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

Dusan Matusica, Fabienne Alfonsi, Bradley Turner, Tim Butler, Stephanie Shepheard, Mary-Louise Rogers, Sune Skeldal, Clare Underwood, Marie Mangelsdorf, Elizabeth Coulson

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    11 Citations (Scopus)

    Abstract

    The p75 neurotrophin receptor (p75NTR; 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 p75NTR-derived trophic cell-permeable peptide, c29, to inhibit p75NTR-mediated motor neuron death. Acute c29 application to axotomized motor neuron axons decreased cell death, and systemic c29 treatment of SOD1G93A 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 p75NTR 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 p75NTR in motor-neuron-like NSC-34 cells, there was no direct effect of c29 on p75NTR 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 SOD1G93A mice. We conclude that the c29 peptide facilitates BDNF-dependent survival of motor neurons in vitro and in vivo.

    Original languageEnglish
    Pages (from-to)517-530
    Number of pages14
    JournalJournal of Cell Science
    Volume129
    Issue number3
    DOIs
    Publication statusPublished - 2016

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  • Cite this

    Matusica, D., Alfonsi, F., Turner, B., Butler, T., Shepheard, S., Rogers, M-L., Skeldal, S., Underwood, C., Mangelsdorf, M., & Coulson, E. (2016). Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment. Journal of Cell Science, 129(3), 517-530. https://doi.org/10.1242/jcs.173864