Accumulation of lysosulfatide in the brain of arylsulfatase A-deficient mice

Lysosomal storage diseases are a group of disorders where accumulation of catabolites is manifested in the lysosomes of different cell types. In metachromatic leukodystrophy (Arylsulfatase A [EC.3.1.6.8] deficiency) storage of the glycosphingolipid sulfatide in the brain leads to demyelination, resulting in neuromotor co-ordination deficits and regression. In a mouse model for metachromatic leukodystrophy, the ASA null mutant mouse, the accumulation of sulfatide in correlation to phenotype has been thoroughly investigated. Another lipid species reported to accumulate in patients with metachromatic leukodystrophy is the sulfatide related lipid lysosulfatide. Lysosulfatide was shown to be a cytotoxic compound in cell culture experiments and thus suggested to be involved in the pathology of metachromatic leukodystrophy. In this study, we further investigated the developmental profile of lysosulfatide in the brain of ASA null mutant mice by using high performance liquid chromatography. Lysosulfatide could be detected in the brain of normal mice (ASA +/+) from 1.8 months up to 23.1 months of age. From the age of 8.8 months the lysosulfatide levels remained constant at 1 pmol/mg wet tissue. The developmental change (< 20 months) of brain lysosulfatide showed an accumulation in ASA null mutant mice at ages above one month compared to its normal counterpart (ASA +/+). Thus, the ASA null mutant mouse might be a suitable model to further investigate the role of lysosulfatide in the pathogenesis of metachromatic leukodystrophy

Pentasialogangliosides of human brain

AbstractA pentasialoganglioside fraction of the ganglio series of glycosphingolipids has been isolated from human cerebellar cortex with a yield of 8.8 nmol NeuAc per g fresh tissue. The structural analysis showed that the material was a mixture of GP1b and GP1c gangliosides

Sialosyllactotetraosylceramide, a novel ganglioside antigen detected in human carcinomas by a monoclonal antibody

AbstractA novel ganglioside was detected in a small cell lung carcinoma by TLC-immunostaining of gangliosides with a monoclonal antibody, the C-50 MAb. Structural characterization showed this ganglioside to be IV3NeuAc-LcOse4Cer, a hitherto unknown ganglioside. This ganglioside has also been detected as a minor component in many different carcinomas using the C-50 MAb. The normally dominant CA-50 ganglioside antigen is IV3NeuAc. III4Fuc-LcOse4Cer. Based upon solid-phase binding to IV3NeuAc, III4-LcOse4Cer and IV3NeuAc-LcOse4Cer it is concluded that the C-50 MAb recognizes an epitope present in sialylated type I carbohydrate chains

Uptake of the glycosphingolipid sulfatide in the gastrointestinal tract and pancreas in vivo and in isolated islets of Langerhans

BACKGROUND: The glycosphingolipid sulfatide has previously been found in several mammalian tissues, but information on the uptake of exogenously administered sulfatide in different organs in vivo is limited. In pancreatic beta cells, sulfatide has been shown to be involved in insulin processing and secretion in vitro. In this study, we examined the uptake of exogenously administered sulfatide and its distribution to the pancreatic beta cells. This might encourage future studies of the function(s) of sulfatide in beta cell physiology in vivo. Radioactive sulfatide was given orally to mice whereafter the uptake of sulfatide in the gastrointestinal tract and subsequent delivery to the pancreas was examined. Sulfatide uptake in pancreas was also studied in vivo by i.p. administration of radioactive sulfatide in mice, and in vitro in isolated rat islets. Isolated tissue/islets were analysed by scintillation counting, autoradiography and thin-layer chromatography-ELISA. RESULTS: Sulfatide was taken up in the gastrointestinal tract for degradation or further transport to other organs. A selective uptake of short chain and/or hydroxylated sulfatide fatty acid isoforms was observed in the small intestine. Exogenously administered sulfatide was found in pancreas after i.p, but not after oral administration. The in vitro studies in isolated rat islets support that sulfatide, independently of its fatty acid length, is endocytosed and metabolised by pancreatic islets. CONCLUSION: Our study supports a selective uptake and/or preservation of sulfatide in the gastrointestinal tract after oral administration and with emphasises on pancreatic sulfatide uptake, i.p. administration results in sulfatide at relevant location

Cerebrospinal fluid markers before and after shunting in patients with secondary and idiopathic normal pressure hydrocephalus

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to explore biochemical changes in the cerebrospinal fluid (CSF) induced by shunt surgery and the relationship between these changes and clinical improvement.</p> <p>Methods</p> <p>We measured clinical symptoms and analysed lumbar CSF for protein content, neurodegeneration and neurotransmission markers in patients with secondary (SNPH, n = 17) and idiopathic NPH (INPH, n = 18) before and 3 months after shunt surgery. Patients were divided into groups according to whether or not there was improvement in clinical symptoms after surgery.</p> <p>Results</p> <p>Preoperatively, the only pathological findings were elevated neurofilament protein (NFL), significantly more so in the SNPH patients than in the INPH patients, and elevated albumin content. Higher levels of NFL correlated with worse gait, balance, wakefulness and neuropsychological performance. Preoperatively, no differences were seen in any of the CSF biomarkers between patients that improved after surgery and those that did not improve. Postoperatively, a greater improvement in gait and balance performance correlated with a more pronounced reduction in NFL. Levels of albumin, albumin ratio, neuropeptide Y, vasoactive intestinal peptide and ganglioside GD3 increased significantly after shunting in both groups. In addition, Gamma amino butyric acid increased significantly in SNPH and tau in INPH.</p> <p>Conclusion</p> <p>We conclude that a number of biochemical changes occur after shunt surgery, but there are no marked differences between the SNPH and INPH patients. The results indicate that NFL may be a marker that can predict a surgically reversible state in NPH.</p

Self-glycolipids modulate dendritic cells changing the cytokine profiles of committed autoreactive T cells.

The impact of glycolipids of non-mammalian origin on autoimmune inflammation has become widely recognized. Here we report that the naturally occurring mammalian glycolipids, sulfatide and β-GalCer, affect the differentiation and the quality of antigen presentation by monocyte-derived dendritic cells (DCs). In response to sulfatide and β-GalCer, monocytes develop into immature DCs with higher expression of HLA-DR and CD86 but lower expression of CD80, CD40 and CD1a and lower production of IL-12 compared to non-modulated DCs. Self-glycolipid-modulated DCs responded to lipopolysaccharide (LPS) by changing phenotype but preserved low IL-12 production. Sulfatide, in particular, reduced the capacity of DCs to stimulate autoreactive Glutamic Acid Decarboxylase (GAD65) - specific T cell response and promoted IL-10 production by the GAD65-specific clone. Since sulfatide and β-GalCer induced toll-like receptor (TLR)-mediated signaling, we hypothesize that self-glycolipids deliver a (tolerogenic) polarizing signal to differentiating DCs, facilitating the maintenance of self-tolerance under proinflammatory conditions

Depression in Myotonic Dystrophy type 1: clinical and neuronal correlates

Abstract Background This study was designed to investigate the prevalence and correlates of depression in Myotonic dystrophy type 1 (DM1). Methods Thirty-one patients with DM1 and 47 subjects in a clinical contrast group, consisting of other neuromuscular disorders, including Spinal muscular atrophy, Limb girdle muscle atrophy and Facioscapulohumeral dystrophy, completed Beck Depression Inventory (BDI). We aimed to establish whether different factors associated with DM1 correlated with ratings in the BDI. Results Signs of a clinical depression were prevalent in 32% of the patients with DM1, which was comparable with ratings in the clinical contrast group. The depressive condition was mild to moderate in both groups. In DM1, a longer duration of clinical symptoms was associated with lower scores on the BDI and higher educational levels were correlated with higher scores on depression. We also found a negative association with brain white matter lesions. Conclusions Findings indicate significantly more DM1 patients than normative collectives showing signs of a clinical depression. The depressive condition is however mild to moderate and data indicate that the need for intervention is at hand preferentially early during the disease process.</p