Molecular analysis of axonal-intrinsic and glial-associated co-regulation of axon degeneration

Cell Death Dis. 2017 Nov 9;8(11):e3166. doi: 10.1038/cddis.2017.489.

Abstract

Wallerian degeneration is an active program tightly associated with axonal degeneration, required for axonal regeneration and functional recovery after nerve damage. Here we provide a functional molecular foundation for our undertstanding of the complex non-cell autonomous role of glial cells in the regulation of axonal degeneration. To shed light on the complexity of the molecular machinery governing axonal degeneration we employ a multi-model, unbiased, in vivo approach combining morphological assesment and quantitative proteomics with in silico-based higher order functional clustering to genetically uncouple the intrinsic and extrinsic processes governing Wallerian degeneration. Highlighting a pivotal role for glial cells in the early stages fragmenting the axon by a cytokinesis-like process and a cell autonomous stage of axonal disintegration associated to mitochondrial dysfunction.

MeSH terms

  • Animals
  • Axons / metabolism*
  • Cell Dedifferentiation / drug effects
  • Cells, Cultured
  • Contractile Proteins / antagonists & inhibitors
  • Contractile Proteins / genetics
  • Contractile Proteins / metabolism
  • Cyclophilin D
  • Cyclophilins / deficiency
  • Cyclophilins / genetics
  • Dactinomycin / pharmacology
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelin Sheath / physiology
  • Neuroglia / cytology
  • Neuroglia / metabolism*
  • Proteomics
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / injuries
  • Wallerian Degeneration / metabolism
  • Wallerian Degeneration / pathology
  • rho-Associated Kinases / metabolism

Substances

  • Contractile Proteins
  • Cyclophilin D
  • PPIF protein, mouse
  • anillin
  • Dactinomycin
  • rho-Associated Kinases
  • Cyclophilins