Brain Disorders and Chemical Pollutants: A Gap Junction Link?

The incidence of brain pathologies has increased during last decades. Better diagnosis (autism spectrum disorders) and longer life expectancy (Parkinson's disease, Alzheimer's disease) partly explain this increase, while emerging data suggest pollutant exposures as a possible but still underestimated cause of major brain disorders. Taking into account that the brain parenchyma is rich in gap junctions and that most pollutants inhibit their function; brain disorders might be the consequence of gap-junctional alterations due to long-term exposures to pollutants.

Cx43 in Neural Progenitors Promotes Glioma Invasion in a 3D Culture System.

The environment that envelops the cancer cells intimately affects the malignancy of human cancers. In the case of glioma, an aggressive adult brain cancer, its high rate of recurrence after total resection is responsible for a poor prognosis. Connexin43 (Cx43) is a gap junction protein with a prominent presence in glioma-associated normal brain cells, specifically in the reactive astrocytes.

Glial Connexins and Pannexins in the Healthy and Diseased Brain.

Over the past several decades a large amount of data have established that glial cells, the main cell population in the brain, dynamically interact with neurons and thus impact their activity and survival. One typical feature of glia is their marked expression of several connexins, the membrane proteins forming intercellular gap junction channels and hemichannels. Pannexins, which have a tetraspan membrane topology as connexins, are also detected in glial cells.

Examination of sulfonamide-based inhibitors of MMP3 using the conditioned media of invasive glioma cells.

Glioblastoma multiforme (GBM) is the deadliest and the most common primary malignant brain tumour. The median survival for patients with GBM is around one year due to the nature of glioma cells to diffusely invade that make the complete surgical resection of tumours difficult. Based upon the connexin43 (Cx43) model of glioma migration we have developed a computational framework to evaluate MMP inhibition in materials relevant to GBM.

Danegaptide Enhances Astrocyte Gap Junctional Coupling and Reduces Ischemic Reperfusion Brain Injury in Mice.

Ischemic stroke is a complex and devastating event characterized by cell death resulting from a transient or permanent arterial occlusion. Astrocytic connexin43 (Cx43) gap junction (GJ) proteins have been reported to impact neuronal survival in ischemic conditions. Consequently, Cx43 could be a potential target for therapeutic approaches to stroke.

Connexin43 peptide, TAT-Cx43266-283, selectively targets glioma cells, impairs malignant growth, and enhances survival in mouse models in vivo.

Background: Malignant gliomas are the most frequent primary brain tumors and remain among the most incurable cancers. Although the role of the gap junction protein, connexin43 (Cx43), has been deeply investigated in malignant gliomas, no compounds have been reported with the ability to recapitulate the tumor suppressor properties of this protein in in vivo glioma models.

Methods: TAT-Cx43266-283 a cell-penetrating peptide which mimics the effect of Cx43 on c-Src inhibition, was studied in orthotopic immunocompetent and immunosuppressed models of glioma.

Cx43-Associated Secretome and Interactome Reveal Synergistic Mechanisms for Glioma Migration and MMP3 Activation.

Extracellular matrix (ECM) remodeling, degradation and glioma cell motility are critical aspects of glioblastoma multiforme (GBM). Despite being a rich source of potential biomarkers and targets for therapeutic advance, the dynamic changes occurring within the extracellular environment that are specific to GBM motility have yet to be fully resolved. The gap junction protein connexin43 (Cx43) increases glioma migration and invasion in a variety of and models.

Targeting MAPK phosphorylation of Connexin43 provides neuroprotection in stroke.

Connexin43 (Cx43) function is influenced by kinases that phosphorylate specific serine sites located near its C-terminus. Stroke is a powerful inducer of kinase activity, but its effect on Cx43 is unknown. We investigated the impact of wild-type (WT) and knock-in Cx43 with serine to alanine mutations at the protein kinase C (PKC) site Cx43, the casein kinase 1 (CK1) sites Cx43, and the mitogen-activated protein kinase (MAPK) sites Cx43 (MK4) on a permanent middle cerebral artery occlusion (pMCAO) stroke model.

Pannexin 2 Localizes at ER-Mitochondria Contact Sites.

Endomembrane specialization allows functional compartmentalization but imposes physical constraints to information flow within the cell. However, the evolution of an endomembrane system was associated with the emergence of contact sites facilitating communication between membrane-bound organelles. Contact sites between the endoplasmic reticulum (ER) and mitochondria are highly conserved in terms of their morphological features but show surprising molecular diversity within and across eukaryote species.

GJA1 (connexin43) is a key regulator of Alzheimer's disease pathogenesis.

GJA1 (connexin43) has been predicted as the top key driver of an astrocyte enriched subnetwork associated with Alzheimer's disease (AD). In this study, we comprehensively examined GJA1 expression across 29 transcriptomic and proteomic datasets from post-mortem AD and normal control brains. We demonstrated that GJA1 was strongly associated with AD amyloid and tau pathologies and cognitive functions.

Modelling glioma invasion using 3D bioprinting and scaffold-free 3D culture.

Glioma is a highly aggressive form of brain cancer, with some subtypes having 5-year survival rates of less than 5%. Tumour cell invasion into the surrounding parenchyma seems to be the primary driver of these poor outcomes, as most gliomas recur within 2 cm of the original surgically-resected tumour. Many current approaches to the development of anticancer therapy attempt to target genetic weaknesses in a particular cancer, but may not take into account the microenvironment experienced by a tumour and the patient-specific genetic differences in susceptibility to treatment.

Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics.

Resistance of malignant glioma, including glioblastoma (GBM), to the chemotherapeutic temozolomide (TMZ) remains a key obstacle in treatment strategies. The gap junction protein connexin43 (Cx43) has complex roles in the establishment, progression, and persistence of malignant glioma. Recent findings demonstrate that connexins play an important role in the microenvironment of malignant glioma and that Cx43 is capable of conferring chemotherapeutic resistance to GBM cells.

Matrix-assisted laser desorption/ionization imaging mass spectrometry of intraperitoneally injected danegaptide (ZP1609) for treatment of stroke-reperfusion injury in mice.

Rationale: This work focuses on direct matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) detection of intraperitoneally (IP)-injected dipeptide ZP1609 in mouse brain tissue. Direct analysis of drug detection in intact tissue sections provides distribution information that can impact drug development. MALDI-IMS capabilities of uncovering drug transport across the blood-brain barrier are demonstrated.

Acute connexin43 temporal and spatial expression in response to ischemic stroke.

Connexin43 (Cx43) gap junctions expressed in astrocytes can significantly impact neuronal survival in stroke. However, little is known regarding Cx43 spatial and temporal expression during the initial stages of brain ischemia. Using immunohistochemistry and Western blot analysis, we examined Cx43 spatial and temporal expression as a function of neuronal injury within the first 24 h after permanent middle cerebral artery occlusion (pMCAO).

Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications.

Connexins are ubiquitous channel forming proteins that assemble as plasma membrane hemichannels and as intercellular gap junction channels that directly connect cells. In the heart, gap junction channels electrically connect myocytes and specialized conductive tissues to coordinate the atrial and ventricular contraction/relaxation cycles and pump function. In blood vessels, these channels facilitate long-distance endothelial cell communication, synchronize smooth muscle cell contraction, and support endothelial-smooth muscle cell communication.

Connexins and pannexins in Alzheimer's disease.

By 2040 neurodegenerative diseases will become the world's second leading cause of death after cardiovascular disease (WHO). Major efforts are required to elucidate the underlying molecular and cellular mechanisms of neurodegenerative diseases. Connexin and pannexin membrane channel proteins are conduits through which neuronal, glial, and vascular tissues interact.

SnapShot: Connexins and Disease.

The connexin family of membrane proteins enable gap junction formation and homeostasis, supporting communication between adjacent cells. This SnapShot highlights mutations in different connexins associated with human pathologies and how they affect gap junction function.

Connexins and Disease.

Inherited or acquired alterations in the structure and function of connexin proteins have long been associated with disease. In the present work, we review current knowledge on the role of connexins in diseases associated with the heart, nervous system, cochlea, and skin, as well as cancer and pleiotropic syndromes such as oculodentodigital dysplasia (ODDD). Although incomplete by virtue of space and the extent of the topic, this review emphasizes the fact that connexin function is not only associated with gap junction channel formation.

Connexin-Dependent Neuroglial Networking as a New Therapeutic Target.

Astrocytes and neurons dynamically interact during physiological processes, and it is now widely accepted that they are both organized in plastic and tightly regulated networks. Astrocytes are connected through connexin-based gap junction channels, with brain region specificities, and those networks modulate neuronal activities, such as those involved in sleep-wake cycle, cognitive, or sensory functions. Additionally, astrocyte domains have been involved in neurogenesis and neuronal differentiation during development; they participate in the "tripartite synapse" with both pre-synaptic and post-synaptic neurons by tuning down or up neuronal activities through the control of neuronal synaptic strength.

An update on minding the gap in cancer.

This article is a report of the "International Colloquium on Gap junctions: 50Years of Impact on Cancer" that was held 8-9 September 2016, at the Amphitheater "Pôle Biologie Santé" of the University of Poitiers (Poitiers, France). The colloquium was organized by M Mesnil (Université de Poitiers, Poitiers, France) and C Naus (University of British Columbia, Vancouver, Canada) to celebrate the 50th anniversary of the seminal work published in 1966 by Loewenstein and Kanno [Intercellular communication and the control of tissue growth: lack of communication between cancer cells, Nature, 116 (1966) 1248-1249] which initiated studies on the involvement of gap junctions in carcinogenesis. During the colloquium, 15 participants presented reviews or research updates in the field which are summarized below.

Pannexin1 knockout and blockade reduces ischemic stroke injury in female, but not in male mice.

The membrane channel Pannexin 1 (Panx1) mediates apoptotic and inflammatory signaling cascades in injured neurons, responses previously shown to be sexually dimorphic under ischemic conditions. We tested the hypothesis that Panx1 plays an underlying role in mediating sex differences in stroke outcome responses. Middle-aged, 8-9 month old male and female wild type and Panx1 KO mice were subjected to permanent middle cerebral artery (MCA) occlusion, and infarct size and astrocyte and microglia activation were assessed 4 days later.

Gap junctions and hemichannels: communicating cell death in neurodevelopment and disease.

Gap junctions are unique membrane channels that play a significant role in intercellular communication in the developing and mature central nervous system (CNS). These channels are composed of connexin proteins that oligomerize into hexamers to form connexons or hemichannels. Many different connexins are expressed in the CNS, with some specificity with regard to the cell types in which distinct connexins are found, as well as the timepoints when they are expressed in the developing and mature CNS.

Bridging the gap to therapeutic strategies based on connexin/pannexin biology.

A unique workshop was recently held focusing on enhancing collaborations leading to identify and update the development of therapeutic strategies targeting connexin/pannexin large pore channels. Basic scientists exploring the functions of these channels in various pathologies gathered together with leading pharma companies which are targeting gap junction proteins for specific therapeutic applications. This highlights how paths of discovery research can converge with therapeutic strategies in innovative ways to enhance target identification and validation.