Methylglyoxal Disrupts Paranodal Axoglial Junctions via Calpain Activation

ASN Neuro. 2018 Jan-Dec:10:1759091418766175. doi: 10.1177/1759091418766175.

Abstract

Nodes of Ranvier and associated paranodal and juxtaparanodal domains along myelinated axons are essential for normal function of the peripheral and central nervous systems. Disruption of these domains as well as increases in the reactive carbonyl species methylglyoxal are implicated as a pathophysiology common to a wide variety of neurological diseases. Here, using an ex vivo nerve exposure model, we show that increasing methylglyoxal produces paranodal disruption, evidenced by disorganized immunostaining of axoglial cell-adhesion proteins, in both sciatic and optic nerves from wild-type mice. Consistent with previous studies showing that increase of methylglyoxal can alter intracellular calcium homeostasis, we found upregulated activity of the calcium-activated protease calpain in sciatic nerves after methylglyoxal exposure. Methylglyoxal exposure altered clusters of proteins that are known as calpain substrates: ezrin in Schwann cell microvilli at the perinodal area and zonula occludens 1 in Schwann cell autotypic junctions at paranodes. Finally, treatment with the calpain inhibitor calpeptin ameliorated methylglyoxal-evoked ezrin loss and paranodal disruption in both sciatic and optic nerves. Our findings strongly suggest that elevated methylglyoxal levels and subsequent calpain activation contribute to the disruption of specialized axoglial domains along myelinated nerve fibers in neurological diseases.

Keywords: calpain; methylglyoxal; myelin; neuron-glia interaction; paranode.

MeSH terms

  • Animals
  • Axons / drug effects*
  • Axons / metabolism
  • Calpain / metabolism*
  • Cytoskeletal Proteins / metabolism
  • Dipeptides / pharmacology
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation / drug effects
  • In Vitro Techniques
  • Male
  • Membrane Proteins / metabolism
  • Membrane Proteins / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Muscle Proteins / metabolism
  • Neuroeffector Junction / drug effects*
  • Neuroglia / drug effects*
  • Neuroglia / metabolism
  • Optic Nerve / cytology
  • Pan paniscus / metabolism
  • Phosphate Transport Proteins / metabolism
  • Pyruvaldehyde / pharmacology*
  • Ranvier's Nodes / drug effects*
  • Sciatic Nerve / cytology
  • Zonula Occludens-1 Protein / metabolism

Substances

  • Cytoskeletal Proteins
  • Dipeptides
  • Membrane Proteins
  • Muscle Proteins
  • Phosphate Transport Proteins
  • Tjp1 protein, mouse
  • Zonula Occludens-1 Protein
  • ank protein, mouse
  • calpain activator
  • dystrophin-related protein 2
  • calpeptin
  • Pyruvaldehyde
  • Calpain