Lectican proteoglycans, their cleaving metalloproteinases, and plasticity in the central nervous system extracellular microenvironment

Abstract

The extracellular matrix (ECM) in the central nervous system actively orchestrates and modulates changes in neural structure and function in response to experience, after injury, during disease, and with changes in neuronal activity. A component of the multi-protein, ECM aggregate in brain, the chondroitin sulfate (CS)-bearing proteoglycans (PGs) known as lecticans, inhibit neurite outgrowth, alter dendritic spine shape, elicit closure of critical period plasticity, and block target reinnervation and functional recovery after injury as the major component of a glial scar. While removal of the CS chains from lecticans with chondroitinase ABC improves plasticity, proteolytic cleavage of the lectican core protein may change the conformation of the matrix aggregate and also modulate neural plasticity. This review centers on the roles of the lecticans and the endogenous metalloproteinase families that proteolytically cleave lectican core proteins, the matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), in neural plasticity. These extracellular metalloproteinases modulate structural neural plasticity-including changes in neurite outgrowth and dendritic spine remodeling-and synaptic plasticity. Some of these actions have been demonstrated to occur via cleavage of the PG core protein. Other actions of the proteases include cleavage of non-matrix substrate proteins, whereas still other actions may occur directly at the cell surface without proteolytic cleavage. The data convincingly demonstrate that metalloproteinases modulate physiological and pathophysiological neural plasticity.

Figure 1

Schematic showing disruption of synaptic stability by proteolytic cleavage of lecticans present in perisynaptic extracellular matrix complexes as a hypotheitical means to stimulate structural plasticity at synapses. (A) Binding of brevican as part of the matrix aggregate to membrane associated hyaluronan adjacent to active sites of synapses promotes synaptic stability. Proteolytic cleavage of brevican, as illustrated in (B), completely dislocates the aggregate resulting in the production of C-terminal and smaller N-terminal fragments of brevican, and the freeing of tenascin-R from the aggregate. The lack of an intact matrix aggregate is thought to allow for structural neural plasticity. Abbreviations: Ig-like (immunoglobulin-like); HA binding (hyaluronic acid binding domains also known as proteoglycan tandem repeat); GAG attachment (glycosaminoglycan attachment regions where CS chains are covalently bound); CS (chondroitin sulfate); CRP-like (complement regulatory protein like motif).

Figure 2

Diagram of MMP and ADAMTS domain structures. (A-I) The minimal MMP domain structure includes the signal peptide, the pro-domain, and the catalytic domain with a zinc binding site (MMP-7 and -26). (A-II) Other MMPs also contain a hinge region as well as a hemopexin-like domain (MMP-1, -3, 8, 10, -11, -12, -13, -19, -20, -27, and -28). The gelatinases (MMP-2 and MMP-9) also contain three fibronectin type II domains. (A-III) Several MMP members are membrane bound with a transmembrane domain (MT1-MMP, MT2-MMP, MT3-MMP, and MT5-MMP) and contain a short cytoplasmic tail at the C-terminus. Other members are linked to the membrane via glycophosphatidylinositol (GPI) linkage (MT4-MMP and MT6-MMP). (B) The ADAMTS domain structure consists of a signal peptide, pro-domain, catalytic domain with a zinc binding site, a disnintegrin-like domain, a thrombospondin type-1 repeat, a cysteine-rich region, and a spacer region. The ADAMTS members differ with respect to additional domains at the C-terminus (including additional thrombospondin type 1 motifs). Shown in this figure is ADAMTS4, which contains no additional C-terminal domains.