New Insights into ADAMTS Metalloproteases in the Central Nervous System

Abstract

Components of the extracellular matrix (ECM) are key players in regulating cellular functions throughout the whole organism. In fact, ECM components not only participate in tissue organization but also contribute to processes such as cellular maintenance, proliferation, and migration, as well as to support for various signaling pathways. In the central nervous system (CNS), proteoglycans of the lectican family, such as versican, aggrecan, brevican, and neurocan, are important constituents of the ECM. In recent years, members of this family have been found to be involved in the maintenance of CNS homeostasis and to participate directly in processes such as the organization of perineural nets, the regulation of brain plasticity, CNS development, brain injury repair, axonal guidance, and even the altering of synaptic responses. ADAMTSs are a family of “A disintegrin and metalloproteinase with thrombospondin motifs” proteins that have been found to be involved in a multitude of processes through the degradation of lecticans and other proteoglycans. Recently, alterations in ADAMTS expression and activity have been found to be involved in neuronal disorders such as stroke, neurodegeneration, schizophrenia, and even Alzheimer’s disease, which in turn may suggest their potential use as therapeutic targets. Herein, we summarize the different roles of ADAMTSs in regulating CNS events through interactions and the degradation of ECM components (more specifically, the lectican family of proteoglycans).

The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair

“…Reduced reelin mRNA levels have been observed in schizophrenia patients [ 221 , 222 , 223 ] and in post-mortem studies in the hippocampus and cerebellum [ 223 ], basal ganglia [ 224 ] and cerebral cortex [ 225 , 226 ]. Reelin is cleaved by MMPs in vivo at two sites located after domains 2 and 6, between repeats 2 and 3 and repeats 6 and 7, resulting in the production of three fragments [ 227 ]. Catabolism of reelin, however, does not appear to decrease its bioactivity.…”

The Role of Extracellular Matrix in Human Neurodegenerative Diseases

“…Matrix remodeling is achieved by the tight regulation of production and degradation of its components; whilst this metabolism is normally slow, select challenges like growth [ 48 ], cell division [ 49 ] and migration [ 50 , 51 ], inflammation [ 52 , 53 ] or injury [ 54 , 55 , 56 ] enhance matrix transformation. Many enzymes contribute to this process, most notably members of the matrix metalloprotease family (MMPs) and their regulators: tissue inhibitors of metalloproteinases (TIMPs), tissue plasminogen activator (tPA), plasminogen activator inhibitor, ADAMTS family, the hyaluronidase/chondroitinase family [ 57 , 58 ] and their various subtypes [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. MMPs are endopeptidases which have a dominant role in extracellular matrix degradation in vivo.…”

“…Irrespective of subtypes, MMPs have zinc content of their active site which is the principal target of their specific inhibitors; TIMPs bind here to chelate their zinc content [ 67 , 68 ] without subtype selectivity [ 69 , 70 , 71 ]. Of note, TIMP-3 emerges as a more potent inhibitor of some of the ADAMTS proteins [ 72 , 73 ], another subtype of metalloproteases, which typically catalyze the degradation of proteoglycans belonging to the lectican family [ 59 ]. The serine protease tPA—besides its role in hemostasis—catalyzes the plasminogen-plasmin conversion in the central nervous system, thereby shaping laminin degradation and activation of trophic factors such as chemoattractant protein-1, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF).…”

Hyalectanase Activities by the ADAMTS Metalloproteases

“…Versican, aggrecan, neurocan and brevican are PGs which form the group of hyalectans, also known as lecticans, and participate in the organization of the ECM of different tissues. For instance, hyalectans and their interacting partners contribute to form a three-dimensional network to control neurite outgrowth in the central nervous system (CNS) [ 44 , 45 ]. Structurally, hyalectans share a common hallmark consisting in a central region containing attachment sites for glycosaminoglycans.…”