Chondroitin sulfate proteoglycan
Chondroitin sulfate proteoglycans (CSPGs) are proteoglycans consisting of a protein core and a chondroitin sulfate side chain. They are known to be structural components of a variety of human tissues, including cartilage, and also play key roles in neural development and glial scar formation. They are known to be involved in certain cell processes, such as cell adhesion, cell growth, receptor binding, cell migration, and interaction with other extracellular matrix constituents. They are also known to interact with laminin, fibronectin, tenascin, and collagen. CSPGs are generally secreted from cells.
Importantly, CSPGs are known to inhibit axon regeneration after spinal cord 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.
Chondroitin sulfate proteoglycans are composed of a core protein and a sugar side chain. The core protein is generally a glycoprotein, and the side chains are glycosaminoglycan (GAG) sugar chains attached through a covalent bond. The GAG side chains are of different lengths depending on the CSPG. Each GAG chain consists of a linear pattern of alternating monosaccharide units: uronic acid and either N-acetylglucosamine or N-acetylgalactosamine.
Types of CSPGs
The following CSPGs have been identified:
- Aggrecan (CSPG1)
- Versican (CSPG2)
- Neurocan (CSPG3)
- CSPG4 (melanoma-associated chondroitin sulfate proteoglycan, NG2)
- SMC3 (CSPG6, structural maintenance of chromosomes 3)
- Brevican (CSPG7)
- CD44 (CSPG8, cluster of differentiation 44)
CSPGs play an active role in the neural development of postnatal babies. During development, CSPGs act as guidance cues for developing growth cones. 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 cords, 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 after central nervous system 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, preventing regrowth up to 82%. Studies examining CSPG (neurocan, brevican, phosphacan, and versican) levels before spinal cord injury and after spinal cord injury indicate that there is a large up-regulation of these CSPGs after injury is induced, suggesting this up-regulation helps to inhibit axon growth. Neurocan, brevican, and versican levels are up-regulated as early as one day post injury, and all of these levels peak at 2 weeks post injury. These CSPG levels all returned to normal roughly 4 weeks post injury. Phosphacan showed no up-regulation one day post injury, and did not have any significant up-regulation until 4 weeks. Phosphacan levels peaked 8 weeks post injury. These results suggest that these four CSPGs work together to inhibit neurogenesis.
Inhibition of EGFR inhibits CSPGs
Epidermal growth factor receptor (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 protein tyrosine phosphatase) 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 suffering from spinal cord injury.
Interferon-gamma (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 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 (ROCK) pathway. Studies have shown that when CSPGs inhibit axon growth in the glial scar, the ROCK pathway is activated. However, using C3 transferase 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.
CSPGs in disease
The two primary markers of Alzheimer's disease are neurofibrillary tangles (NFT) and senile plaques (SP). Studies have shown that CSPGs are present in the frontal cortex and hippocampus 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.[clarification needed]
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 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.[clarification needed]
Epilepsy is a neurological disorder characterized by excessive neurological activity in the brain, causing seizures. 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.
- Rhodes, K. E.; Fawcett, J. W. (2004). "Chondroitin sulphate proteoglycans: Preventing plasticity or protecting the CNS?". Journal of Anatomy 204 (1): 33–48. doi:10.1111/j.1469-7580.2004.00261.x. PMC 1571240. PMID 14690476.
- Siebert, J. R.; Osterhout, D. J. (2011). "The inhibitory effects of chondroitin sulfate proteoglycans on oligodendrocytes". Journal of Neurochemistry 119 (1): 176–188. doi:10.1111/j.1471-4159.2011.07370.x. PMID 21848846.
- Jones, L. L.; Margolis, R. U.; Tuszynski, M. H. (2003). "The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury". Experimental neurology 182 (2): 399–411. doi:10.1016/S0014-4886(03)00087-6. PMID 12895450.
- Snow, D. M.; Steindler, D. A.; Silver, J. (1990). "Molecular and cellular characterization of the glial roof plate of the spinal cord and optic tectum: A possible role for a proteoglycan in the development of an axon barrier". Developmental biology 138 (2): 359–376. doi:10.1016/0012-1606(90)90203-u. PMID 1690673.
- Siebert JR, Conta Steencken A, Osterhout DJ (September 2014). "Chondroitin Sulfate Proteoglycans in the Nervous System: Inhibitors to Repair". Biomed Res Int 2014: 845323. doi:10.1155/2014/845323. PMC 4182688. PMID 25309928.
- Monnier, P. P.; Sierra, A.; Schwab, J. M.; Henke-Fahle, S.; Mueller, B. K. (2003). "The Rho/ROCK pathway mediates neurite growth-inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar". Molecular and cellular neurosciences 22 (3): 319–330. doi:10.1016/s1044-7431(02)00035-0. PMID 12691734.
- Koprivica, V.; Cho, K. S.; Park, J. B.; Yiu, G.; Atwal, J.; Gore, B.; Kim, J. A.; Lin, E.; Tessier-Lavigne, M.; Chen, D. F.; He, Z. (2005). "EGFR Activation Mediates Inhibition of Axon Regeneration by Myelin and Chondroitin Sulfate Proteoglycans". Science 310 (5745): 106–110. doi:10.1126/science.1115462. PMID 16210539.
- Shen, Y.; Tenney, A. P.; Busch, S. A.; Horn, K. P.; Cuascut, F. X.; Liu, K.; He, Z.; Silver, J.; Flanagan, J. G. (2009). "PTPσ is a Receptor for Chondroitin Sulfate Proteoglycan, an Inhibitor of Neural Regeneration". Science 326 (5952): 592–596. doi:10.1126/science.1178310. PMC 2811318. PMID 19833921.
- Fujiyoshi, T.; Kubo, T.; Chan, C. C. M.; Koda, M.; Okawa, A.; Takahashi, K.; Yamazaki, M. (2010). "Interferon-γ Decreases Chondroitin Sulfate Proteoglycan Expression and Enhances Hindlimb Function after Spinal Cord Injury in Mice". Journal of Neurotrauma 27 (12): 2283–2294. doi:10.1089/neu.2009.1144. PMID 20925481.
- Dewitt, D. A.; Silver, J.; Canning, D. R.; Perry, G. (1993). "Chondroitin Sulfate Proteoglycans Are Associated with the Lesions of Alzheimer's Disease". Experimental Neurology 121 (2): 149–152. doi:10.1006/exnr.1993.1081. PMID 8339766.
- Galtrey, C. M.; Fawcett, J. W. (2007). "The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system". Brain Research Reviews 54 (1): 1–18. doi:10.1016/j.brainresrev.2006.09.006. PMID 17222456.