Matrix metalloproteinases, purinergic signaling, and epigenetics, hubs in the spinal neuroglial network following nerve injury.

Abstract The neuroglial network characterizes synaptic transmission and accounts for both cellular elements (neurons and glia) and neural extracellular matrix (nECM) roles. Glial cells, neuron, and nECMnetwork is strongly interconnected, in physiological and pathological conditions as shownin several neurodegenerative diseases. Purinergic activation and matrix metalloproteinases (MMPs) remodeling of the spinal cord is pivotal in maladaptive plastic changes following peripheral nerve injury (PNI). To understand how purinergic and MMPs inhibition may modulate and potentially reverse the neuroglial network failure, we used the spared nerve injury (SNI) model of the sciatic nerve. Molecular and morphological analysis of astrocytic and microglial activation, purinergic and neurotrophic receptors, Histone Deacetylase (HDAC)1, HDAC2 were analyzed to define the pathways in response to the purinergic and MMPs inhibition. The data suggest complex protein interconnections, which are not passively influenced by epigenetics but actively contribute to modify the transcriptomics machinery. The present study contributes to unveiling the spinal network consistency and ultimately encourages new paths for targeted treatments in neurological diseases with benefits of neuroprotection, plasticity, and functional recovery.

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LIMK2-1, a new isoform of human LIMK2, regulates actin cytoskeleton remodeling via a different signaling pathway than that of its two homologs, LIMK2a and LIMK2b

Biochemical Journal ◽

10.1042/bcj20170961 ◽

2018 ◽

Vol 475 (23) ◽

pp. 3745-3761 ◽

Cited By ~ 2

Author(s):

Béatrice Vallée ◽

Hélène Cuberos ◽

Michel Doudeau ◽

Fabienne Godin ◽

David Gosset ◽

...

Keyword(s):

Actin Cytoskeleton ◽

Neurological Diseases ◽

Mrna Level ◽

Fiber Formation ◽

Actin Stress Fiber ◽

C Terminus ◽

Targeted Treatments ◽

Cytoskeleton Remodeling ◽

Inhibitory Domain ◽

Cytoskeleton Dynamics

LIMK1 and LIMK2 (LIMKs, LIM kinases) are kinases that play a crucial role in cytoskeleton dynamics by independently regulating both actin filament and microtubule remodeling. LIMK1 and, more recently, LIMK2 have been shown to be involved in cancer development and metastasis, resistance of cancer cells to microtubule-targeted treatments, neurological diseases, and viral infection. LIMKs have thus recently emerged as new therapeutic targets. Databanks describe three isoforms of human LIMK2: LIMK2a, LIMK2b, and LIMK2-1. Evidence suggests that they may not have completely overlapping functions. We biochemically characterized the three isoforms to better delineate their potential roles, focusing on LIMK2-1, which has only been described at the mRNA level in a single study. LIMK2-1 has a protein phosphatase 1 (PP1) inhibitory domain at its C-terminus which its two counterparts do not. We showed that the LIMK2-1 protein is indeed synthesized. LIMK2-1 does not phosphorylate cofilin, the canonical substrate of LIMKs, although it has kinase activity and promotes actin stress fiber formation. Instead, it interacts with PP1 and partially inhibits its activity towards cofilin. Our data suggest that LIMK2-1 regulates actin cytoskeleton dynamics by preventing PP1-mediated cofilin dephosphorylation, rather than by directly phosphorylating cofilin as its two counterparts, LIMK2a and LIMK2b. This specificity may allow for tight regulation of the phospho-cofilin pool, determining the fate of the cell.

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Novel sonomicrometry of ex vivo diaphragm after phrenic nerve injury: Role of matrix metalloproteinases

Synapse ◽

10.1002/syn.21552 ◽

2012 ◽

Vol 66 (8) ◽

pp. 677-685

Author(s):

Huan Wang ◽

Yukio Imamura ◽

Naoya Matsumoto ◽

Hong Wang ◽

Hiroshi Ogura ◽

...

Keyword(s):

Matrix Metalloproteinases ◽

Nerve Injury ◽

Phrenic Nerve ◽

Ex Vivo ◽

Phrenic Nerve Injury

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Nerve injury induces glial cell line-derived neurotrophic factor (gdnf) expression in schwann cells through purinergic signaling and the pkc-pkd pathway

Glia ◽

10.1002/glia.22491 ◽

2013 ◽

Vol 61 (7) ◽

pp. 1029-1040 ◽

Cited By ~ 28

Author(s):

Pin Xu ◽

Kenneth M. Rosen ◽

Kristian Hedstrom ◽

Osvaldo Rey ◽

Sushovan Guha ◽

...

Keyword(s):

Cell Line ◽

Glial Cell ◽

Schwann Cells ◽

Nerve Injury ◽

Neurotrophic Factor ◽

Purinergic Signaling

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Soluble Neuregulin1 is strongly up-regulated in the rat model of Charcot-Marie-Tooth 1A disease

Experimental Biology and Medicine ◽

10.1177/1535370218754492 ◽

2018 ◽

Vol 243 (4) ◽

pp. 370-374 ◽

Cited By ~ 6

Author(s):

Benedetta Elena Fornasari ◽

Giulia Ronchi ◽

Davide Pascal ◽

Davide Visigalli ◽

Giovanna Capodivento ◽

...

Keyword(s):

Growth Factor ◽

Peripheral Nerve ◽

Schwann Cells ◽

Nerve Injury ◽

Therapeutic Approach ◽

Neurological Diseases ◽

Gene Expression Pattern ◽

Charcot Marie Tooth ◽

Negative Role ◽

High Concentrations

Neuregulin1 (NRG1) is a growth factor playing a pivotal role in peripheral nerve development through the activation of the transmembrane co-receptors ErbB2–ErbB3. Soluble NRG1 isoforms, mainly secreted by Schwann cells, are strongly and transiently up-regulated after acute peripheral nerve injury, thus suggesting that they play a crucial role also in the response to nerve damage. Here we show that in the rat experimental model of the peripheral demyelinating neuropathy Charcot-Marie-Tooth 1A (CMT1A) the expression of the different NRG1 isoforms (soluble, type α and β, type a and b) is strongly up-regulated, as well as the expression of NRG1 co-receptors ErbB2–ErbB3, thus showing that CMT1A nerves have a gene expression pattern highly reminiscent of injured nerves. Because it has been shown that high concentrations of soluble NRG1 negatively affect myelination, we suggest that soluble NRG1 over-expression might play a negative role in the pathogenesis of CMT1A disease, and that a therapeutic approach, aimed to interfere with NRG1 activity, might be beneficial for CMT1A patients. Further studies will be necessary to test this hypothesis in animal models and to evaluate NRG1 expression in human patients. Impact statement Charcot-Marie-Tooth1A (CMT1A) is one of the most frequent inherited neurological diseases, characterized by chronic demyelination of peripheral nerves, for which effective therapies are not yet available. It has been recently proposed that the treatment with soluble Neuregulin1 (NRG1), a growth factor released by Schwann cells immediately after acute nerve injury, might be effective in CMT1A treatment. However, the expression of the different isoforms of endogenous NRG1 in CMT1A nerves has not been yet investigated. In this preliminary study, we demonstrate that different isoforms of soluble NRG1 are strongly over-expressed in CMT1A nerves, thus suggesting that a therapeutic approach based on NRG1 treatment should be carefully reconsidered. If soluble NRG1 is over-expressed also in human CMT1A nerves, a therapeutic approach aimed to inhibit (instead of stimulate) the signal transduction pathways driven by NRG1 might be fruitfully developed. Further studies will be necessary to test these hypotheses.

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Upregulation of Matrix Metalloproteinases following Nerve Injury Is Not Mediated by Mast Cell Activation

NeuroImmunoModulation ◽

10.1159/000085653 ◽

2005 ◽

Vol 12 (4) ◽

pp. 211-219 ◽

Cited By ~ 2

Author(s):

Yun-Xia Zuo ◽

David J. Tracey ◽

Carolyn Geczy

Keyword(s):

Mast Cell ◽

Matrix Metalloproteinases ◽

Nerve Injury ◽

Cell Activation ◽

Mast Cell Activation

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Microglia monitor and protect neuronal function via specialized somatic purinergic junctions

10.1101/606079 ◽

2019 ◽

Author(s):

Csaba Cserép ◽

Balázs Pósfai ◽

Barbara Orsolits ◽

Gábor Molnár ◽

Steffanie Heindl ◽

...

Keyword(s):

Purinergic Signaling ◽

Neurological Diseases ◽

Neuronal Cell ◽

Neuronal Function ◽

Neuronal Cell Bodies ◽

Injured Brain ◽

Calcium Load ◽

Neuronal Functions ◽

Induced Changes ◽

Brain Homeostasis

AbstractMicroglia are the main immune cells in the brain with emerging roles in brain homeostasis and neurological diseases, while mechanisms underlying microglia-neuron communication remain elusive. Here, we identify a novel site of interaction between neuronal cell bodies and microglial processes in mouse and human brain. Somatic microglia-neuron junctions possess specialized nanoarchitecture optimized for purinergic signaling. Activity of neuronal mitochondria is linked with microglial junction formation, which is rapidly induced in response to neuronal activation and blocked by inhibition of P2Y12-receptors (P2Y12R). Brain injury-induced changes at somatic junctions trigger P2Y12R-dependent microglial neuroprotection, regulating neuronal calcium load and functional connectivity. Collectively, our results suggest that microglial processes at these junctions are in ideal position to monitor and protect neuronal functions in both the healthy and injured brain.One-sentence summaryNeuronal cell bodies possess specialized, pre-formed sites, through which microglia monitor their status and exert neuroprotection.

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Myelin sheath structure and regeneration in peripheral nerve injury repair

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1910292116 ◽

2019 ◽

Vol 116 (44) ◽

pp. 22347-22352 ◽

Cited By ~ 6

Author(s):

Bin Liu ◽

Wang Xin ◽

Jian-Rong Tan ◽

Rui-Ping Zhu ◽

Ting Li ◽

...

Keyword(s):

Sciatic Nerve ◽

Nerve Injury ◽

Myelin Sheath ◽

Peripheral Nerves ◽

Basic Protein ◽

Neurological Diseases ◽

Oculomotor Nerve ◽

Dense Line ◽

Transmission Electron ◽

Sheath Structure

Observing the structure and regeneration of the myelin sheath in peripheral nerves following injury and during repair would help in understanding the pathogenesis and treatment of neurological diseases caused by an abnormal myelin sheath. In the present study, transmission electron microscopy, immunofluorescence staining, and transcriptome analyses were used to investigate the structure and regeneration of the myelin sheath after end-to-end anastomosis, autologous nerve transplantation, and nerve tube transplantation in a rat model of sciatic nerve injury, with normal optic nerve, oculomotor nerve, sciatic nerve, and Schwann cells used as controls. The results suggested that the double-bilayer was the structural unit that constituted the myelin sheath. The major feature during regeneration was the compaction of the myelin sheath, wherein the distance between the 2 layers of cell membrane in the double-bilayer became shorter and the adjacent double-bilayers tightly closed together and formed the major dense line. The expression level of myelin basic protein was positively correlated with the formation of the major dense line, and the compacted myelin sheath could not be formed without the anchoring of the lipophilin particles to the myelin sheath.

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Microglia monitor and protect neuronal function through specialized somatic purinergic junctions

Science ◽

10.1126/science.aax6752 ◽

2019 ◽

Vol 367 (6477) ◽

pp. 528-537 ◽

Cited By ~ 51

Author(s):

Csaba Cserép ◽

Balázs Pósfai ◽

Nikolett Lénárt ◽

Rebeka Fekete ◽

Zsófia I. László ◽

...

Keyword(s):

Purinergic Signaling ◽

Neurological Diseases ◽

Neuronal Cell ◽

Neuronal Function ◽

Neuronal Cell Bodies ◽

Calcium Load ◽

Neuronal Functions ◽

Induced Changes ◽

The Brain ◽

Brain Homeostasis

Microglia are the main immune cells in the brain and have roles in brain homeostasis and neurological diseases. Mechanisms underlying microglia–neuron communication remain elusive. Here, we identified an interaction site between neuronal cell bodies and microglial processes in mouse and human brain. Somatic microglia–neuron junctions have a specialized nanoarchitecture optimized for purinergic signaling. Activity of neuronal mitochondria was linked with microglial junction formation, which was induced rapidly in response to neuronal activation and blocked by inhibition of P2Y12 receptors. Brain injury–induced changes at somatic junctions triggered P2Y12 receptor–dependent microglial neuroprotection, regulating neuronal calcium load and functional connectivity. Thus, microglial processes at these junctions could potentially monitor and protect neuronal functions.

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