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

Krishnaswamy, V.; Benbenishty, Amit; Blinder, Pablo; Sagi, Irit

doi:10.1007/s00018-019-03182-6

Cited by 72 publications

(84 citation statements)

References 285 publications

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“…Resident OPCs are recruited at the lesion sites, proliferate and differentiate, but often they cannot become mature due to the presence of a highly inflammatory environment. Moreover, in response to lesions, virtually all the glial cells overproduce ECM components, in particular fibronectin and proteoglycans, whose inhibitory effect on remyelination and axonal regeneration is well documented [13]. Of note, ECM mechanical cues induce alteration in the activity of SREBP, a master regulator of lipid metabolism activated by the presence of sterol intermediates.…”

Section: Discussionmentioning

confidence: 99%

“…Although the ECM is one of the main elements that constitute the central nervous system (CNS) parenchyma, new roles for the ECM components in regeneration and repair responses to CNS injury have only recently been documented. Indeed, CNS ECM has emerged as an information-rich environment that can influence cell proliferation, differentiation, migration, synapse formation and remodeling, and responses to injury through the transmission of intracellular signals [13]. Highly relevant, recent studies highlight a link between ECM mechanical cues and alteration of lipid metabolism.Here, we describe crucial regulators and enzymes involved in lipid biosynthetic pathways showing their potential involvement as targets to promote remyelination.…”

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confidence: 99%

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Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

Marangon

Boccazzi

Lecca

et al. 2020

JCM

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Myelin is an essential structure that protects axons, provides metabolic support to neurons and allows fast nerve transmission. Several neurological diseases, such as multiple sclerosis, are characterized by myelin damage, which is responsible of severe functional impairment. Myelin repair requires the timely recruitment of adult oligodendrocyte precursor cells (OPCs) at the lesion sites, their differentiation and maturation into myelinating oligodendrocytes. As a consequence, OPCs undergo profound changes in their morphology, functions, and interactions with other cells and extracellular environment, thus requiring the reorganization of both their lipid metabolism and their membrane composition, which is substantially different compared to other plasma membranes. Despite the growing knowledge in oligodendroglia biology and in the mechanisms involved in OPC-mediated regeneration, the identification of strategies to promote remyelination still remains a challenge. Here, we describe how altered lipid metabolism in oligodendrocytes influences the pathogenesis of demyelination, and we show that several FDA-approved drugs with a previously unknown remyelination potential do act on cholesterol and lipid biosynthetic pathways. Since the interplay between myelin lipids and axons is strictly coordinated by the extracellular matrix (ECM), we also discuss the role of different ECM components, and report the last findings on new ECM-modifiers able to foster endogenous remyelination.Damage to myelin sheath is present in different severe neurological conditions such as multiple sclerosis (MS), brain ischemia, and amyotrophic lateral sclerosis (ALS). Loss of myelin ultimately results in reduction of nerve conduction velocity and in altered transfer of energy metabolites to neurons which contribute to disease [5,6]. Myelin repair, through the activation, recruitment and differentiation of adult oligodendrocyte precursor cells (OPCs), which become new myelin forming OLs [7], is crucial for limiting axon degeneration and progressive disease disability. During the remyelination process, OPCs undergo profound morphological and functional changes and progressively remodel their membrane composition, increasing the biosynthesis of cholesterol and galactosphingolipids, and reducing the relative amount of phospholipids and proteins [4]. An intricate interaction of environmental signals and cell-intrinsic mechanisms triggered by the immune and inflammatory response to injury is known to limit the regenerative potential of OPCs in MS [8,9]. However, the role of modulators of lipid metabolism in OPC-mediated repair is still not completely elucidated. Of note, recent studies suggest that targeting the lipid pathways in OLs may be a good strategy to promote remyelination [10].Furthermore, in MS, remyelination failure is also strictly correlated to an altered extracellular signaling microenvironment that, among others, affects the organization of OL membranes, which causes defects in myelin at the molecular level [11,12]. Although the ECM is ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

Marangon

Boccazzi

Lecca

et al. 2020

JCM

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“…cellular key events such as adhesion, differentiation, migration, proliferation as well as survival 43 (Hynes, 2009;Theocharidis et al, 2014;Faissner and Reinhard, 2015;Krishnaswamy et al, 2019;44 Roll and Faissner, 2019; Theocharis et al, 2019). ECM molecules can provide an inhibitory 45 environment for neural regeneration and migration in the retina (Reinhard et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Loss of the extracellular matrix molecule tenascin-C leads to absence of reactive gliosis and promotes anti-inflammatory cytokine expression in an autoimmune glaucoma mouse model

Wiemann¹,

Reinhard-Recht²,

Reinehr³

et al. 2020

Preprint

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“…The brain extracellular matrix (ECM) is a multicomponent macromolecular meshwork containing chondroitin sulfate carrying proteoglycans (CSPGs), which anchors to the neuronal surface via hyaluronic acid synthesizing enzymes (Krishnaswamy et al, 2019;Roll and Faissner, 2014). Neuronal activity induces the consolidation of ECM molecules (Dityatev et al, 2007) forming densely packed lattice-shaped layers around a subpopulation of neurons.…”

Section: Introductionmentioning

confidence: 99%

Extracellular matrix supports excitation-inhibition balance in neuronal networks by stabilizing inhibitory synapses

Dzyubenko

Fleischer

Manrique-Castano

et al. 2020

Preprint

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Maintaining the balance between excitation and inhibition is essential for the appropriate control of neuronal network activity. Sustained excitation-inhibition (E-I) balance relies on the orchestrated adjustment of synaptic strength, neuronal activity and network circuitry. While growing evidence indicates that extracellular matrix (ECM) of the brain is a crucial regulator of neuronal excitability and synaptic plasticity, it remains unclear whether and how ECM contributes to neuronal circuit stability. Here we demonstrate that the integrity of ECM supports the maintenance of E-I balance by retaining inhibitory connectivity. Depletion of ECM in mature neuronal networks preferentially decreases the density of inhibitory synapses and the size of individual inhibitory postsynaptic scaffolds. After ECM depletion, inhibitory synapse strength homeostatically increases via the reduction of presynaptic GABAB receptors. However, the inhibitory connectivity reduces to an extent that inhibitory synapse scaling is no longer efficient in controlling neuronal network state. Our results indicate that the brain ECM preserves the balanced network state by stabilizing inhibitory control.

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

Cited by 72 publications

References 285 publications

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

Loss of the extracellular matrix molecule tenascin-C leads to absence of reactive gliosis and promotes anti-inflammatory cytokine expression in an autoimmune glaucoma mouse model

Extracellular matrix supports excitation-inhibition balance in neuronal networks by stabilizing inhibitory synapses

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