chondroitin-sulfates and Nervous-System-Diseases

The brain extracellular matrix (ECM) is involved in several aspects of neuronal development, plasticity, and pathophysiology. Chondroitin sulfate proteoglycans (CSPGs), consisting of core proteins with covalently attached chondroitin sulfate (CS) chains, are essential components of the brain ECM. During late postnatal development, CSPGs condense around parvalbumin-expressing inhibitory neurons (PV-cells) and form lattice-like ECM structures called perineuronal nets (PNNs). Enzymatic or genetic manipulation of PNNs reactivates neuronal plasticity in the adult brain, probably by resetting the excitatory/inhibitory balance in neural networks. Recent studies have indicated that PNNs control PV-cell function by enhancing the accumulation of specific proteins at the cell surface and/or acting as neuroprotective shields against oxidative stress. Since dysfunction of PV-cells and remodeling of CSPGs are commonly observed in several disorders, including schizophrenia, Costello syndrome, Alzheimer's disease, and epilepsy, modulation of PV-cell function by CSPGs may provide a novel strategy for these neuronal disorders. Here we review the potential roles of CSPGs as therapeutic targets for neuronal disorders, with particular focus on structural changes of CS chains under pathological conditions.

Topics: Animals; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Humans; Models, Neurological; Nerve Net; Nervous System Diseases; Neurodevelopmental Disorders; Neuronal Plasticity; Neurons; Neuroprotective Agents

Previously, we identified two missense mutations in the chondroitin N-acetylgalactosaminyltransferase-1 gene in patients with neuropathy. These mutations are associated with a profound decrease in chondroitin N-acetylgalactosaminyltransferase-1 enzyme activity. Here, we describe a patient with neuropathy who is heterozygous for a chondroitin synthase-1 mutation. Chondroitin synthase-1 has two glycosyltransferase activities: it acts as a GlcUA and a GalNAc transferase and is responsible for adding repeated disaccharide units to growing chondroitin sulfate chains.. Recombinant wild-type chondroitin synthase-1 enzyme and the F362S mutant were expressed. These enzymes and cells expressing them were then characterized.. The mutant chondroitin synthase-1 protein retained approximately 50% of each glycosyltransferase activity relative to the wild-type chondroitin synthase-1 protein. Furthermore, unlike chondroitin polymerase comprised of wild-type chondroitin synthase-1 protein, the non-reducing terminal 4-O-sulfation of GalNAc residues synthesized by chondroitin N-acetylgalactosaminyltransferase-1 did not facilitate the elongation of chondroitin sulfate chains when chondroitin polymerase that consists of the mutant chondroitin synthase-1 protein was used as the enzyme source.. The chondroitin synthase-1 F362S mutation in a patient with neuropathy resulted in a decrease in chondroitin polymerization activity and the mutant protein was defective in regulating the number of chondroitin sulfate chains via chondroitin N-acetylgalactosaminyltransferase-1. Thus, the progression of peripheral neuropathies may result from defects in these regulatory systems.. The elongation of chondroitin sulfate chains may be tightly regulated by the cooperative expression of chondroitin synthase-1 and chondroitin N-acetylgalactosaminyltransferase-1 in peripheral neurons and peripheral neuropathies may result from synthesis of abnormally truncated chondroitin sulfate chains.

Topics: Amino Acid Sequence; Animals; Base Sequence; Chondroitin Sulfates; DNA Primers; Humans; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation, Missense; N-Acetylgalactosaminyltransferases; Nervous System Diseases; Real-Time Polymerase Chain Reaction; Sequence Homology, Amino Acid

Given the high short-term risk of stroke after transient ischemic attack, we hypothesized that substantial acute neurological recovery in patients presenting with cerebral ischemia would be associated with a greater risk of subsequent neurological deterioration due to recurrent cerebral ischemia. Data from the Trial of ORG10172 in Acute Stroke Treatment, a randomized trial of the heparinoid danaparoid, were analyzed to determine whether substantial acute recovery, defined as an improvement of greater than or equal to 75% on National Institutes of Health Stroke Scale (NIHSS) between baseline and 24 hours, was associated with a greater risk of subsequent deterioration, defined as a worsening on the NIHSS between day 1 and day 90. Of 1,184 subjects meeting entry criteria, 63 (5.3%) had substantial acute recovery. Subsequent deterioration was more common in those with substantial acute recovery compared with others (48 vs 33%; p = 0.028 by Fisher's exact test). In multivariable models, substantial acute recovery remained an independent predictor of subsequent deterioration (odds ratio, 3.0; 95% confidence interval, 1.7-5.2; p < 0.001). Among patients with acute cerebral ischemia, those who recover substantially within 24 hours may be at greater risk of subsequent neurological deterioration due to causes other than hemorrhage.

Topics: Aged; Anticoagulants; Blood Glucose; Blood Pressure; Case-Control Studies; Chondroitin Sulfates; Dermatan Sulfate; Disease Progression; Drug Combinations; Female; Follow-Up Studies; Heart Rate; Heparitin Sulfate; Humans; Ischemic Attack, Transient; Male; Middle Aged; Nervous System Diseases; Neurologic Examination; Odds Ratio; Randomized Controlled Trials as Topic; Recovery of Function; Risk; Time Factors

Anti-chondroitin sulfates (ChSs) antibodies have been reported in neuropathy and neurodegenerative diseases. Differences in specificities may account for their association with different diseases. Sera from 303 neurological patients were tested for antibodies to ChSs A, B, C. Titers >/=51,200 were found in 16 patients (eight peripheral neuropathy, three motor neuron disease, four multiple sclerosis, one myelitis). Three patients also had anti-sulfatides antibodies, which in two cases cross-reacted with ChSs. By indirect immunofluorescence, positive sera stained nuclei on normal human peripheral nerve sections. These findings indicate that human anti-ChSs antibodies are broadly reactive and not specific to any neurological disease.

Topics: Absorption; Antibodies; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Humans; Immune Sera; Motor Neuron Disease; Multiple Sclerosis; Myelitis; Nervous System Diseases; Statistics as Topic; Sulfoglycosphingolipids

Antibodies to chondroitin sulfate C (ChS C) have been previously associated with sensory axonal neuropathy. Investigation of these antibodies has, however, been limited by the lack of a sensitive and reliable test for their detection. We developed a new enzyme-linked immunoassorbent assay (ELISA), where biotinylated ChS C was made to adhere to avidin-coated microwells. The new ELISA showed a much greater sensitivity than other currently available ELISAs for detection of anti-ChS C antibodies. A total of 480 sera (466 patients and 14 normal volunteers) were tested at increasing dilutions for anti-ChS C antibody activity. Normal subjects had IgM anti-ChS C antibody titers of up to 3,200 and mildly elevated titers of 6,400 were seen in a variety of diseases. Eleven patients had titers of 12,800 or higher. These included seven patients with sensory axonal neuropathy, three with amyotrophic lateral sclerosis and one with corticobasal ganglionic degeneration. These studies indicate that anti-ChS antibodies do occur in patients with axonal sensory neuropathy, but are not limited to that disease.

Topics: Antibodies, Monoclonal; Antibody Specificity; Autoantibodies; Biotin; Chondroitin Sulfates; Enzyme-Linked Immunosorbent Assay; Humans; Immunoblotting; Immunoenzyme Techniques; Immunoglobulin M; Motor Neurons; Nervous System Diseases; Neurons, Afferent

We have studied the specificities of two human monoclonal, IgM containing sera, s/IgMMAC and s/IgMFIS, from patients with polyneuropathy. s/IgMMAC precipitates only with chondroitin sulfate C and not with A and B whereas s/IgMFIS is precipitated by chondroitins A, B (dermatan sulfate), and C. Inhibition assays using 2-acetamido-2-deoxy-3-O-(4-deoxy-beta-L-threo-hex-4-enopyranosyluroni c acid)-D-galactose and its 6- and 4-sulfate derivatives showed that the disaccharide 6-sulfate was the best inhibitor of precipitation of s/IgMMAC by chondroitin sulfate C, and the disaccharide 4-sulfate the best inhibitor of precipitation of s/IgMFIS by either chondroitin sulfates C or B. The nonsulfated disaccharide was a good inhibitor in each instance. D-Glucose 6-sulfate, Na2SO4, several sugar phosphates, and phosphate buffer also inhibited but to different extents with the s/IgMMAC and s/IgMFIS. All studies were carried out in 0.15M NaCl. The data indicate that both monoclonal proteins are antibodies comparable to the phosphorylcholine-binding myeloma proteins, and that the reactions show specificities above and beyond charge effects. The relation of various cross-reacting macromolecules to the monoclonal antibody was studied by diffusion in gels.

Topics: Antibodies, Monoclonal; Antigen-Antibody Complex; Carbohydrates; Chondroitin; Chondroitin Sulfates; Epitopes; Humans; Immunoglobulin M; Nervous System Diseases; Structure-Activity Relationship

Topics: Adult; Age Factors; Aged; Calcinosis; Chondroitin Sulfates; Endocrine System Diseases; Humans; Joint Diseases; Middle Aged; Nervous System Diseases; Vascular Diseases