1. Cell Biology
  2. Neuroscience
Download icon

Genetic defects in β-spectrin and tau sensitize C. elegans axons to movement-induced damage via torque-tension coupling

  1. Michael Krieg
  2. Jan Stühmer
  3. Juan G Cueva
  4. Richard Fetter
  5. Kerri A Spliker
  6. Daniel Cremers
  7. Kang Shen
  8. Alexander R Dunn
  9. Miriam B Goodman  Is a corresponding author
  1. Institute of Photonic Sciences, Spain
  2. Technical University of Munich, Germany
  3. Stanford University, United States
Research Article
  • Cited 43
  • Views 2,628
  • Annotations
Cite this article as: eLife 2017;6:e20172 doi: 10.7554/eLife.20172

Abstract

Our bodies are in constant motion and so are the neurons that invade each tissue. Motion-induced neuron deformation and damage are associated with several neurodegenerative conditions. Here, we investigated the question of how the neuronal cytoskeleton protects axons and dendrites from mechanical stress, exploiting mutations in UNC-70 β-spectrin, PTL-1 tau/MAP2-like and MEC-7 β-tubulin proteins in Caenorhabditis elegans. We found that mechanical stress induces supercoils and plectonemes in the sensory axons of spectrin and tau double mutants. Biophysical measurements, super-resolution and electron microscopy, as well as numerical simulations of neurons as discrete, elastic rods provide evidence that a balance of torque, tension, and elasticity stabilizes neurons against mechanical deformation. We conclude that the spectrin and microtubule cytoskeletons work in combination to protect axons and dendrites from mechanical stress, and propose that defects in -spectrin and tau may sensitize neurons to damage.

Article and author information

Author details

  1. Michael Krieg

    Institute of Photonic Sciences, Barcelona, Spain
    Competing interests
    No competing interests declared.
  2. Jan Stühmer

    Department of Informatics, Technical University of Munich, München, Germany
    Competing interests
    No competing interests declared.
  3. Juan G Cueva

    Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  4. Richard Fetter

    Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  5. Kerri A Spliker

    Institute of Photonic Sciences, Barcelona, Spain
    Competing interests
    No competing interests declared.
  6. Daniel Cremers

    Department of Informatics, Technical University of Munich, München, Germany
    Competing interests
    No competing interests declared.
  7. Kang Shen

    Department of Biology, Stanford University, Stanford, United States
    Competing interests
    Kang Shen, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4059-8249
  8. Alexander R Dunn

    Department of Chemical Engineering, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6096-4600
  9. Miriam B Goodman

    Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
    For correspondence
    mbgoodmn@stanford.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5810-1272

Funding

National Institute of Neurological Disorders and Stroke (R01NS092099-02)

  • Alexander R Dunn
  • Miriam B Goodman

National Institute of Neurological Disorders and Stroke (5K99NS089942-02)

  • Michael Krieg

Howard Hughes Medical Institute

  • Kang Shen
  • Alexander R Dunn

H2020 European Research Council (ERC-2014-CoG)

  • Jan Stühmer
  • Daniel Cremers

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Anna Akhmanova, Utrecht University, Netherlands

Publication history

  1. Received: July 29, 2016
  2. Accepted: January 17, 2017
  3. Accepted Manuscript published: January 18, 2017 (version 1)
  4. Version of Record published: February 8, 2017 (version 2)
  5. Version of Record updated: February 10, 2017 (version 3)

Copyright

© 2017, Krieg et al.

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

Metrics

  • 2,628
    Page views
  • 607
    Downloads
  • 43
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    Chaitanya A Kulkarni et al.
    Research Article

    Alkb homolog 7 (ALKBH7) is a mitochondrial α-ketoglutarate dioxygenase required for DNA alkylation induced necrosis, but its function and substrates remain unclear. Herein we show ALKBH7 regulates dialdehyde metabolism, which impacts the cardiac response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we find no evidence ALKBH7 functions as a prolyl-hydroxylase, but we do find Alkbh7-/- mice have elevated glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Metabolic pathways related to the glycolytic by-product methylglyoxal (MGO) are rewired in Alkbh7-/- mice, along with elevated levels of MGO protein adducts. Despite greater glycative stress, hearts from Alkbh7-/- mice are protected against IR injury, in a manner blocked by GLO-1 inhibition. Integrating these observations, we propose ALKBH7 regulates glyoxal metabolism, and that protection against necrosis and cardiac IR injury bought on by ALKBH7 deficiency originates from the signaling response to elevated MGO stress.

    1. Cell Biology
    Eben G Estell et al.
    Short Report

    The myokine irisin facilitates muscle-bone crosstalk and skeletal remodeling in part by its action on osteoblasts and osteocytes. In the current study we investigated whether irisin also directly regulates osteoclasts. In vitro, irisin (2-10 ng/mL) increased osteoclast differentiation in C57BL/6J mouse bone marrow progenitors; this increase was blocked by a neutralizing antibody to integrin αVβ5. Irisin also increased bone resorption on several substrates in situ. RNAseq revealed differential gene expression induced by irisin including upregulation of markers for osteoclast differentiation and resorption, as well as osteoblast-stimulating 'clastokines'. Forced expression of the irisin precursor Fndc5 in transgenic C57BL/6J mice resulted in low bone mass at three ages, and greater in vitro osteoclastogenesis from Fndc5-transgenic bone marrow progenitors. This work demonstrates that irisin acts directly on osteoclast progenitors to increase differentiation and promote bone resorption, supporting the tenet that irisin not only stimulates bone remodeling but may also be an important counter-regulatory hormone.