Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment.
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.
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia Department of Anatomy & Histology, Centre for Neuroscience, Flinders University, GPO Box 2100, Adelaide, South Australia 5001, Australia.
Dusan
D
Matusica
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
Fabienne
F
Alfonsi
The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3052, Victoria 3051, Australia.
Bradley J
BJ
Turner
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
Tim J
TJ
Butler
Department of Human Physiology, Centre for Neuroscience, Flinders University, GPO Box 2100, Adelaide, South Australia 5001, Australia.
Stephanie R
SR
Shepheard
Department of Human Physiology, Centre for Neuroscience, Flinders University, GPO Box 2100, Adelaide, South Australia 5001, Australia.
Mary-Louise
ML
Rogers
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
Sune
S
Skeldal
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
Clare K
CK
Underwood
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
Marie
M
Mangelsdorf
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia e.coulson@uq.edu.au.
Elizabeth J
EJ
Coulson
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D057846:Cell-Penetrating Peptides / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D057846:Cell-Penetrating Peptides; D020800:Receptor, Nerve Growth Factor; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
ALS; BDNF; Motor neuron; NGFR; Survival; TrkB; p75NTR