.

Topics: Demyelinating Diseases; Fluorescent Antibody Technique; Glycolipids; HIV Antibodies; HIV Infections; Humans; Immunohistochemistry; Nerve Fibers; Paraffin Embedding; Peripheral Nervous System Diseases; Protein Binding; Sciatic Nerve; Sulfoglycosphingolipids

Vertebrate myelin is enriched in the lipid galactocerebroside (GalC) and its sulfated derivated sulfatide. To understand the in vivo function of these lipids, we analyzed myelination in mice that contain a null mutation in the gene encoding UDP-galactose:ceramide galactosyltransferase, the enzyme responsible for catalyzing the final step in GalC synthesis. Galactolipid-deficient myelin is regionally unstable and progressively degenerates. At postnatal day 30, demyelination is restricted to the midbrain and hindbrain, but by postnatal day 90, it spreads throughout the central nervous system. Activated microglial cells and reactive astrocytes appear with the loss of myelin in older animals. Nonetheless, major myelin protein gene mRNA levels are normal throughout the life of these animals, suggesting that widespread oligodendrocyte death is not the primary cause of demyelination. The developmental switch in myelin-associated glycoprotein isoform expression, however, does not occur normally in these mice, suggesting an alteration in oligodendrocyte maturation. Taken together, these findings indicate that GalC and sulfatide are required for the long-term maintenance of myelin and that their absence may have subtle effects on the development of oligodendrocytes.

Topics: Animals; Brain; Demyelinating Diseases; Galactosylceramides; Galactosyltransferases; Ganglioside Galactosyltransferase; Gene Expression Regulation, Developmental; Mice; Mice, Knockout; Mice, Neurologic Mutants; Myelin Proteins; Myelin Sheath; Myelin-Associated Glycoprotein; Nerve Tissue Proteins; Oligodendroglia; Protein Isoforms; RNA, Messenger; Sulfoglycosphingolipids

Increased titers of circulating antisulfatide antibodies are consistently associated with a variety of chronic axonal and demyelinating polyneuropathy syndromes. Previous studies have shown that the pattern of antisulfatide binding to neural tissues correlates with the type of neuropathy. This suggests a possible role for antisulfatide antibodies in inducing peripheral nerve dysfunction, although their exact contribution to the pathogenesis of neuropathy is still unknown. We examined sural nerve biopsy specimens from two patients with sensorimotor and small fiber sensory neuropathy associated with high titers of IgM monoclonal antibodies to sulfatide. Electrophysiological and pathological findings were consistent with predominant demyelination in the patient with sensorimotor involvement, whereas evidence of demyelination was obtained only by teased fiber examination in the other patient. The ultrastructural study disclosed in both cases the presence of myelinated fibers with widely spaced myelin, due to a separation of leaflets of the intraperiod lines. Immunocytochemistry, performed on frozen sections, demonstrated the presence of IgM and complement product C3d bound to myelin sheaths of almost all fibers. Few fibers were immunoreactive for complement components C1q and C5. In addition, the terminal complement complex neoantigen C5b-C9, not associated with S protein, was detected on some myelinated fibers. The results suggest that, at the least in some forms of demyelinating neuropathy associated with antisulfatide antibodies, pathological changes are complement mediated. Our data further confirm previous clinical and experimental observations that complement activation initiates separation of myelin intraperiod lines.

Topics: Aged; Antibodies; Complement System Proteins; Demyelinating Diseases; Electrophysiology; Female; Fluorescent Antibody Technique, Direct; Humans; Male; Myelin Sheath; Peripheral Nervous System Diseases; Sulfoglycosphingolipids

Previous studies of small numbers of patients have shown that antisulphatide autoantibodies are associated with polyneuropathies having a prominent sensory component. However, clinical and electrodiagnostic features are variable. The range of clinical and electrodiagnostic findings in 19 patients with polyneuropathies and high titre (> 4500) serum IgM antisulphatide antibodies is described, together with testing for serum monoclonal (M) proteins.. About 20000 serum samples that were referred to the clinical laboratory from 1990 to the end of 1994 were screened by enzyme linked immunosorbent assay (ELISA) for specific high titre antisulphatide antibodies. The clinical and electrodiagnostic data in 23 patients with positive results were reviewed. IgM binding to peripheral nerve structures was also evaluated in these patients.. Nineteen patients had predominantly distal, symmetric pansensory loss. Patients with IgM antisulphatide antibodies and no serum M protein usually had clinical syndromes that included: (1) neuropathic pain or dysaesthesiae, (2) no functionally significant weakness, and (3) an axonal neuropathy on electrodiagnostic testing. On immunocytochemical studies serum IgM from the patients without M proteins usually (nine of 10; 90%) bound to peripheral nerve axons, but never to myelin. Patients with antisulphatide antibodies and a serum M protein, usually IgM, were more likely than patients without a serum M protein, to have syndromes with: (1) no pain or dysaesthesiae, (2) motor abnormalities, and (3) a demyelinating polyneuropathy by electrodiagnostic criteria. In immunocytochemical studies serum IgM most often bound to either peripheral nerve myelin or endoneurial structures.. Patients with polyneuropathy and high titre serum IgM antisulphatide antibodies can be classified into subgroups according to the presence or absence of a serum M protein. Patients without an M protein are more likely to have pure sensory syndromes, pain, an axonal neuropathy, and serum IgM binding to axons. Patients with a serum M protein commonly had syndromes with prominent motor involvement, no pain, and a demyelinating neuropathy.

Topics: Adult; Aged; Autoantibodies; Binding Sites; Demyelinating Diseases; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin M; Immunohistochemistry; Male; Middle Aged; Peripheral Nervous System Diseases; Sulfoglycosphingolipids

Antibodies to sulfatide are associated with polyneuropathy. To investigate the role of anti-sulfatide antibodies in this neurological disorder, guinea-pigs were immunized with sulfatide, and their behavior, serology and pathology were compared with animals injected with simple Freund's adjuvant. Eleven of 13 guinea-pigs that developed raised serum anti-sulfatide antibodies after five injections of sulfatide showed definite motor weakness. Demyelination of peripheral nerves and immunoglobulin deposits at peripheral nerve myelin sheath were found in symptomatic animals only. Functional impairment of the animals was significantly correlated with serum anti-sulfatide IgG levels and pathological findings in nerve fiber studies. Control animals and animals that received 1-3 injections of sulfatide were behaviorally and pathologically normal.

Topics: Animals; Antibodies, Monoclonal; Demyelinating Diseases; Female; Fluorescent Antibody Technique, Direct; Freund's Adjuvant; Guinea Pigs; Immunization; Male; Microscopy, Electron; Peripheral Nervous System Diseases; Sulfoglycosphingolipids

Twenty-nine patients with paraproteinaemia, 12 with neuropathy and 17 without a previous record of neurological symptoms were clinically characterized. All 12 neuropathy patients had a moderate to severe sensorimotor demyelinating neuropathy. The patients were examined with regard to serum antibodies to gangliosides, including GM1, GD1a, GD1b, GT1b, and LM1, and other acidic glycolipids, including LK1 and sulphatide, of human brain and peripheral nerve. Sera from 80 blood donors, 40 men and 40 women 20-60 years of age, were used as normal controls. The sera were analysed with an ELISA performed on thin-layer chromatography plates. At a dilution of 1/400 none of the control sera gave a detectable reaction and a titre of > or = 1:400 was considered as a positive test. In 11 of the 12 neuropathy patients the paraproteinaemia was of IgM type and 10 of them had a positive antibody titre against LK1 and Hex-LK1, acidic glycolipids with a terminal glucuronyl-3-sulphate group. The antibody titre against LK1 in 1 patient was 1:400 and varied between 1:5,000 and 1:3,200,000 in the other 9. One of the patients also had a positive titre, 1:64,000, to sulphatide. None of the sera from the 17 paraproteinaemia patients without a previous record of neurological symptoms contained antibodies to LK1 or to any glycolipid antigen examined, except for sulphatide. A positive titre (> or = 1:400) of antibodies to sulphatide was found in sera from 4 of these patients, the titres being < or = 3,200.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Demyelinating Diseases; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Glycolipids; Humans; Immunoglobulin A; Immunoglobulin M; Male; Middle Aged; Paraproteinemias; Sulfoglycosphingolipids

Topics: Autoantibodies; Demyelinating Diseases; G(M1) Ganglioside; Heart Transplantation; Humans; Immunosuppression Therapy; Male; Middle Aged; Polyneuropathies; Sulfoglycosphingolipids

The effects of psychosine on the metabolism of myelin associated glycolipids such as galactocerebroside and sulfatide in mouse brain cell cultures were investigated in order to clarify the mechanism of demyelination in globoid cell leukodystrophy (Krabbe's disease). The incorporation of 3H-galactose into cerebroside and sulfatide was studied in the presence of psychosine (1-3 micrograms/ml medium). These data indicated that psychosine inhibited the incorporation of 3H-galactose into cerebroside and sulfatide not in astroglial cell culture but in oligodendroglial cell culture. Oligodendrocytes produce myelin in the central nervous system, and cerebroside and sulfatide are major components of myelin. These results suggest that psychosine influences the lipid metabolisms of myelin and subsequently leads to the demyelination in Krabbe's disease.

Topics: Animals; Cells, Cultured; Demyelinating Diseases; Galactosylceramides; Leukodystrophy, Globoid Cell; Mice; Oligodendroglia; Psychosine; Sphingosine; Sulfoglycosphingolipids

We report the development of a simple and reliable method for the study of demyelination in vitro based on the measurement of 2':3'-cyclic nucleotide 3'-phosphodiesterase in isolated myelin. Using only small quantities of myelin (equivalent to 100 micrograms of myelin protein) the system was tested under conditions that are believed to approximate those found at the site of an inflammatory demyelinating lesion. Treatment with a combination of trypsin, phospholipase A2, and lysophosphatidylcholine was used to evaluate the method. This microsystem has the potential not only for testing the myelinotoxicity of soluble factors but also for investigating the involvement of inflammatory cells in the demyelinating process. Myelin degradation by elicited peritoneal macrophages could be demonstrated at relatively high densities of these cells. Nylon wool purified lymph node T cells from myelin basic protein-primed SJL/J mice, after selective expansion with antigen and interleukin 2, failed to induce any significant myelin breakdown unless a limited number of syngeneic activated macrophages were also present. T cells from mice that had been inoculated with keyhole limpet haemocyanin failed to show any effect. The advantages of this technique over other in vitro systems are that it enables the study of demyelination using syngeneic sources of myelin and defined cell populations.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Antigens; Demyelinating Diseases; Female; Hemocyanins; In Vitro Techniques; Lysophosphatidylcholines; Macrophages; Male; Mice; Mice, Inbred BALB C; Myelin Basic Protein; Myelin Sheath; Phagocytosis; Phospholipases A; Phospholipases A2; Sulfoglycosphingolipids; T-Lymphocytes; Trypsin

Topics: Animals; Demyelinating Diseases; Free Radicals; Guinea Pigs; Hydrogen Peroxide; Neutrophils; Oxygen; Sulfoglycosphingolipids

Sciatic nerves from 15-day-old trembler and control mice were maintained in vitro up to 53 h and the metabolism of myelin lipids and the oxygen consumption were investigated [35S]Sulfate was incorporated into sulfatides at a higher rate and turned over more rapidly in trembler nerves than in controls. [14C]Galactose was incorporated into cerebrosides of trembler nerves at a lower rate and turned over like the controls. In contrast, synthesis of sulfatides labeled with [14]galactose was increased in mutants and no significant turnover was observed for both trembler and control nerves during the whole incubation period. Similar results were obtained using [3H]serine as a precursor and no significant differences were observed in the turnover rates of sphingomyelin and phosphatidylcholine between trembler and control nerves. These data suggest the presence of two different pools of cerebrosides, a small one formed by the fast recycling of sulfatides and which does not mix with a second, larger one. The rate of oxygen consumption did not change significantly during the incubation period and was 2-3-fold higher in trembler nerves than in controls, reflecting, at least partly, the increased sulfatide metabolism.

Topics: Animals; Cerebrosides; Demyelinating Diseases; Lipid Metabolism; Mice; Mice, Inbred CBA; Mice, Neurologic Mutants; Myelin Sheath; Oxygen Consumption; Phosphatidylcholines; Sciatic Nerve; Sphingomyelins; Sulfoglycosphingolipids

Topics: Animals; Autolysis; Brain; Cerebrosides; Demyelinating Diseases; Lipid Metabolism; Macrophages; Necrosis; Oligodendroglia; Phospholipids; Rabbits; Sphingomyelins; Sulfoglycosphingolipids; Time Factors; Tritium

The fine structural characteristics of storage products in peripheral nerve, kidney and cerebral white matter, from a case of adult metachromatic leukodystrophy are described. There were pronounced differences from the fine structural aspects in late infantile cases. A large proportion of the inclusions did not exhibit a unit membrane. An hypothesis is proposed to clarify the delayed manifestation of this type of metachromatic leukodystrophy until childhood.

Topics: Acid Phosphatase; Adult; Brain; Demyelinating Diseases; Humans; Inclusion Bodies; Kidney Tubules; Kidney Tubules, Distal; Leukodystrophy, Metachromatic; Lysosomes; Macrophages; Male; Neurons; Peripheral Nerves; Schwann Cells; Sulfoglycosphingolipids

Topics: Age Factors; Autopsy; Cerebral Cortex; Cerebrosides; Chromatography, Gas; Chromatography, Thin Layer; Demyelinating Diseases; Fatty Acids; Histocytochemistry; Humans; Leukodystrophy, Metachromatic; Sulfoglycosphingolipids

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Animals, Newborn; Binding Sites; Carbon Radioisotopes; Cerebellum; Chick Embryo; Cholesterol; Culture Techniques; Demyelinating Diseases; Depression, Chemical; Dose-Response Relationship, Drug; Hexachlorophene; Lipids; Microscopy, Electron; Myelin Sheath; Nerve Tissue Proteins; Peripheral Nerves; Peripheral Nervous System Diseases; Rats; Rats, Inbred Strains; Sulfates; Sulfoglycosphingolipids; Sulfur Radioisotopes; Time Factors

Topics: Aged; Brain; Brain Chemistry; Cerebrosides; Child, Preschool; Chromatography, Thin Layer; Demyelinating Diseases; Diffuse Cerebral Sclerosis of Schilder; Encephalitis; Galactosidases; Gangliosides; Humans; Infant; Lipidoses; Lipids; Multiple Sclerosis; Sphingomyelins; Sulfatases; Sulfoglycosphingolipids

Topics: Adenosine Monophosphate; Adenosine Triphosphate; Age Factors; Animals; Autoradiography; Brain; Cerebrosides; Demyelinating Diseases; Fatty Acids; Female; Hot Temperature; Hydrogen-Ion Concentration; Male; Mice; Mutation; Myelin Sheath; Organophosphorus Compounds; Radioisotopes; Sulfoglycosphingolipids; Sulfuric Acids; Sulfurtransferases

Topics: Anemia, Macrocytic; Atrophy; Autopsy; Blood Vessels; Brain; Brain Chemistry; Cerebrosides; Child; Cholesterol; Chromatography, Thin Layer; Demyelinating Diseases; Esters; Fatty Acids; Fatty Acids, Unsaturated; Female; Galactose; Gliosis; Globus Pallidus; Homocystinuria; Humans; Malonates; Metabolism, Inborn Errors; Phosphatidylcholines; Phospholipids; Sphingomyelins; Sulfoglycosphingolipids; Vitamin B 12

Topics: Animals; Brain; Cell Differentiation; Central Nervous System Diseases; Cholesterol; Chromatography, Thin Layer; Demyelinating Diseases; Diffuse Cerebral Sclerosis of Schilder; Disease Models, Animal; DNA; Electrophoresis, Polyacrylamide Gel; Male; Mice; Mice, Inbred Strains; Myelin Basic Protein; Myelin Sheath; Nerve Fibers, Myelinated; Nerve Tissue Proteins; Neuroglia; Phospholipids; RNA; Sulfoglycosphingolipids

Topics: Acid Phosphatase; Animals; Complement System Proteins; Culture Techniques; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Galactosidases; Glucosephosphate Dehydrogenase; Glucuronidase; Isocitrate Dehydrogenase; Mice; Myelin Sheath; Nucleotides; Phosphoric Monoester Hydrolases; Spinal Cord; Sulfatases; Sulfoglycosphingolipids; Tissue Extracts

Topics: Animals; Centrifugation, Density Gradient; Demyelinating Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Evoked Potentials; Hexachlorophene; Myelin Sheath; Neural Conduction; Peripheral Nervous System Diseases; Rats; Sciatic Nerve; Sulfoglycosphingolipids

Topics: Brain Chemistry; Cerebral Cortex; Cerebrosides; Cholesterol; Demyelinating Diseases; Diffuse Cerebral Sclerosis of Schilder; Histocytochemistry; Humans; Macrophages; Male; Middle Aged; Neuroglia; Neurons; Phospholipids; Staining and Labeling; Sulfoglycosphingolipids

Topics: Animals; Chromatography; Demyelinating Diseases; Fatty Acids; Hydrolysis; Kidney; Methylation; Mice; Mice, Inbred Strains; Mutation; Sulfoglycosphingolipids

Topics: Brain; Cerebrosides; Cholesterol; Demyelinating Diseases; Diffuse Cerebral Sclerosis of Schilder; Humans; Infant; Lipid Metabolism; Phosphatidylethanolamines; Sulfoglycosphingolipids

Topics: Animals; Brain; Cerebrosides; Demyelinating Diseases; Hydrogen-Ion Concentration; Kidney; Male; Mice; Myelin Sheath; Sciatic Nerve; Sulfoglycosphingolipids; Sulfur Isotopes; Sulfurtransferases

Topics: Adenine Nucleotides; Animals; Brain; Cerebrosides; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Myelin Sheath; Rats; Sulfatases; Sulfoglycosphingolipids; Sulfur Isotopes; Sulfurtransferases

Topics: Animals; Carbon Radioisotopes; Cerebrosides; Cholesterol; Demyelinating Diseases; DNA; Galactose; Glucosyltransferases; Glycolipids; Mice; Mutation; Myelin Sheath; Nucleic Acid Hybridization; Phospholipids; RNA; Sulfoglycosphingolipids

Topics: Brain Chemistry; Cell Membrane; Cerebrosides; Demyelinating Diseases; Diffuse Cerebral Sclerosis of Schilder; Glycolipids; Humans; Myelin Sheath; Sulfoglycosphingolipids