Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment

J Cell Sci. 2016 Feb 1;129(3):517-30. doi: 10.1242/jcs.173864. Epub 2015 Oct 26.

Abstract

The p75 neurotrophin receptor (p75(NTR); also known as NGFR) can mediate neuronal apoptosis in disease or following trauma, and facilitate survival through interactions with Trk receptors. Here we tested the ability of a p75(NTR)-derived trophic cell-permeable peptide, c29, to inhibit p75(NTR)-mediated motor neuron death. Acute c29 application to axotomized motor neuron axons decreased cell death, and systemic c29 treatment of SOD1(G93A) mice, a common model of amyotrophic lateral sclerosis, resulted in increased spinal motor neuron survival mid-disease as well as delayed disease onset. Coincident with this, c29 treatment of these mice reduced the production of p75(NTR) cleavage products. Although c29 treatment inhibited mature- and pro-nerve-growth-factor-induced death of cultured motor neurons, and these ligands induced the cleavage of p75(NTR) in motor-neuron-like NSC-34 cells, there was no direct effect of c29 on p75(NTR) cleavage. Rather, c29 promoted motor neuron survival in vitro by enhancing the activation of TrkB-dependent signaling pathways, provided that low levels of brain-derived neurotrophic factor (BDNF) were present, an effect that was replicated in vivo in SOD1(G93A) mice. We conclude that the c29 peptide facilitates BDNF-dependent survival of motor neurons in vitro and in vivo.

Keywords: ALS; BDNF; Motor neuron; NGFR; Survival; TrkB; p75NTR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cell Death / physiology*
  • Cell Survival / physiology
  • Cell-Penetrating Peptides / metabolism*
  • Cells, Cultured
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Neurons / metabolism*
  • Receptor, Nerve Growth Factor / metabolism*
  • Signal Transduction / physiology
  • Spinal Cord / metabolism
  • Spinal Cord / physiology
  • Superoxide Dismutase / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Cell-Penetrating Peptides
  • Receptor, Nerve Growth Factor
  • SOD1 G93A protein
  • Superoxide Dismutase