Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of a critical sulfation in chondroitin that inhibits axonal regeneration.

ABSTRACT: The failure of mammalian CNS neurons to regenerate their axons derives from a combination of intrinsic deficits and extrinsic factors. Following injury, chondroitin sulfate proteoglycans (CSPGs) within the glial scar inhibit axonal regeneration, an action mediated by the sulfated glycosaminoglycan (GAG) chains of CSPGs, especially those with 4-sulfated (4S) sugars. Arylsulfatase B (ARSB) selectively cleaves 4S groups from the non-reducing ends of GAG chains without disrupting other, growth-permissive motifs. We demonstrate that ARSB is effective in reducing the inhibitory actions of CSPGs both in in vitro models of the glial scar and after optic nerve crush (ONC) in adult mice. ARSB is clinically approved for replacement therapy in patients with mucopolysaccharidosis VI and therefore represents an attractive candidate for translation to the human CNS.

SUBMITTER: Pearson CS

PROVIDER: S-EPMC5976435 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Identification of a critical sulfation in chondroitin that inhibits axonal regeneration.

Pearson Craig S CS Mencio Caitlin P CP Barber Amanda C AC Martin Keith R KR Geller Herbert M HM

eLife 20180515

The failure of mammalian CNS neurons to regenerate their axons derives from a combination of intrinsic deficits and extrinsic factors. Following injury, chondroitin sulfate proteoglycans (CSPGs) within the glial scar inhibit axonal regeneration, an action mediated by the sulfated glycosaminoglycan (GAG) chains of CSPGs, especially those with 4-sulfated (4S) sugars. Arylsulfatase B (ARSB) selectively cleaves 4S groups from the non-reducing ends of GAG chains without disrupting other, growth-permi ...[more]

PMID: 29762123

Similar Datasets

Chondroitin-4-sulfation negatively regulates axonal guidance and growth.

Project description:Glycosaminoglycan (GAG) side chains endow extracellular matrix proteoglycans with diversity and complexity based upon the length, composition and charge distribution of the polysaccharide chain. Using cultured primary neurons, we show that specific sulfation in the GAG chains of chondroitin sulfate mediates neuronal guidance cues and axonal growth inhibition. Chondroitin-4-sulfate (CS-A), but not chondroitin-6-sulfate (CS-C), exhibits a strong negative guidance cue to mouse cerebellar granule neurons. Enzymatic and gene-based manipulations of 4-sulfation in the GAG side chains alter their ability to direct growing axons. Furthermore, 4-sulfated chondroitin sulfate GAG chains are rapidly and significantly increased in regions that do not support axonal regeneration proximal to spinal cord lesions in mice. Thus, our findings show that specific sulfation along the carbohydrate backbone carries instructions to regulate neuronal function.

| S-EPMC2562295 | biostudies-literature

Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction.

Project description:Sympathetic denervation of the heart following ischemia/reperfusion induced myocardial infarction (MI) is sustained by chondroitin sulfate proteoglycans (CSPGs) in the cardiac scar. Denervation predicts risk of sudden cardiac death in humans. Blocking CSPG signaling restores sympathetic axon outgrowth into the cardiac scar, decreasing arrhythmia susceptibility. Axon growth inhibition by CSPGs can depend on the sulfation status of the glycosaminoglycan (CS-GAG) side chains. Tandem sulfation of CS-GAGs at the 4th (4S) and 6th (6S) positions of n-acetyl-galactosamine inhibits outgrowth in several types of central neurons, but we don't know if sulfation is similarly critical during peripheral nerve regeneration. We asked if CSPG sulfation prevented sympathetic axon outgrowth after MI. Reducing 4S with the 4-sulfatase enzyme Arylsulfatase-B (ARSB) enhanced outgrowth of dissociated rat sympathetic neurons over CSPGs. Likewise, reducing 4S with ARSB restored axon outgrowth from mouse sympathetic ganglia co-cultured with cardiac scar tissue. We quantified enzymes responsible for adding and removing sulfation, and found that CHST15 (4S dependent 6-sulfotransferase) was upregulated, and ARSB was downregulated after MI. This suggests a mechanism for production and maintenance of sulfated CSPGs in the cardiac scar. We decreased 4S,6S CS-GAGs in vivo by transient siRNA knockdown of Chst15 after MI, and found that reducing 4S,6S restored tyrosine hydroxylase (TH) positive sympathetic nerve fibers in the cardiac scar. Reinnervation reduced isoproterenol induced arrhythmias. Our results suggest that modulating CSPG-sulfation after MI may be a therapeutic target to promote sympathetic nerve regeneration in the cardiac scar and reduce post-MI cardiac arrhythmias.

| S-EPMC9197393 | biostudies-literature

Role of Chondroitin Sulfation Following Spinal Cord Injury.

Project description:Traumatic spinal cord injury produces long-term neurological damage, and presents a significant public health problem with nearly 18,000 new cases per year in the U.S. The injury results in both acute and chronic changes in the spinal cord, ultimately resulting in the production of a glial scar, consisting of multiple cells including fibroblasts, macrophages, microglia, and reactive astrocytes. Within the scar, there is an accumulation of extracellular matrix (ECM) molecules-primarily tenascins and chondroitin sulfate proteoglycans (CSPGs)-which are considered to be inhibitory to axonal regeneration. In this review article, we discuss the role of CSPGs in the injury response, especially how sulfated glycosaminoglycan (GAG) chains act to inhibit plasticity and regeneration. This includes how sulfation of GAG chains influences their biological activity and interactions with potential receptors. Comprehending the role of CSPGs in the inhibitory properties of the glial scar provides critical knowledge in the much-needed production of new therapies.

| S-EPMC7419623 | biostudies-literature

Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans.

Project description:Axotomized neurons within the damaged CNS are thought to be prevented from functional regeneration by inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors. Here, we provide a transgenic test of the role of CSPGs in limiting regeneration, using the gfap promotor to express a CSPG-degrading enzyme chondroitinase ABC (ChABC) in astrocytes. Corticospinal axons extend within the lesion site, but not caudal to it, after dorsal hemisection in the transgenic mice. The presence of the gfap-ChABC transgene yields no significant improvement in motor function recovery in this model. In contrast, functionally significant sensory axon regeneration is observed after dorsal rhizotomy in transgenic mice. These transgenic studies confirm a local efficacy for reduced CSPG to enhance CNS axon growth after traumatic injury. CSPGs appear to function in a spatially distinct role from myelin inhibitors, implying that combination-based therapy will be especially advantageous for CNS injuries.

| S-EPMC2848955 | biostudies-other

The nociceptin receptor inhibits axonal regeneration and recovery from spinal cord injury.

Project description:Axonal growth after traumatic spinal cord injury is limited by endogenous inhibitors, selective blockade of which promotes partial neurological recovery. The partial repair phenotypes suggest that compensatory pathways limit improvement. Gene expression profiles of mice deficient in Ngr1, which encodes a receptor for myelin-associated inhibitors of axonal regeneration such as Nogo, revealed that trauma increased the mRNA expression of ORL1, which encodes the receptor for the opioid-related peptide nociceptin. Endogenous and overexpressed ORL1 coimmunoprecipitated with immature NgR1 protein, and ORL1 enhanced the O-linked glycosylation and surface expression of NgR1 in HEK293T and Neuro2A cells and primary neurons. ORL1 overexpression inhibited cortical neuron axon regeneration independently of NgR1. Furthermore, regeneration was inhibited by an ORL1 agonist and enhanced by the ORL1 antagonist J113397 through a ROCK-dependent mechanism. Mice treated with J113397 after dorsal hemisection of the mid-thoracic spinal cord recovered greater locomotor function and exhibited lumbar raphespinal axon sprouting. These effects were further enhanced by combined Ngr1 deletion and ORL1 inhibition. Thus, ORL1 limits neural repair directly and indirectly by enhancing NgR1 maturation, and ORL1 antagonists enhance recovery from traumatic CNS injuries in wild-type and Ngr1 null mice.

| S-EPMC6179440 | biostudies-literature

Sulfation of the bikunin chondroitin sulfate chain determines heavy chain·hyaluronan complex formation.

Project description:Inter-?-trypsin inhibitor (I?I) is a complex comprising two heavy chains (HCs) that are covalently bound by an ester bond to chondroitin sulfate (CS), which itself is attached to Ser-10 of bikunin. I?I is essential for the trans-esterification of HCs onto hyaluronan (HA). This process is important for the stabilization of HA-rich matrices during ovulation and some inflammatory processes. Bikunin has been isolated previously by anion exchange chromatography with a salt gradient up to 0.5 M NaCl and found to contain unsulfated and 4-sulfated CS disaccharides. In this study, bikunin-containing fractions in plasma and urine were separated by anion exchange chromatography with a salt gradient of 0.1-1.0 M NaCl, and fractions were analyzed for their reactivity with the 4-sulfated CS linkage region antibody (2B6). The fractions that reacted with the 2B6 antibody (0.5-0.8 M NaCl) were found to predominantly contain sulfated CS disaccharides, including disulfated disaccharides, whereas the fractions that did not react with this antibody (0.1-0.5 M NaCl) contained unsulfated and 4-sulfated CS disaccharides. I?I in the 0.5-0.8 M NaCl plasma fraction was able to promote the trans-esterification of HCs to HA in the presence of TSG-6, whereas the 0.1-0.5 M NaCl fraction had a much reduced ability to transfer HC proteins to HA, suggesting that the CS containing 4-sulfated linkage region structures and disulfated disaccharides are involved in the HC transfer. Furthermore, these data highlight that the structure of the CS attached to bikunin is important for the transfer of HC onto HA and emphasize a specific role of CS chain sulfation.

| S-EPMC3743471 | biostudies-literature

HSV-mediated gene transfer of C3 transferase inhibits Rho to promote axonal regeneration.

Project description:Although surgical re-implantation of spinal roots may improve recovery of proximal motor function after cervical root avulsion, recovery of sensory function necessary for fine motor coordination of the hand has been difficult to achieve, in large part because of failure of regeneration of axons into the spinal cord. In order to enhance regeneration, we constructed a non-replicating herpes simplex virus (HSV)-vector carrying the gene coding for bacterial C3 transferase (C3t). Subcutaneous inoculation of the vector into the skin of the forepaw 1 week after a dorsal C5-T1 rhizotomy resulted in expression of C3t in dorsal root ganglion (DRG) neurons and inhibition of Rho GTPase activity, resulting in extensive axonal regeneration into the spinal cord that correlated with improved sensory-motor coordination of the forepaw.

| S-EPMC3418484 | biostudies-literature

Rabs and axonal regeneration.

Project description:Membrane trafficking processes are presumably vital for axonal regeneration after injury, but mechanistic understanding in this regard has been sparse. A recent loss-of-function screen had been carried out for factors important for axonal regeneration by cultured cortical neurons and the results suggested that the activity of a number of Rab GTPases might act to restrict axonal regeneration. A loss of Rab27b, in particular, is shown to enhance axonal regeneration in vitro, as well as in C. elegans and mouse central nervous system injury models in vivo. Possible mechanisms underlying this new finding, which has important academic and translational implication, are discussed.

| S-EPMC6352601 | biostudies-literature

Altered sulfation status of FAM20C-dependent chondroitin sulfate is associated with osteosclerotic bone dysplasia.

Project description:Raine syndrome, a lethal osteosclerotic bone dysplasia in humans, is caused by loss-of-function mutations in FAM20C; however, Fam20c deficiency in mice does not recapitulate the human disorder, so the underlying pathoetiological mechanisms remain poorly understood. Here we show that FAM20C, in addition to the reported casein kinase activity, also fine-tunes the biosynthesis of chondroitin sulfate (CS) chains to impact bone homeostasis. Specifically, FAM20C with Raine-originated mutations loses the ability to interact with chondroitin 4-O-sulfotransferase-1, and is associated with reduced 4-sulfation/6-sulfation (4S/6S) ratio of CS chains and upregulated biomineralization in human osteosarcoma cells. By contrast, overexpressing chondroitin 6-O-sulfotransferase-1 reduces CS 4S/6S ratio, and induces osteoblast differentiation in vitro and higher bone mineral density in transgenic mice. Meanwhile, a potential xylose kinase activity of FAM20C does not impact CS 4S/6S ratio, and is not associated with Raine syndrome mutations. Our results thus implicate CS 4S/6S ratio imbalances caused by FAM20C mutations as a contributor of Raine syndrome etiology.

| S-EPMC9792594 | biostudies-literature

C4ST-1/CHST11-controlled chondroitin sulfation interferes with oncogenic HRAS signaling in Costello syndrome.

Project description:Costello syndrome is a pediatric genetic disorder linked to oncogenic germline mutations in the HRAS gene. The disease is characterized by multiple developmental abnormalities, as well as predisposition to malignancies. Our recent observation that heart tissue from patients with Costello syndrome showed a loss of the glycosaminoglycan chondroitin-4-sulfate (C4S) inspired our present study aimed to explore a functional involvement of the chondroitin sulfate (CS) biosynthesis gene Carbohydrate sulfotransferase 11/Chondroitin-4-sulfotransferase-1 (CHST11/C4ST-1), as well as an impaired chondroitin sulfation balance, as a downstream mediator of oncogenic HRAS in Costello syndrome. Here we demonstrate a loss of C4S, as well as a reduction in C4ST-1 mRNA and protein expression, in primary fibroblasts from Costello syndrome patients. We go on to show that expression of oncogenic HRAS in normal fibroblasts can repress C4ST-1 expression, whereas interference with oncogenic HRAS signaling in Costello syndrome fibroblasts elevated C4ST-1 expression, thus identifying C4ST-1 as a negatively regulated target gene of HRAS signaling. Importantly, we show that forced expression of C4ST-1 in Costello fibroblasts could rescue the proliferation and elastogenesis defects associated with oncogenic HRAS signaling in these cells. Our results indicate reduced C4ST-1 expression and chondroitin sulfation imbalance mediating the effects of oncogenic HRAS signaling in the pathogenesis of Costello syndrome. Thus, our work identifies C4ST-1-dependent chondroitin sulfation as a downstream vulnerability in oncogenic RAS signaling, which might be pharmacologically exploited in future treatments of not only Costello syndrome and other RASopathies, but also human cancers associated with activating RAS mutations.

| S-EPMC3400726 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data