
Chondroitin sulfate proteoglycans (CSPGs) are
proteoglycans
Proteoglycans are proteins that are heavily glycosylation, glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalent bond, covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a ...
consisting of a protein core and a
chondroitin sulfate
Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars (N-Acetylgalactosamine, N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan. A chondroit ...
side chain. They are known to be structural components of a variety of human tissues, including
cartilage
Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...
, and also play key roles in
neural development
The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field ...
and
glial scar
A glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the central nervous system. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and beg ...
formation. They are known to be involved in certain cell processes, such as
cell adhesion
Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as Cell_junction, cell junc ...
, cell growth, receptor binding, cell migration, and interaction with other
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
constituents.
They are also known to interact with
laminin
Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major constituents of the basement membrane, namely the basal lamina (the protein network foundation for most cells and organs). Laminins are vital to bi ...
,
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as col ...
,
tenascin
Tenascins are extracellular matrix glycoproteins. They are abundant in the extracellular matrix of developing vertebrate embryos and they reappear around healing wounds and in the stroma of some tumors.
Types
There are four members of the tena ...
, and
collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
.
CSPGs are generally secreted from cells.
Importantly, CSPGs are known to inhibit
axon
An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
regeneration after
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
injury. CSPGs contribute to glial scar formation post injury, acting as a barrier against new axons growing into the injury site.
CSPGs play a crucial role in explaining why the spinal cord doesn't self-regenerate after an injury.
General structure
Chondroitin sulfate proteoglycans are composed of a core protein and a sugar side chain. The core protein is generally a
glycoprotein
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
, and the side chains are
glycosaminoglycan
Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case o ...
(GAG) sugar chains attached through a
covalent bond
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...
.
The GAG side chains are of different lengths depending on the CSPG. Each GAG chain consists of a linear pattern of alternating
monosaccharide
Monosaccharides (from Greek '' monos'': single, '' sacchar'': sugar), also called simple sugars, are the simplest forms of sugar and the most basic units (monomers) from which all carbohydrates are built.
Chemically, monosaccharides are polyhy ...
units:
uronic acid
300px, The glucose.html" ;"title="Fischer projections of D-glucose">Fischer projections of D-glucose (left) and D-glucuronic acid (right). Glucose's terminal carbon's primary alcohol group has been oxidized to a carboxylic acid.
Uronic acids ...
and either
N-acetylglucosamine or
N-acetylgalactosamine.
Types
The following CSPGs have been identified:
*
Aggrecan
Aggrecan (ACAN), also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ''ACAN'' gene. This gene is a member of the lectican ( chondroitin sulfate pr ...
(CSPG1)
*
Versican
Versican is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the ''VCAN'' gene.
Versican is a large chondroitin sulfate proteoglycan with an apparent molecular mass of more than 1000kDa. I ...
(CSPG2)
*
Neurocan (CSPG3)
*
CSPG4
Chondroitin sulfate proteoglycan 4, also known as melanoma-associated chondroitin sulfate proteoglycan (MCSP) or neuron-glial antigen 2 (NG2), is a chondroitin sulfate proteoglycan that in humans is encoded by the ''CSPG4'' gene.
Function
CSP ...
(melanoma-associated chondroitin sulfate proteoglycan, NG2)
*
CSPG5
*
SMC3
Structural maintenance of chromosomes protein 3 (SMC3) is a protein that in humans is encoded by the SMC3 gene. SMC3 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin ...
(CSPG6, structural maintenance of chromosomes 3)
*
Brevican (CSPG7)
*
CD44
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhes ...
(CSPG8, cluster of differentiation 44)
*
Phosphacan
Neurocan, brevican, versican, and aggrecan all share similar
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
and
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...
domains.
Neural development
CSPGs play an active role in the neural development of postnatal babies. During development, CSPGs act as guidance cues for developing
growth cones
Growth may refer to:
Biology
*Auxology, the study of all aspects of human physical growth
*Bacterial growth
*Cell growth
*Growth hormone, a peptide hormone that stimulates growth
*Human development (biology)
*Plant growth
*Secondary growth, growt ...
.
CSPGs guide growth cones through the use of negative signals, as seen by the fact that growing axons avoid CSPG dense areas.
Tests done on embryonic roof plates, located on the dorsal midline of developing
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
s, support this. CSPGs were found near and around the embryonic roof plates that inhibited axon elongation through the spinal cord, and directed the axons in another direction, but were absent in roof plates that attracted axon elongation.
These results suggest that CSPGs act in neural development as an inhibitory signal to help guide growing axons.
Spinal cord injury
CSPGs have been implicated in inhibiting axonal regeneration and
neurogenesis
Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...
after
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
injury.
CSPGs are known to be part of the glial scar that forms post injury, acting as a barrier to prevent axon extension and regrowth.
Studies examining CSPG (neurocan, brevican, versican, and phosphacan) levels in rats before spinal cord injury and after spinal cord injury indicate that there is a large up-regulation of these CSPGs after injury is induced.
Neurocan, brevican, and versican levels are up-regulated one day post injury, and neurocan and versican remain elevated 4 weeks post injury (brevican remained elevated at 8 weeks post injury, the final time point in the study).
Phosphacan showed no up-regulation until 4 weeks post injury.
These results, along with previous results showing CSPGs inhibit axon growth, suggest that these four CSPGs work together to inhibit axon growth in spinal cord injury.
Regulation
Inhibition of EGFR inhibits CSPGs
Epidermal growth factor receptor
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor (biochemistry), receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligand (biochemistry ...
(EGFR) has been suggested to regulate CSPG function. Inhibiting EGFR has been shown to block the activities of certain CSPGs, including neurocan, phosphacan, versican, and aggrecan.
When EGFR was inactive, CSPGs had little effect on neurons.
As a result, neurogenesis occurred, with significantly longer and many more neurons forming than seen with EGFR active.
When EGFR is active, CSPG functioned normally, restricting neurogenesis.
Drugs manipulating EGFR may be helpful in preventing the adverse effects CSPGs have during spinal cord injury.
PTP-sigma is a CSPG receptor
PTP-sigma (a
transmembrane
A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...
protein tyrosine phosphatase
Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins:
: proteintyrosine phosphate + H2O = ...
) is a recently discovered receptor for CSPGs, and is important for proper CSPG function. PTP-sigma binds with very high affinity to CSPGs, specifically neurocan and aggrecan.
To simulate more physiological situations, researchers looked at PTP-sigma effects on spinal cord injury sites in mice. Mice with induced spinal cord injury lacking PTP-sigma showed significantly more axon regrowth, with normal amounts of CSPG present.
This suggests that without PTP-sigma, CSPGs cannot bind to anything to function properly at the site of a glial scar.
Because PTP-sigma is a functional receptor for CSPGs and promotes proper function of CSPGs, drugs manipulating PTP-sigma may help patients with spinal cord injury.
Interferon-gamma
Interferon-gamma
Interferon gamma (IFNG or IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. ...
(IFN-gamma) is a cytokine that is useful against fighting bacterial infections and helping to suppress tumors. It has also been shown to be beneficial in decreasing CSPG expression after spinal cord injury. Using immunohistochemistry, scientists have shown that CSPGs at the site of spinal cord injury in mice were significantly decreased when treated with IFN-gamma compared to mice without IFN-gamma treatments.
Control mice had 80% more levels of CSPGs after spinal cord injury compared to mice treated with IFN-gamma, and scientists suggest that IFN-gamma works by inhibiting
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
expression.
Rho/ROCK pathway mediates CSPGs
The CSPG inhibition of axon regrowth and neurogenesis post spinal cord injury has been shown to be associated with the
rho-associated protein kinase
Rho-associated protein kinase or Rho-associated coiled-coil kinase (ROCK) is a kinase belonging to the AGC (PKA/ PKG/PKC) family of serine-threonine specific protein kinases. It is involved mainly in regulating the shape and movement of cells by ...
(ROCK) pathway.
Studies have shown that when CSPGs inhibit axon growth in the glial scar, the ROCK pathway is activated.
However, using C3
transferase
In biochemistry, a transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved ...
and
Y27632, two inhibitors of the ROCK signaling pathway, researchers showed that neurogenesis and new neuron length both significantly increased.
With C3 transferase, there was a 57% increase in new neuron length, and Y27632 produced a 77% increase in length.
Neurogenesis was greatly improved, but not quantifiable. Deactivating the ROCK pathway greatly decreased CSPG inhibition of axon regrowth. These results indicate that the CSPG effect of neurogenesis inhibition is mediated through the ROCK pathway.
In disease
Chondroitin sulfate proteoglycans have been implicated in
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
,
stroke
Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
, and
epilepsy
Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
.
Alzheimer's
The two primary markers of Alzheimer's disease are
neurofibrillary tangles
Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...
(NFT) and
senile plaques
Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of amyloid beta (Aβ) protein that present mainly in the grey matter of the brain. Degeneration (medical), Degenerative neuronal ...
(SP). Studies have shown that CSPGs are present in the
frontal cortex
The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove betw ...
and
hippocampus
The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
NFTs and SPs of postmortem brains of Alzheimer's patients. CSPG-4 and CSPG-6 are both localized on the perimeter of NFTs and SPs, and were also found on dystrophic neurons as well.
Given CSPGs inhibitory effects, these results suggest that CSPGs play an important role in Alzheimer's Disease progression, and could be responsible for facilitating the regression of neurons around NFTs and SPs.
Medications that target the CSPGs in the NFT and SP may help to alleviate some of the symptoms of Alzheimer's disease.
Stroke
A stroke is a sudden loss of brain function due to either a blood clot or blood leakage in the brain. Often, a stroke seriously debilitates the patient. However, in those patients that do regain some brain function in affected areas, down-regulations of CSPGs are shown to occur. After stroke,
plasticity
Plasticity may refer to:
Science
* Plasticity (physics), in engineering and physics, the propensity of a solid material to undergo permanent deformation under load
* Behavioral plasticity, change in an organism's behavior in response to exposur ...
occurs in some regions of the brain and is associated with some return of brain function.
Rats that were able to recover from induced stroke had down-regulations of several CSPGs, including aggrecan, versican, and phosphacan
Rats that did not return any brain function did not have significant down-regulation of CSPGs. The reduction of CSPGs in rats that returned some brain function after stroke suggest that more neurological connections could be made with less CSPGs present. Medications that are able to down-regulate CSPGs may help return more brain function to stroke patients.
Epilepsy
Epilepsy is a
neurological disorder
Neurological disorders represent a complex array of medical conditions that fundamentally disrupt the functioning of the nervous system. These disorders affect the brain, spinal cord, and nerve networks, presenting unique diagnosis, treatment, and ...
characterized by excessive neurological activity in the brain, causing
seizures
A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
. Researchers have observed that CSPGs are somewhat removed from the brain in epilepsy patients.
Research has shown a decrease in phosphacan in both the temporal lobe and the hippocampus in epilepsy cases, suggesting that there CSPGs play a role in the control of axonal regrowth.
References
{{Glycoproteins
Human proteins
Proteoglycans
C-type lectins