Demystifying the extracellular matrix and its proteolytic remodeling in the brain: structural and functional insights

Abstract

The extracellular matrix (ECM) plays diverse roles in several physiological and pathological conditions. In the brain, the ECM is unique both in its composition and in functions. Furthermore, almost all the cells in the central nervous system contribute to different aspects of this intricate structure. Brain ECM, enriched with proteoglycans and other small proteins, aggregate into distinct structures around neurons and oligodendrocytes. These special structures have cardinal functions in the normal functioning of the brain, such as learning, memory, and synapse regulation. In this review, we have compiled the current knowledge about the structure and function of important ECM molecules in the brain and their proteolytic remodeling by matrix metalloproteinases and other enzymes, highlighting the special structures they form. In particular, the proteoglycans in brain ECM, which are essential for several vital functions, are emphasized in detail.

Keywords: Brain; Extracellular matrix; Matrix remodeling; Nodes of Ranvier; Perineuronal nets; Proteases; Synapses.

Fig. 1

Diagrammatic sketch of the special ECM structures around the neurons. a The perineuronal net (PNN), which enwraps the soma and dendrites, is primarily made up of lecticans (aggrecan, versican, neurocan and brevican) that are bound to the hyaluronic acid (HA) backbone synthesized by the membrane bound enzyme hyaluronic acid synthetase (HAS). Lecticans are connected to HA with link proteins, which are crucial for the structure. Other molecules such as tenascin-R (TNR), which interact with PNN molecules, also play an important role in stabilizing the structure. b The gaps between the myelin sheaths, namely, the nods of Ranvier, are exposed to a myriad of ECM molecules through which it can interact with the adjacent astrocytes. These ECM molecules not only stabilize the nodes but also act as a regulator of neuron-glia communication. c Different ECM molecules present at pre-synaptic boutons and post-synaptic clefts interact dynamically. These molecular interactions regulate vital processes like synaptogenesis, neuronal migration and cell–cell communications