Chondroitin Sulfate Proteoglycans in CNS Development and Pathophysiology

Chondroitin sulfate proteoglycans (CSPGs) are major components of the matrix in many tissues including the central nervous system (CNS). Interactions between extracellular CSPGs and different cell types are crucial for the development of the CNS as CSPGs are heavily involved in maintaining the pool of progenitors, neurogenesis, neuronal migration and maturation, cortical lamination, synapse formation and stabilization, neuronal plasticity, and memory formation. CSPGs play distinct roles in CNS development and pathology. While physiologic levels of CSPGs have key roles in CNS development, CNS pathologies result in upregulation of CSPGs that pose a barrier to neuroregeneration. Extensive evidence shows that pathologic CSPGs interfere with various regenerative mechanisms including axonal elongation, immunomodulation, synaptogenesis, cellular replacement, and remyelination. At the cellular level, CSPGs' effects are mainly mediated through activation of leukocyte common antigen-related receptor (LAR) and protein tyrosine phosphatase sigma (PTP-σ) receptors. Various approaches have been developed to overcome the inhibitory effects of pathologic CSPGs including enzymatic degradation of CSPGs, blocking CSPG/LAR/PTP-σ axis, and inhibition of CSPGs synthesis. Here, we will discuss the current understanding on the role and mechanisms of CSPGs in CNS development and pathologies and signaling pathways that mediate CSPGs' effects in the CNS. We will also review how CSPGs have been modulated in neurological disorders.