Matrix metalloproteinases, new insights into the understanding of neurodegenerative disorders

Abstract

Matrix metalloproteinases (MMPs) are a subfamily of zinc-dependent proteases that are responsible for degradation and remodeling of extracellular matrix proteins. The activity of MMPs is tightly regulated at several levels including cleavage of prodomain, allosteric activation, compartmentalization and complex formation with tissue inhibitor of metalloproteinases (TIMPs). In the central nervous system (CNS), MMPs play a wide variety of roles ranging from brain development, synaptic plasticity and repair after injury to the pathogenesis of various brain disorders. Following general discussion on the domain structure and the regulation of activity of MMPs, we emphasize their implication in various brain disorder conditions such as Alzheimer's disease, multiple sclerosis, ischemia/reperfusion and Parkinson's disease. We further highlight accumulating evidence that MMPs might be the culprit in Parkinson's disease (PD). Among them, MMP-3 appears to be involved in a range of pathogenesis processes in PD including neuroinflammation, apoptosis and degradation of α-synuclein and DJ-1. MMP inhibitors could represent potential novel therapeutic strategies for treatments of neurodegenerative diseases.

Keywords: MMP-3; Matrix metalloproteinases; Microglia; Neurodegenerative disorders; Parkinson’s disease.

Fig. 1.. Domain structure of matrix metalloproteinases family. All MMPs consist of a N-terminal signal peptide and a propeptide domain followed by a C-terminal catalytic domain. A propeptide domain contains a cysteine switch which forms complex with catalytic zinc in a catalytic domain inhibiting their enzymatic activity. MMP-7 and -26 have only the minimal domain. Most of MMPs have a linker (hinge-region) and hemopexin like domain at the C-terminal to a catalytic domain. MMP-11, -21 and -28 have a furin-activating motif, RX[K/R]R, at the C-terminal end of their propeptide domains. Two gelatinases, MMP-2 and -9, contain three fibronectin II like repeats in the catalytic domains. MMP-9 is the only MMP which has a heavily O-glycosylated hinge region. All membrane-anchored MMPs contain a furin-activating motif. MT4, -6-MMPs are anchored to the plasma membrane through GPI-anchor. MT1, -2, -3 and-5-MMPs are bound to the cell membrane through type I transmembrane domain while MMP-23 is through type II transmembrane domain. The C-terminal of MMP-23 contains cysteine array (Ca) and immunoglobulin (Ig)-like domain replacing hemopexin domain.

Fig. 2.. The role of MMP-3 in the pathogenesis of Parkinson’s disease. Emerging evidence suggests that MMP-3 plays a key role in dopaminergic neuronal degeneration. Under stress conditions, MMP-3 is induced in dopaminergic neurons generating proMMP-3. Activation of MMP-3 might be achieved in cytoplasm as well as extracellular space. Catalytically active MMP-3 (actMMP-3) triggers microglial activation resulting in release of proinflammatory cytokine such as IL-1β, TNF-α and IL-6. Microglial substrates for act MMP-3 and signaling event leading to microglial activation are yet to be elucidated. NADPH oxidase (NOX2)-mediated ROS generation was also observed in microglia treated with actMMP-3. In addition, MMP-3 could be also activated intracellularly by unknown serine proteases upon stress such as 6-OHDA or MPP+, a selective dopaminergic toxin. Activated MMP-3 could cleave α-synuclein into several fragments by C-terminal truncation. These fragmented peptides are prone to aggregate and result in increased cytotoxicity. MMP-3 could also degrade DJ-1 and impair its antioxidant function resulting in increased oxidative stress. Intracellular actMMP-3 is directly linked apoptotic pathway in dopaminergic cells as well.