Metalloproteinases in nervous system function and pathology: introduction

Abstract

This multi-author review in CMLS includes ten articles that provide an update of current knowledge on the role of metalloproteinases in the physiology and pathology of the central nervous system. The collection covers a wide range of situations in which matrix metalloproteinases, adamalysins and meprins are regulated and in turn regulate substrates or signalling pathways involved in: nervous system development, learning and memory, neuroinflammation, degeneration and repair after traumatic and ischemic injury or neurodegenerative mechanisms underlying retinopathies, psychiatric and neurodegenerative disorders. The authors also argue that these proteinases can be considered in some cases as biomarkers or potential therapeutic targets for diseases of the nervous system. Overall, metalloproteinases are placed among the key factors that can help us better understand the cellular and molecular processes that govern neuropathophysiology and implement the strategies that result from this knowledge to open up much-needed treatment opportunities.

Metalloproteinases constitute the largest group of proteolytic enzymes in the animal kingdom. Matrix metalloproteinases (MMP), a disintegrin and metalloproteinase (ADAM) and meprins are part of the metzincin metalloproteinase superfamily, which will be discussed in the various reviews in this multi-author-review in CMLS. Although these metalloproteinases are involved in all the fundamental biological mechanisms of living organisms, the idea that they could have significant functions in the central nervous system (CNS) initially encountered conceptual resistance that could be summarized in two main questions: (1) how to integrate degrading proteolytic activities into a “stable” network of billions of interconnected neurons that finely orchestrate proper brain and spinal cord function?; (2) how to reconcile the role of metalloproteinases—at least MMPs—in the CNS in the absence of some of their main substrates, extracellular matrix proteins (ECM)? These questions are no longer relevant as we now know that continuous remodelling of neural/neurovascular networks is carried out in a proteolysis-dependent manner during physiological and post-injury plasticity. In addition, we have learnt that ECM is indeed present in the brain and supports neural plasticity, thus contributing to the integration of environmental stimuli and the provision of appropriate cognitive and adaptive behavioural responses. Another critical step that has helped to consolidate the role of metalloproteinases in the nervous system has been the discovery in recent years of many new pericellular and intracellular non-matrix substrates, including signalling and cell adhesion molecules, transmembrane receptors, nuclear proteins and inflammatory mediators, with the consequent identification of new functions associated with these interactions. In addition, it can be anticipated that new functions will also be discovered with the emergence of non-proteolytic interactions of metalloproteinases with other proteins and even with nucleic acids.

Our knowledge of the biology of metalloproteinases has increased considerably over the past two decades, confirming their involvement in the control of neural network remodelling, neuron–glial cell intercommunication, neuroinflammatory and neuroimmune interactions, proteostasis, blood–brain barrier (BBB) function, neuronal survival and death, neuronal activity, cognition and behaviour. The activity of metalloproteinases is tightly controlled, particularly at the post-translational level by metalloproteinase tissue inhibitors (TIMPs). These are generally produced in excess of their enzymatic targets, thus ensuring proteolytic balance and tissue homeostasis; the loss of this balance can then lead to pathology. In this context, the multifaceted nature and importance of their functions place metalloproteinases as potential biomarkers and/or therapeutic targets in a number of neural disorders and lesions. The prospects for effective therapeutic targeting of metalloproteinases require, however, the establishment of conditions for the specific modulation of a given enzyme (or subset of enzymes) in a given spatio–temporal context. To this end, we need to better understand the beneficial and harmful interactions between metalloproteinases and their molecular and cellular environments, and implement innovative drug discovery strategies that interfere with the former while sparing the latter. These objectives are the backbone of this unique multi-author-review of CMLS, which brings together ten leading teams in the field to critically examine the current state of knowledge on metalloproteinases in the nervous system.

Hsia et al. [1] open this series of articles on the regulation and functions of ADAMs in the nervous system. The article describes a detailed and insightful scenario of the diversity and complexity of each ADAM’s physiological and pathological roles, mainly based on the interplay with their substrates, whether through proteolytic or non-proteolytic interactions. The authors discuss at the end the potential use of ADAMs as biomarkers or therapeutic targets in neurological and psychiatric disorders.

Chopra et al. [2] take us on a journey beyond the matrix with the role of MMPs in the regulation of cytokines and chemokines, and their impact on CNS pathologies, with a particular focus on interferon. They remind us that non-matrix substrates represent about 70% of the total number of MMP substrates, challenging our traditional perception of MMP in terms of functional diversity, with the emergence of a range of new functions that are both harmful and protective. The authors also point out that these new substrates can themselves become targets for indirectly modulating the detrimental effects of MMPs without affecting their benefits.

Muri et al. [3] discuss the role of MMPs and ADAMs on neuroinflammatory processes associated with neuroinfectious diseases and multiple sclerosis. They stress the importance of critically examining the control of metalloproteinases on spatio-temporal events affecting BBB permeability and immune cell infiltration to limit the therapeutic window to the harmful phase that precedes regeneration. The authors are confident that current knowledge of these phenomena makes it possible to reconsider the therapeutic inhibition of metalloproteinases in these inflammatory diseases, provided that the inhibitors are properly administered and dosed.

Montaner et al. [4] focus on the role of MMPs and ADAMs in acute ischemic stroke and other neurovascular diseases such as small vessel disease and intracerebral haemorrhages, with a particular interest in BBB function and the resulting neuroinflammatory regulation. Like the previous review, the authors caution against chronic use of metalloproteinase inhibitors after stroke, as they may interfere with the post-lesion repair functions of enzymes. They finally discuss the integration of circulating MMPs and ADAMs in a panel of guiding prognostic biomarkers for decision-making in stroke.

Trivedi et al. [5] highlight in detail the dynamics of pathological and repair events following brain and spinal cord injury. They dissect in a specific temporal and cellular context the expression of different MMPs and their potential role in neurovascular, axonal and synaptic lesions during the acute phase, then during regeneration and glial scar formation. The use of MMP inhibitors in the acute phase is discussed in ongoing clinical trials in dogs with spinal cord injuries.

An interesting study by Opdenakker and Abu El-Asrar [6] examines new evidence that MMPs and ADAMs, and their interaction with TIMPs, can help control retinal neuropathy and diabetes-induced vasculopathy. The authors highlight regulatory mechanisms that collectively involve hypoxia, inflammation and oxidative stress to activate certain metalloproteinases such as MMP-9, which may play an important role in eye diseases. The authors also discuss the use of metalloproteinases as biomarkers or targets at specific stages of retinopathy.

Rivera et al. [7] discuss metalloproteinases and TIMPs in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. They place metalloproteinases at the crossroads of neuroinflammation, proteostasis and synaptic dysfunction, which are major common features of many neurodegenerative diseases. The functional duality of metalloproteinases is also highlighted, especially for membrane-bound MMPs (MT-MMP), which bring new insights into the metabolism of amyloid precursor protein (APP) and Alzheimer’s pathogenesis.

In the same vein, Scharfenberg et al. [8] propose an original topic on the recently discovered molecular interactions involving the shedding of meprin-β by ADAM10, and the functional consequences that could result from such interaction. Arguments are put forward to defend the idea that meprin-β is a new β-secretase, whose function has an impact on the physiological and pathological processing of APP, thus opening new avenues for better understanding the pathology of Alzheimer’s disease.

Beroun et al. [9] bring us into the field of neuropsychiatric disorders to defend the idea that MMPs are essential for the control of synaptic plasticity in diseases such as epilepsy, schizophrenia, autism, fragile X syndrome, dependence or depression. The authors point out that MMPs modulate the perisynaptic environment and major neurotransmitter receptors, thus helping to regulate neuronal activity and learning processes through mechanisms still poorly understood that go beyond traditional neurotransmitter–receptor interactions.

Finally, Krishnaswamy et al. [10] close this collection by analysing the structure and function of ECM in the brain, whose presence was still debated not so long ago. This may be the reason why this subject is still under-explored in the field of neuroscience, despite growing evidence of the importance of ECM in ensuring the structure of neural networks and synapses and proper brain functioning. The data outlined here also reflect ongoing efforts to decipher how metalloproteinases and other proteolytic enzymes modulate ECM and the resulting possible functional impact.

I was honoured to be the guest editor of this multi-author-review of CMLS on “Metalloproteinases in Nervous System Function and Pathology”. I would like to thank all the colleagues who have contributed to this collective effort, which demonstrates the strength of the field at a time when metalloproteinases are facing profound changes in the principles that have defined until now their cellular distribution, their mode of action, their molecular interactions and ultimately their functions. We are entering a new era that promises to be rich in exciting fundamental discoveries about proteolytic—and non-proteolytic—mechanisms that help us to better understand how the nervous system works and to better fight its dysfunctions.