Metalloproteinases in biology and pathology of the nervous system

Abstract

Matrix metalloproteinases (MMPs) and ADAMs (a disintegrin and metalloproteinase) are part of a larger family of structurally related zinc-dependent metalloproteinases called metzincins. Structurally, MMPs are divided in three domains: an amino-terminal propeptide region, an amino-terminal catalytic domain, and a carboxy-terminal domain that is involved in substrate binding. ADAMs have a prodomain, a metalloprotease region, a disintegrin domain for adhesion, a cysteine-rich region, epidermal-growth-factor repeats, a transmembrane module and a cytoplasmic tail. The activity of MMPs is tightly regulated in several ways: at the level of transcription, by post-translational modifications such as proteolysis, and through the action of endogenous tissue inhibitors of metalloproteinases. The regulation of ADAMs is less well understood, although there is some evidence that the same three levels of regulation might control ADAM activity. MMPs and ADAMs have been implicated in neuroinflammation and multiple sclerosis (MS), in the pathogenesis of malignant gliomas, and in other neurological conditions such as stroke, viral infections and Alzheimer's disease. In the case of ADAMs, their role in these pathological states has begun to be explored, but the available literature is still in its infancy. Although the detrimental roles of metalloproteinases are well documented, some of their functions in the central nervous system (CNS) might be beneficial. For example, some metalloproteinases are expressed in the CNS during development, pointing to a possible role in brain maturation. Similarly, metalloproteinases have been implicated in myelinogenesis and axon growth. Furthermore, metalloproteinases are upregulated after injury to the CNS, indicating a possible relevance to tissue repair. Several challenges remain in the study of metalloproteinases and their role in brain function. It will be necessary to understand the balance between the beneficial and detrimental roles of MMPs to determine whether they can be used as targets for therapeutic intervention. It will also be important to identify the physiological substrates of the different metalloproteinases, and to develop selective antagonists against the various members of the metalloproteinase families; the lack of such tools constitutes one of the main limitations to the growth of the field at present.