Calpains mediate axonal cytoskeleton disintegration during Wallerian degeneration

Marek Ma, Toby A. Ferguson, Kathleen M. Schoch, Jian Li, Yaping Qian, Frances S. Shofer, Kathryn E. Saatman, Robert W. Neumar

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

In both the central nervous system (CNS) and peripheral nervous system (PNS), transected axons undergo Wallerian degeneration. Even though Augustus Waller first described this process after transection of axons in 1850, the molecular mechanisms may be shared, at least in part, by many human diseases. Early pathology includes failure of synaptic transmission, target denervation, and granular disintegration of the axonal cytoskeleton (GDC). The Ca2+-dependent protease calpains have been implicated in GDC but causality has not been established. To test the hypothesis that calpains play a causal role in axonal and synaptic degeneration in vivo, we studied transgenic mice that express human calpastatin (hCAST), the endogenous calpain inhibitor, in optic and sciatic nerve axons. Five days after optic nerve transection and 48h after sciatic nerve transection, robust neurofilament proteolysis observed in wild-type controls was reduced in hCAST transgenic mice. Protection of the axonal cytoskeleton in sciatic nerves of hCAST mice was nearly complete 48h post-transection. In addition, hCAST expression preserved the morphological integrity of neuromuscular junctions. However, compound muscle action potential amplitudes after nerve transection were similar in wild-type and hCAST mice. These results, in total, provide direct evidence that calpains are responsible for the morphological degeneration of the axon and synapse during Wallerian degeneration.

Original languageEnglish
Pages (from-to)34-46
Number of pages13
JournalNeurobiology of Disease
Volume56
DOIs
StatePublished - Aug 2013

Bibliographical note

Funding Information:
We thank Steven S. Scherer (University of Pennsylvania) for his guidance in many aspects of this project, Glenn C. Telling (Colorado State University) who created the transgenic mice, and Dewight Williams (University of Pennsylvania) and John M. Hoffpauir for assistance with electron microscopy. This work was supported by National Institutes of Health grants K08NS055880 (MM), K08NS065157 (TAF), P30AR050950 (TAF, S. S. Scherer, Penn Center for Musculoskeletal Disorders), F31NS071804 (KMS), and P01NS058484 (KES), Shriners Pediatric Research Center Seed funding (TAF), and Kentucky Spinal Cord and Head Injury Research Trust (KSCHIRT) 6–12 (KES).

Keywords

  • Axon
  • Calpain
  • Calpastatin
  • Neurofilament
  • Neuromuscular junction
  • Wallerian degeneration

ASJC Scopus subject areas

  • Neurology

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