Abstract
Axon growth inhibitors generated by reactive glial scars play an important role in failure of axon regeneration after CNS injury in mature mammals. Among the inhibitory factors, chondroitin sulfate proteoglycans (CSPGs) are potent suppressors of axon regeneration and are important molecular targets for designing effective therapies for traumatic brain injury or spinal cord injury (SCI). CSPGs bind with high affinity to several transmembrane receptors, including two members of the leukocyte common antigen related (LAR) subfamily of receptor protein tyrosine phosphatases (RPTPs). Recent studies demonstrate that multiple intracellular signaling pathways downstream of these two RPTPs mediate the growth-inhibitory actions of CSPGs. A better understanding of these signaling pathways may facilitate development of new and effective therapies for CNS disorders characterized by axonal disconnections. This review will focus on recent advances in the downstream signaling pathways of scar-mediated inhibition and their potential as the molecular targets for CNS repair.
Highlights
Axonal disconnections in the CNS usually result in permeant dysfunction
Lecticans interact with carbohydrate and protein ligands in the extracellular matrix (ECM) to form the perineuronal nets (PNNs; Yamaguchi, 2000), which are primarily composed of hyaluronan, chondroitin sulfate proteoglycans (CSPGs), tenascin R, and link proteins
We focus on the progress that has been made recently in identifying CSPG signaling pathways and on their potential as the molecular targets for treating CNS injuries (Table 1), primarily in mammalian models
Summary
Glial scars play supportive role in tissue repair (Anderson et al, 2016), eventually they create an inhibitory environment for axon regeneration and contribute to functional loss after CNS injuries (Bradbury et al, 2002; Jones et al, 2003; Busch and Silver, 2007). Glial scars form a physical barrier and upregulate chondroitin sulfate proteoglycans (CSPGs) and other extracellular matrix (ECM) molecules, which potently inhibit regrowth of injured axons into and beyond the lesion (Bradbury et al, 2002; Jones et al, 2003; Busch and Silver, 2007). Lectican core proteins (size: 97–262 kD) are connected by a dominant chondroitin sulfate glycosaminoglycan
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