13
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Septin/anillin filaments scaffold central nervous system myelin to accelerate nerve conduction

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Myelination of axons facilitates rapid impulse propagation in the nervous system. The axon/myelin-unit becomes impaired in myelin-related disorders and upon normal aging. However, the molecular cause of many pathological features, including the frequently observed myelin outfoldings, remained unknown. Using label-free quantitative proteomics, we find that the presence of myelin outfoldings correlates with a loss of cytoskeletal septins in myelin. Regulated by phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P 2)-levels, myelin septins (SEPT2/SEPT4/SEPT7/SEPT8) and the PI(4,5)P 2-adaptor anillin form previously unrecognized filaments that extend longitudinally along myelinated axons. By confocal microscopy and immunogold-electron microscopy, these filaments are localized to the non-compacted adaxonal myelin compartment. Genetic disruption of these filaments in Sept8-mutant mice causes myelin outfoldings as a very specific neuropathology. Septin filaments thus serve an important function in scaffolding the axon/myelin-unit, evidently a late stage of myelin maturation. We propose that pathological or aging-associated diminishment of the septin/anillin-scaffold causes myelin outfoldings that impair the normal nerve conduction velocity.

          DOI: http://dx.doi.org/10.7554/eLife.17119.001

          eLife digest

          Normal communication within the brain or between the brain and other parts of the body requires information to flow quickly around the nervous system. This information travels along nerve cells in the form of electrical signals. To speed up the signals, a part of the nerve cell called the axon is frequently wrapped in an electrically insulating sheath made up of a membrane structure called myelin.

          The myelin sheath becomes impaired as a result of disease or ageing. In order to understand what might produce these changes, Patzig et al. have used biochemical and microscopy techniques to study mice that had similar defects in their myelin sheaths.

          The study reveals that forming a normal myelin sheath around an axon requires a newly identified ‘scaffold’ made of a group of proteins called the septins. Combining with another protein called anillin, septins assemble into filaments in the myelin sheath. These filaments then knit together into a scaffold that grows lengthways along the myelin-wrapped axon. Without this scaffold, the myelin sheath grew defects known as outfoldings. Axons transmitted electrical signals much more slowly than normal when the septin scaffold was missing from the myelin sheath.

          Future studies are needed to understand the factors that control how the septin scaffold forms. This could help to reveal ways of reversing the changes that alter the myelin sheath during ageing and disease.

          DOI: http://dx.doi.org/10.7554/eLife.17119.002

          Related collections

          Most cited references43

          • Record: found
          • Abstract: found
          • Article: not found

          Myelination of the nervous system: mechanisms and functions.

          Myelination of axons in the nervous system of vertebrates enables fast, saltatory impulse propagation, one of the best-understood concepts in neurophysiology. However, it took a long while to recognize the mechanistic complexity both of myelination by oligodendrocytes and Schwann cells and of their cellular interactions. In this review, we highlight recent advances in our understanding of myelin biogenesis, its lifelong plasticity, and the reciprocal interactions of myelinating glia with the axons they ensheath. In the central nervous system, myelination is also stimulated by axonal activity and astrocytes, whereas myelin clearance involves microglia/macrophages. Once myelinated, the long-term integrity of axons depends on glial supply of metabolites and neurotrophic factors. The relevance of this axoglial symbiosis is illustrated in normal brain aging and human myelin diseases, which can be studied in corresponding mouse models. Thus, myelinating cells serve a key role in preserving the connectivity and functions of a healthy nervous system.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination.

            Myelination of axons by oligodendrocytes enables rapid impulse propagation in the central nervous system. But long-term interactions between axons and their myelin sheaths are poorly understood. Here we show that Cnp1, which encodes 2',3'-cyclic nucleotide phosphodiesterase in oligodendrocytes, is essential for axonal survival but not for myelin assembly. In the absence of glial cyclic nucleotide phosphodiesterase, mice developed axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. But, in contrast to previously studied myelin mutants, the ultrastructure, periodicity and physical stability of myelin were not altered in these mice. Genetically, the chief function of glia in supporting axonal integrity can thus be completely uncoupled from its function in maintaining compact myelin. Oligodendrocyte dysfunction, such as that in multiple sclerosis lesions, may suffice to cause secondary axonal loss.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Identification of long-lived proteins reveals exceptional stability of essential cellular structures.

              Intracellular proteins with long lifespans have recently been linked to age-dependent defects, ranging from decreased fertility to the functional decline of neurons. Why long-lived proteins exist in metabolically active cellular environments and how they are maintained over time remains poorly understood. Here, we provide a system-wide identification of proteins with exceptional lifespans in the rat brain. These proteins are inefficiently replenished despite being translated robustly throughout adulthood. Using nucleoporins as a paradigm for long-term protein persistence, we found that nuclear pore complexes (NPCs) are maintained over a cell's life through slow but finite exchange of even its most stable subcomplexes. This maintenance is limited, however, as some nucleoporin levels decrease during aging, providing a rationale for the previously observed age-dependent deterioration of NPC function. Our identification of a long-lived proteome reveals cellular components that are at increased risk for damage accumulation, linking long-term protein persistence to the cellular aging process. PAPERCLIP: Copyright © 2013 Elsevier Inc. All rights reserved.
                Bookmark

                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                09 August 2016
                2016
                : 5
                : e17119
                Affiliations
                [1 ]deptDepartment of Neurogenetics , Max Planck Institute of Experimental Medicine , Goettingen, Germany
                [2 ]deptInstitute of Immunology , University Medical Center, Johannes Gutenberg University , Mainz, Germany
                [3 ]Center for Nanoscale Microscopy and Molecular Physiology of the Brain , Göttingen, Germany
                [4 ]deptDepartement of Biomedicine , University Hospital Basel , Basel, Switzerland
                [5]Boston Children's Hospital, Harvard Medical School , United States
                [6]Boston Children's Hospital, Harvard Medical School , United States
                Author notes
                Author information
                http://orcid.org/0000-0002-7710-5738
                Article
                17119
                10.7554/eLife.17119
                4978525
                27504968
                38986860-98f1-4365-87dd-2e37a95c8ddb
                © 2016, Patzig et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 21 April 2016
                : 13 July 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung;
                Award ID: 31003A-125210
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung;
                Award ID: 31003A-141185
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: Advanced Grant
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: WE2720/2-1
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Neuroscience
                Research Article
                Custom metadata
                2.5
                A newly identified component in the architecture of the axon/myelin-unit – the septin/anillin scaffold – maintains the structure of myelin in the central nervous system, thereby preventing myelin outfoldings.

                Life sciences
                glial cells,myelinated axons,neuropathology,myelin structure,label-free proteomics,septin cytoskeleton,mouse

                Comments

                Comment on this article