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

Elife. 2016 Aug 9;5:e17119. doi: 10.7554/eLife.17119.

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)P2)-levels, myelin septins (SEPT2/SEPT4/SEPT7/SEPT8) and the PI(4,5)P2-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.

Keywords: glial cells; label-free proteomics; mouse; myelin structure; myelinated axons; neuropathology; neuroscience; septin cytoskeleton.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Central Nervous System / chemistry
  • Central Nervous System / physiology*
  • Contractile Proteins / metabolism*
  • Cytoskeleton / metabolism
  • Gene Knockout Techniques
  • Gene Targeting
  • Mice
  • Microscopy, Confocal
  • Microscopy, Immunoelectron
  • Myelin Sheath / metabolism*
  • Nerve Fibers, Myelinated / chemistry
  • Nerve Fibers, Myelinated / physiology
  • Neural Conduction*
  • Protein Multimerization
  • Proteome / analysis
  • Proteomics
  • Septins / genetics
  • Septins / metabolism*

Substances

  • Contractile Proteins
  • Proteome
  • anillin
  • Septins

Grant support

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