Review
From barriers to bridges: chondroitin sulfate proteoglycans in neuropathology

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Emerging studies have revealed new roles for the neural extracellular matrix in neuropathologies. The structure of this matrix is unusual and uniquely enriched in chondroitin sulfate proteoglycans, particularly those of the lectican family. Historically, lecticans have attracted considerable interest in the normal and injured brain for their prominent roles as inhibitors of cellular motility, neurite extension and synaptic plasticity. However, these molecules are structurally heterogeneous, have distinct expression patterns and mediate unique interactions, suggesting that they might have other functions in addition to their traditional role as chemorepulsants. Here, we review recent work demonstrating unique modifications and structural microheterogeneity of the lecticans in the diseased CNS, which might relate to novel roles of these molecules in neuropathologies.

Section snippets

Extracellular matrix in the central nervous system

The extracellular matrix (ECM) of the CNS has become a novel research frontier in neural development and neuropathology for its involvement in essential neurodevelopmental processes, including cell migration, neurite extension, synaptogenesis and regulation of synaptic plasticity. Changes in the neural ECM have also been correlated with alterations in cellular motility and connectivity during CNS injury and disease. Understanding the molecules and processes that are involved in the organization

The lecticans: structure, expression and interactions of the matrix organizers

The lectican family is composed of four members in mammals: two of them (aggrecan and versican) are widely distributed, whereas the other two [neurocan and brain-enriched hyaluronan-binding protein (BEHAB), also known as brevican or B/b] are mainly restricted to the CNS [2]. All lecticans are secreted CSPGs with a structure that consists of a major globular domain at each end, joined by a stretched domain that carries the CS chains 2, 5 (Figure 1). The binding of the terminal domains to HA and

Lectican CSPGs in neural injury

The reactive gliosis that occurs after CNS injury results in the formation of a glial scar, which is rich in CSPGs, that acts as a barrier for the re-extension of axons from undamaged regions [19]. The lecticans are deposited in a dense fashion in the scar around the lesion site [20] and have been identified as the major group of neural CSPGs with inhibitory effects on growing axons both in vitro and in vivo 6, 7.

The inhibitory role of the lecticans on neurite regeneration has been

The lectican CSPGs in neurodegenerative pathologies

The role of neural CSPGs has not been studied in chronic neurodegenerative diseases as exhaustively as in acute neural injury. However, it is known that both CSPGs and heparan sulfate PGs (HSPGs) are upregulated in the advanced stages of at least some of these pathologies, and hypotheses on their putative etiological involvement in neurodegeneration have been proposed for over a quarter of a century 46, 47, 48, 49.

In amyloidopathies, which are characterized by extracellular plaques with

Lectican CSPGs in primary brain tumors: from ‘barriers’ to ‘bridges’

Gliomas, which are tumors of glial origin, are the most common and deadly primary tumors of the CNS because of their striking ability to infiltrate into the normal neural tissue [60]. The particularly insidious invasive behavior of malignant gliomas relies, in part, on their ability to overcome the normally inhibitory effect of the adult neural ECM. Glioma cells subvert the normal cell–matrix relationship by overexpressing or making their own altered versions of neural ECM molecules 61, 62,

Concluding remarks

The lectican family of CSPGs is a vastly heterogeneous group of multidomain glycoproteins that influences cellular positioning, motility and connectivity during neural development and disease. The molecular heterogeneity of these molecules supports various regulatory functions on processes such as cellular adhesion, process motility, and synaptic formation and regulation.

As the questions of Box 1 reveal, the CSPGs in the CNS have proved more complex than a relatively homogeneous group of

Glossary

Chondroitin sulfate (CS)
a GAG formed by the repetition of a unit of N-acetyl-galactosamine and glucuronic acid. It is never found free but only attached to the core protein of proteoglycans. Different subtypes of CS differ in their degree of sulfation: CS-A (chondroitin-4-sulfate); CS-C (chondroitin-6-sulfate), CS-D (chondroitin-2,6-sulfate) and CS-E (chondroitin-4,6-sulfate). CS-B is an isomer of CS-A that contains iduronic instead of glucuronic acid and is known as dermatan sulfate.
Glycoforms

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