Journal
JOURNAL OF CELL SCIENCE
Volume 129, Issue 3, Pages 517-530Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.173864
Keywords
ALS; BDNF; TrkB; Motor neuron; p75NTR; NGFR; Survival
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Funding
- National Health and Medical Research Council of Australia [569601, 10012610]
- Australian Research Council
- NuNerve Pty Ltd [LP10012610]
- Goodenough and Wantoks bequest
- Australian Government
- Ross Maclean Fellowship
- Centre for Neuroscience, Flinders University and the Flinders Medical Centre Research Foundation
- Australian Rotary Health
- Motor Neuron Disease Reseach Instititue of Australia
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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.
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