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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.

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Fig. 1

Abbreviations

AMPAR:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

AP-1:

Activator protein 1

ASD:

Autism spectrum disorders

Bral:

Brain-specific hyaluronan-binding protein

CAM:

Cell adhesion molecule

Cbln:

Cerebellin

CNS:

Central nervous system

CREB:

cAMP-response element-binding

CRP:

Complement regulatory protein

CSPG:

Chondroitin sulfate proteoglycan

DCC:

Deleted in colorectal cancer

ECD:

Extracellular domain

ECM:

Extracellular matrix

GAG:

Glycosaminoglycan

HA:

Hyaluronic acid

HAPLN1:

Hyaluronan and proteoglycan link protein 1

HAS:

Hyaluronan synthase

HSPG:

Heparin sulfate proteoglycan

LTD:

Long-term depression

LTP:

Long-term potentiation

L-VDCC:

l-type voltage-dependent Ca2+ channels

MMP:

Matrix metalloproteinase

NMDAR:

N-methyl-d-aspartate receptor

Narp:

Neuronal activity-regulated pentraxin

NF-186:

Neurofascin-186

NGC:

Neuroglycan C

NrCAM:

Neuron–glia-related cell adhesion molecule

PNN:

Perineuronal net

PSI:

Phosphacan short isoform

PTR:

Proteoglycan tandem repeat

RPTP:

Receptor-type protein-tyrosine phosphatase

SGGL:

Sulfoglucuronyl glycolipid

SNAP-25:

Synaptosomal nerve-associated protein 25

TIMP:

Tissue inhibitor of MMPs

TNC:

Tenascin-C

TNR:

Tenascin-R

tPA:

Tissue plasminogen activator

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Acknowledgements

Irit Sagi is an Incumbent of the Maurizio Pontecorvo Professorial Chair and has received funding from the Israeli Science Foundation (1226/13), the European Research Council AdG (THZCALORIMETRY—DLV-695437), and the USA-Israel Binational Science Foundation (712506-01). She is grateful for the Azrieli Foundation for its generous grant to conduct research on the extracellular matrix of the brain.

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Krishnaswamy, V.R., Benbenishty, A., Blinder, P. et al. Demystifying the extracellular matrix and its proteolytic remodeling in the brain: structural and functional insights. Cell. Mol. Life Sci. 76, 3229–3248 (2019). https://doi.org/10.1007/s00018-019-03182-6

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Keywords

  • Brain
  • Extracellular matrix
  • Matrix remodeling
  • Nodes of Ranvier
  • Perineuronal nets
  • Proteases
  • Synapses