Metalloproteinases in biology and pathology of the nervous system

Abstract

Matrix metalloproteinases (MMPs) have been implicated in several diseases of the nervous system. Here we review the evidence that supports this idea and discuss the possible mechanisms of MMP action. We then consider some of the beneficial functions of MMPs during neural development and speculate on their roles in repair after brain injury. We also introduce a family of proteins known as ADAMs (a disintegrin and metalloproteinase), as some of the properties previously ascribed to MMPs are possibly the result of ADAM activity.

Figure 1. Domain structure of MMPs and ADAMs.

The generic structure of matrix metalloproteinases (MMPs) shown here describes most MMP family members. Note that gelatinases (MMP2 and -9) have a unique fibronectin type II-like domain inserted into the catalytic site, whereas MT-MMPs have a transmembrane domain at the carboxy terminus. Matrilysin (MMP7) lacks the hinge and the carboxyl terminus. The hemopexin-like module of MMPs contains four repeat units; the first and fourth are connected by a disulphide bridge. The 'C' at the propeptide region denotes the cysteine residue that ligates the zinc in the catalytic domain to keep the enzyme inactive. For ADAMs (a disintegrin and metalloproteinase), the core structure of most members is also depicted. Most ADAMs are integral membrane proteins owing to the presence of the transmembrane domain. However, alternative splicing generates a secreted form of some ADAMs. It should be noted that some ADAMs (ADAM2, -7, -11, -14, -18, -22 and -29) lack the intact zinc-binding site and, furthermore, that the metalloprotease domain is not retained in several mature proteins of this family (for example, ADAM1 and -2). These proteins are therefore not considered true degradative enzymes. Last, the ADAMTS proteins are ADAMs that contain one or more thrombospondin type I motifs at the carboxyl terminus. They are also distinguished from ADAMs by the lack of epidermal-growth-factor (EGF)-like, transmembrane and cytoplasmic domains.

Figure 2. Mechanisms by which MMPs contribute to neuropathology.

Leukocytes express matrix metalloproteinases (MMPs) to facilitate their entry into the central nervous system (CNS). This process disrupts the basement membrane that surrounds the vasculature and results in blood–brain barrier (BBB) impairment. In the central nervous system, high MMP content and its indiscriminate localization result in perpetuation of an inflammatory response, which contributes to demyelination and neuronal or oligodendrocyte death. ECM, extracellular matrix.

Figure 3. Metalloproteinases regulate axonal growth.

Several growth factors, including nerve growth factor (NGF), increase the expression of metalloproteinases (MPs) by neurons. MPs, in turn, regulate neurotrophic factor activity. One mechanism involves the release of growth factors that are anchored to the extracellular matrix (ECM). MPs that are located in the vicinity of growth cones can promote the elongation of axons owing to their ability to remodel the ECM and degrade inhibitory molecules such as the Nogo proteins. By interacting with molecules implicated in axonal guidance, for example, by shedding DCC (deleted in colorectal carcinoma) receptors or by breaking Eph receptor–ephrin bonds, MPs can affect the directional growth of axons.