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Articles, Development/Plasticity/Repair

Death Domain Signaling by Disulfide-Linked Dimers of the p75 Neurotrophin Receptor Mediates Neuronal Death in the CNS

Kazuhiro Tanaka, Claire E. Kelly, Ket Yin Goh, Kim Buay Lim and Carlos F. Ibáñez
Journal of Neuroscience 18 May 2016, 36 (20) 5587-5595; DOI: https://doi.org/10.1523/JNEUROSCI.4536-15.2016
Kazuhiro Tanaka
1Department of Physiology, National University of Singapore, Singapore 117597, Singapore,
2Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore,
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Claire E. Kelly
3Department of Neuroscience, Karolinska Institute, Stockholm S-17177, Sweden, and
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Ket Yin Goh
1Department of Physiology, National University of Singapore, Singapore 117597, Singapore,
2Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore,
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Kim Buay Lim
1Department of Physiology, National University of Singapore, Singapore 117597, Singapore,
2Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore,
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Carlos F. Ibáñez
1Department of Physiology, National University of Singapore, Singapore 117597, Singapore,
2Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore,
3Department of Neuroscience, Karolinska Institute, Stockholm S-17177, Sweden, and
4Stellenbosch Institute for Advanced Study, Wallenberg Research Centre at Stellenbosch University, Stellenbosch 7600, South Africa
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Abstract

The p75 neurotrophin receptor (p75NTR) mediates neuronal death in response to neural insults by activating a caspase apoptotic pathway. The oligomeric state and activation mechanism that enable p75NTR to mediate these effects have recently been called into question. Here, we have investigated mutant mice lacking the p75NTR death domain (DD) or a highly conserved transmembrane (TM) cysteine residue (Cys259) implicated in receptor dimerization and activation. Neuronal death induced by proneurotrophins or epileptic seizures was assessed and compared with responses in p75NTR knock-out mice and wild-type animals. Proneurotrophins induced apoptosis of cultured hippocampal and cortical neurons from wild-type mice, but mutant neurons lacking p75NTR, only the p75NTR DD, or just Cys259 were all equally resistant to proneurotrophin-induced neuronal death. Homo-FRET anisotropy experiments demonstrated that both NGF and proNGF induce conformational changes in p75NTR that are dependent on the TM cysteine. In vivo, neuronal death induced by pilocarpine-mediated seizures was significantly reduced in the hippocampus and somatosensory, piriform, and entorhinal cortices of all three strains of p75NTR mutant mice. Interestingly, the levels of protection observed in mice lacking the DD or only Cys259 were identical to those of p75NTR knock-out mice even though the Cys259 mutant differed from the wild-type receptor in only one amino acid residue. We conclude that, both in vitro and in vivo, neuronal death induced by p75NTR requires the DD and TM Cys259, supporting the physiological relevance of DD signaling by disulfide-linked dimers of p75NTR in the CNS.

SIGNIFICANCE STATEMENT A detailed understanding of the physiological significance of distinct structural determinants in the p75 neurotrophin receptor (p75NTR) is crucial for the identification of suitable drug targets in this receptor. We have tested the relevance of the p75NTR death domain (DD) and the highly conserved transmembrane residue Cys259 for the ability of p75NTR to induce apoptosis in neurons of the CNS using gene-targeted mutant mice. The physiological importance of these determinants had been contested in some recent in vitro studies. Our results indicate a requirement for DD signaling by disulfide-linked dimers of p75NTR for neuronal death induced by proneurotrophins and epileptic seizures. These new mouse models will be useful for clarifying different aspects of p75NTR physiology.

  • apoptosis
  • disulfide bond
  • epilepsy
  • neurotrophins
  • seizures
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The Journal of Neuroscience: 36 (20)
Journal of Neuroscience
Vol. 36, Issue 20
18 May 2016
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Death Domain Signaling by Disulfide-Linked Dimers of the p75 Neurotrophin Receptor Mediates Neuronal Death in the CNS
Kazuhiro Tanaka, Claire E. Kelly, Ket Yin Goh, Kim Buay Lim, Carlos F. Ibáñez
Journal of Neuroscience 18 May 2016, 36 (20) 5587-5595; DOI: 10.1523/JNEUROSCI.4536-15.2016

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Death Domain Signaling by Disulfide-Linked Dimers of the p75 Neurotrophin Receptor Mediates Neuronal Death in the CNS
Kazuhiro Tanaka, Claire E. Kelly, Ket Yin Goh, Kim Buay Lim, Carlos F. Ibáñez
Journal of Neuroscience 18 May 2016, 36 (20) 5587-5595; DOI: 10.1523/JNEUROSCI.4536-15.2016
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Keywords

  • apoptosis
  • disulfide bond
  • epilepsy
  • neurotrophins
  • seizures

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