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

D Matusica, F Alfonsi, B Turner, T Butler, S Skeldal, CK Underwood, M Mangelsdorf, EJ Coulson

Research output: Contribution to conferenceAbstractpeer-review


The neurotrophin receptor (p75 NTR) is expressed by developing, injured and degenerating motor neurons, and can be activated by nerve growth factor (NGF) to mediate motor neuron apoptosis. p75NTR undergoes regulated intramembrane proteolysis (RIP), which regulates the activation of many if its signalling pathways. Here we report that inhibition of p75 NTR extracellular proteolysis prevents NGF-induced death of cultured motor neurons. By contrast,
inhibition of intracellular proteolysis of p75 NTR , preventing the generation of p75 ICD, promoted motor neuron death. We have recently reported that p75 ICD is required for facilitating survival signalling by TrkA receptors and that a 29 amino acid juxtamembrane intracellular region of p75ICD mediated this effect. Here, we found that a peptide orthologue of this domain, c29, similarly facilitates of TrkB receptor signaling. c29 treatment inhibited NGF-induced death of cultured motor neurons, and enhanced the survival of motor neurons undergoing growth factor withdrawal in a BDNF, but not CNTF- and GDNF-dependent manner. Furthermore, in an injury paradigm, c29 treatment prevented the death of axotomised ulnar motor neurons invivo. More importantly treatment of Sod1 G93A motor neuron disease mice with c29 for 60 days significantly enhanced the survival of spinal motor neurons in late disease. We conclude that proteolysis of p75 NTR plays an important role in mediating NGF-mediated cell death and facilitating BDNF-dependent survival of motor neurons. These studies also suggest that modulation of BDNF/TrkB signaling by the c29 peptide mimetic of the p75 NTR intracellular domain represents a novel strategy for treating motor neuron degeneration. (245)
Original languageEnglish
Number of pages1
Publication statusPublished - 30 Jan 2014
Externally publishedYes
EventAustralian Neuroscience Society 34th Annual Meeting: "The major neuroscience conference in Australasia" - Adelaide Convention Centre, Adelaide, Australia
Duration: 28 Jan 201431 Jan 2014 (ANS 2014 Programme)


ConferenceAustralian Neuroscience Society 34th Annual Meeting
Abbreviated titleANS Adelaide
Internet address


  • Conference abstract
  • Conference poster
  • Australasian Neuroscience Society (ANS)
  • neurotrophin receptor (p75 NTR)
  • nerve growth factor (NGF)
  • regulated intramembrane proteolysis (RIP)
  • inhibition of p75 NTR extracellular proteolysis


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