Glia Signalling during Neurological Damage and Disease

Abstract

While glia were once thought to be nothing more than glue‐like cells that hold the nervous system together, there is growing evidence that signals to and from glia are indispensable for development, cell‐to‐cell communication and maintenance of efficient nervous system function. Several studies show that glia often receive conflicting signals during disease progression and can play dual roles as both antagonists and neuroprotectors in distinct settings.

Key Concepts

  • Glia play neuroprotective and neurodegenerative role during the initiation and progression stage of neurodegenerative diseases.
  • Astrocytes mediate calcium‐related neurotoxicity in Alzheimer's disease.
  • Microglia regulate neurodegeneration in Parkinson's disease through NO‐related apoptotic pathway.
  • Oligodendrocytes and Schwann cells regulate myelin wasting diseases in central and peripheral nervous system through Wnt and ErbB2/ErbB3 signalling pathways.
  • Glial cells form a scar following spinal cord injury that affects regenerative abilities.

Keywords: Glia; astrocytes; microglia; oligodendrocytes; Schwann cells; signal transduction; neurodegeneration; multiple sclerosis; nerve regeneration; glial scar

Figure 1. Glia signalling during neurological damage and disease. (a) In Alzheimer's disease, increased amyloid‐β load in the brain promotes Ca2+ channel expression on astrocytes. Glutamate released into the tripartite synapses trigger mGluR‐PLC‐IP3‐Ca2+ signalling, further elevating cytoplasmic Ca2+ concentration in astrocytes. The activated astrocytes increase the release of gliotransmitters, including glutamate, ATP, d‐serine and TNFα, to promote excitotoxicity in neurons. In Parkinson's disease, activated microglia that are exposed to α‐synuclein produce high level of iNOS, which release NO to cytosol of microglia and neurons. Increased NO activated Bax on the mitochondria, inducing the cytochrome release, which then activate caspase 9‐mediated apoptosis pathway and neurodegeneration. NO also promote S‐nitrosylation modification of Ras, activating ERK pathway to increase the expression of TNFα and other cytokines, resulting in inflammation in microglia. (b) Wnt signalling is known to play an important role in multiple sclerosis pathology, but it is unclear whether this is a helpful or hurtful role. Binding of Wnt to Frizzled releases β‐catenin to travel into the nucleus and bind transcription factors such as Tcf. On the one hand, activation of the pathway may prevent maturation of OPCs into OLs and may suppress the transcription of myelin genes. On the other hand, this pathway has been implicated as having a necessary role in the transcription of myelin genes. See text for more details. (c) One major form of signalling in demyelinating CMT funnels through Nrg activation of the ErbB2/3 heterodimer. Activation of this pathway may have opposing effects. Signalling through the PLC route results in activation of promyelinating genes, whereas the MAPK pathway induces cell death through activation of JNK. See text for further description of other pathways. (d) The glial scar forms following axonal injury, surrounding the site of injury. It is composed of a basal lamina and activated astrocytes, bound by tight junctions. It serves as a physical barrier as well as a chemical one. The activated astrocytes secrete CSPGs, which are more highly concentrated at the site of injury and diffuse outwards. These are growth inhibitory factors and are received by Sema5a receptors on the surface of the axon, preventing growth cone extension. Myelin also begins to break apart, releasing other growth inhibitory molecules. Macrophages come in and clean up the myelin debris. This process intends to limit further neuronal degeneration and inflammatory effects.
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Yong, Yu, Heckle, Lindsay A, Arena, Kimberly A, Goertz, Jennifer E, Kucenas, Sarah, and Deppmann, Christopher D(Aug 2017) Glia Signalling during Neurological Damage and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027501]