Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL

Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):6007-12. doi: 10.1073/pnas.0508774103. Epub 2006 Mar 31.

Abstract

The reasons for the cellular specificity and slow progression of motoneuron diseases such as ALS are still poorly understood. We previously described a motoneuron-specific cell death pathway downstream of the Fas death receptor, in which synthesis of nitric oxide (NO) is an obligate step. Motoneurons from ALS model mice expressing mutant SOD1 showed increased susceptibility to exogenous NO as compared with controls. Here, we report a signaling mechanism whereby NO leads to death of mutant, but not control, motoneurons. Unexpectedly, exogenous NO triggers expression of Fas ligand (FasL) in cultured motoneurons. In mutant SOD1(G93A) and SOD1(G85R), but not in control motoneurons, this up-regulation results in activation of Fas, leading through Daxx to phosphorylation of p38 and further NO synthesis. This Fas/NO feedback amplification loop is required for motoneuron death in vitro. In vivo, mutant SOD1(G93A) and SOD1(G85R) mice show increased numbers of positive motoneurons and Daxx nuclear bodies weeks before disease onset. Moreover, FasL up-regulation is reduced in the presence of transgenic dominant-negative Daxx. We propose that chronic low-level activation of the Fas/NO feedback loop may underlie the motoneuron loss that characterizes familial ALS and may help to explain its slowly progressive nature.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Co-Repressor Proteins
  • Crosses, Genetic
  • Fas Ligand Protein
  • Feedback
  • Female
  • Homozygote
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Models, Animal
  • Molecular Chaperones
  • Motor Neuron Disease / genetics
  • Motor Neuron Disease / pathology
  • Motor Neuron Disease / physiopathology*
  • Motor Neurons / physiology*
  • Nitric Oxide / physiology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide
  • Spinal Cord / pathology
  • Spinal Cord / physiopathology
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1
  • Tumor Necrosis Factors / genetics
  • Tumor Necrosis Factors / physiology*
  • fas Receptor / genetics
  • fas Receptor / physiology*

Substances

  • Carrier Proteins
  • Co-Repressor Proteins
  • Daxx protein, mouse
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Molecular Chaperones
  • Nuclear Proteins
  • Tumor Necrosis Factors
  • fas Receptor
  • Nitric Oxide
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1