Elsevier

Brain Research

Volume 1487, 3 December 2012, Pages 61-68
Brain Research

Review
Brain connexins in demyelinating diseases: Therapeutic potential of glial targets

https://doi.org/10.1016/j.brainres.2012.07.003Get rights and content

Abstract

Several demyelinating syndromes have been linked to mutations in glial gap junction proteins, the connexins. Although mutations in connexins of the myelinating cells, Schwann cells and oligodendrocytes, were initially described, recent data have shown that astrocytes also play a major role in the demyelination process. Alterations in astrocytic proteins directly affect the oligodendrocytes’ ability to maintain myelin structure, and associated astrocytic proteins that regulate water and ionic fluxes, including aquaporins, can also regulate myelin integrity. Here, we will review the main evidence from human disorders and transgenic mouse models that implicate glial gap junction proteins in demyelinating diseases and the therapeutic potential of some of these targets.

This article is part of a Special Issue entitled Electrical Synapses.

Introduction

Myelination is essential for brain function in mammals, as it speeds up transmission of neural information. Several sheaths of myelin surround every single axon. This creates an insulating layer of fat with regular discontinuities called nodes of Ranvier. These nodes concentrate the necessary machinery to propagate action potentials and allow the electrical signals to travel in a saltatory manner to reach other cells located hundred of mms away within milliseconds (Sherman and Brophy, 2005).

Although, in principle, the concept of layers of lipid membranes for insulation sounds simple, myelin formation and organization is a rather complex process. Apart from the unique lipid composition of its plasma membrane, several proteins exclusive to myelin serve as structural support within the myelin membranes. Proteolipid protein (PLP) and myelin-associated glyocoprotein (MAG) are some of the main integral proteins in myelin (Nave, 2010) although their exact role is still elusive. In the intracellular space, myelin basic protein (MBP), one of the most critical myelin proteins, creates a framework for attachment, not only of lipids but also of diverse membrane proteins including ionic channels, transporters, gap junctions as well as cytoskeletal proteins, and signaling molecules.

The complexity of white matter organization suggests that myelin contributes not only to insulation but also to signaling within the myelinating cell and axon. For example, the intimate neuro-glial interaction obtained through myelination has proven crucial for axonal integrity and survival. In addition, myelination also allows energy savings by concentrating critical ionic channels in a very restricted area of the axons, thereby reducing the amount of ATP consumed in restoring ionic gradients after every action potential (Nave, 2010).

Many different human disorders have been described to date that affect either the production or the maintenance of myelin. Some of these demyelination pathologies have been linked to a particular group of proteins – the connexins (Cxs) – that form intercellular gap junction channels with adjacent cells, connecting their cytoplasms. These channels allow the exchange of ions and small metabolites up to 1 kDa in size and contribute to cooperative metabolism among cells, electrical coupling and spatial buffering (Bruzzone et al., 1996). Alterations in connexins present in the myelynating glial cells (forming intercellular junctions in oligodendrocytes and autaptic – within themselves – in Schwann cells) all promote demyelination diseases. Interestingly, connexins present in the astrocytes, the major macroglial cell type in the nervous system and not traditionally associated with the myelination process, also contribute to some myelin pathologies.

Here, we will discuss the evidence that supports a role for connexins and related proteins present in both oligodendrocytes and astrocytes in myelin disorders. We will also discuss putative signaling mechanisms that could be involved and the potential for therapeutic intervention based on these targets.

Section snippets

Oligodendrocyte-mediated demyelination: connexins

Oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS) are the cells involved in synthesizing, organizing and wrapping myelin around the nerves. One single oligodendrocyte can wrap many axons, giving a web-like appearance to these cells in the white matter (Nave, 2010). Oligodendrocytes and Schwann cells express three different connexins: Cx47, Cx32 and Cx29, although only the first two are believed to form gap junction channels (Ahn et

Astrocyte-mediated demyelination: connexins, AQP4 and potassium

Although demyelination appears more related to defects in the myelinating cells and the myelin structure itself, several recent reports suggest a critical role for astrocytes in certain demyelinating diseases, highlighting the importance of these cells in all cellular brain interactions. Astrocytes are the most abundant cell type in the nervous system, and provide metabolic and structural support to neurons, regulate potassium and water homeostasis, glucose uptake and are also implicated in

Connexins and inflammation

An interesting aspect of NMO and related disorders is the involvement of a robust T-cell response against major myelin proteins. This, in turn, initiates a cascade of CNS inflammation, with increased levels of T-helper-1 (Th1), interferon γ (IFNγ) and of the cytokines IL-17 and IL-8 (Kira, 2011) that correlate positively with lesion size.

Sharma et al. (2010) have also shown involvement of an inflammation step in a model of lipopolysaccharide (LPS)-induced demyelination. Injection of LPS into

Conclusions

Demyelinating disorders linked to mutations in connexins and related astrocytic proteins have in recent years uncovered a wealth of new data suggesting that gap junction proteins play much more important roles in human disease than previously /NIHledged. The precise mechanism by which deficient gap junction communication alters myelin formation and maintenance, and why some axonal fibers are more affected than others are questions that remain to be answered. However, the discovery of new

Acknowledgment

This work was supported by the National Institute of Neurological Disorders and Stroke/NIH.

References (58)

  • T. López-Hernández et al.

    Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism

    Am. J. Hum. Genet.

    (2011)
  • S.E. Lutz et al.

    Loss of astrocyte connexins 43 and 30 does not significantly alter susceptibility or severity of acute experimental autoimmune encephalomyelitis in mice

    J. Neuroimmunol.

    (2012)
  • T. Nakase et al.

    Increased apoptosis and inflammation after focal brain ischemia in mice lacking connexin43 in astrocytes

    Am. J. Pathol.

    (2004)
  • Y. Sawaishi

    Review of Alexander disease: beyond the classical concept of leukodystrophy

    Brain Dev.

    (2009)
  • B. Uhlenberg et al.

    Mutations in the gene encoding gap junction protein α12 (connexin 46.6) cause Pelizaeus–Merzbacher-Like disease

    Am. J. Hum. Genet.

    (2004)
  • M. Ahn et al.

    Cx29 and Cx32, two connexins expressed in myelinating glia, do not interact and are functionally distinct

    J. Neurosci. Res.

    (2008)
  • M. Brenner et al.

    Alexander disease: a genetic disorder of astrocytes

  • R. Bruzzone et al.

    Connections with connexins: the molecular basis of direct intercellular signaling

    Eur. J. Biochem.

    (1996)
  • M. Bugiani et al.

    Leukoencephalopathy with Vanishing White Matter: a review

    J. Neuropathol. Exp. Neurol.

    (2010)
  • M.L. Cotrina et al.

    Adhesive properties of connexin hemichannels

    Glia

    (2008)
  • E. Dere et al.

    Connexin30-deficient mice show increased emotionality and decreased rearing activity in the open-field along with neurochemical changes

    Eur. J. Neurosci.

    (2003)
  • J. Dietrich et al.

    EIF2B5 mutations compromise GFAP+ astrocyte generatin in vanishing white matter leukodystrophy

    Nat. Med.

    (2005)
  • F. Gankam et al.

    Astrocytes are an early target in osmotic demyelination syndrome

    J. Am. Soc. Nephrol.

    (2011)
  • S.R. Hinson et al.

    Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2

    J. Exp. Med.

    (2008)
  • C. Huang et al.

    Critical role of Connexin 43 in secondary expansion of traumatic spinal cord injury

    J. Neurosci.

    (2012)
  • K.A. Kleopa

    The role of gap junctions in Charcot–Marie-Tooth Disease

    J. Neurosci.

    (2011)
  • X. Li et al.

    Connexin47, connexin29 and connexin32 coexpression in oligodendrocytes and Cx47 association with zonula occludens-1 (ZO-1) in mouse brain

    Neuroscience

    (2004)
  • X. Li et al.

    Ablation of Cx47 in transgenic mice leads to the loss of MUPP1, ZONAB and multiple connexins at oligodendrocyte-astrocyte gap junctions

    Eur. J. Neurosci.

    (2008)
  • J.H.C. Lin et al.

    Connexin 43 enhances de adhesivity and mediates the invasion of malignant glioma cells

    J. Neurosci.

    (2002)
  • Cited by (25)

    • Connexins in oligodendrocytes and astrocytes: Possible factors for demyelination in multiple sclerosis

      2020, Neurochemistry International
      Citation Excerpt :

      Connexin-formed, gap junction-mediated communication is important for myelination. Previous reviews have discussed the role of connexins in the demyelination process (Kleopa et al., 2010; Cotrina and Nedergaard, 2012). Whereas, we still lack a system level understanding of this role.

    • Connexin type and fluorescent protein fusion tag determine structural stability of gap junction plaques

      2015, Journal of Biological Chemistry
      Citation Excerpt :

      Other integral membrane proteins, such as AQP4 and Kir4.1, are highly localized to the same area where Cx43 and Cx30 plaques cluster in the endfoot. Localization of AQP4 and Kir4.1 to the astrocyte endfoot has been shown to be important in the pathological manifestation of mouse models of neural disease and human brain samples (59–65). We speculate that different properties imparted to the endfoot and perisynaptic domains of astrocytes by stable or fluid GJ plaques affect astrocyte morphology and localization of other proteins that are required for brain homeostasis, including AQP4 and Kir4.1.

    • Mix and match: Investigating heteromeric and heterotypic gap junction channels in model systems and native tissues

      2014, FEBS Letters
      Citation Excerpt :

      Taken together these data are most consistent with the majority of gap junction channels at O:A junctions being Cx32 + Cx30 and Cx47 + Cx43 heterotypic channels. Furthermore, in contrast to mice harboring a single connexin knockout that retains some O:A coupling, Cx30 + Cx43 double knockout mice lack detectable O:A gap junctional communication consistent with two parallel heterotypic communication pathways [87,92–95]. As with any mouse knockout model, connexin deficiency can have pleiotropic effects beyond the effects on specific, compatible connexins.

    • Reduced connexin 43 immunolabeling in the orbitofrontal cortex in alcohol dependence and depression

      2014, Journal of Psychiatric Research
      Citation Excerpt :

      Nevertheless, alcoholism and major depression can differ in specific aspects of astrocyte involvement (Miguel-Hidalgo and Rajkowska, 2003; Miguel-Hidalgo et al., 2010), such as the levels of astrocytic glutamate transporters or glutamine synthetase (Miguel-Hidalgo et al., 2010). Some of the neuronal support functions of astrocytes (Haydon and Carmignoto, 2006; Volterra and Meldolesi, 2005) strongly depend on astrocytes' ability to communicate with each other and with other cells through gap junctions and hemichannels (Cotrina and Nedergaard, 2012; Figiel et al., 2007; Giaume et al., 1997; Rouach et al., 2002), mainly composed of the protein connexin 43 (Cx43), with a smaller involvement of connexin 30 (Cx30). Thus, deficient expression or modifications of Cx43 could contribute to prefrontal physiopathology.

    • Central myelin gene expression during postnatal development in rats exposed to nicotine gestationally

      2013, Neuroscience Letters
      Citation Excerpt :

      Although we only reported mRNA expression in this study, our previous study has shown that the alteration in protein expression of MBP is consistent with that of mRNA in adolescent brains [8]. The membrane-associated proteins such as MAL and GJE3 interact with neighbor cells to support myelin structure and function [11,40]. Other proteins, such as PLP1 and CNP, are less involved in myelination but help shape the underlying axon and also support axon function [19,26].

    View all citing articles on Scopus
    View full text