RT Journal Article
SR Electronic
T1 Death Domain Signaling by Disulfide-Linked Dimers of the p75 Neurotrophin Receptor Mediates Neuronal Death in the CNS
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 5587
OP 5595
DO 10.1523/JNEUROSCI.4536-15.2016
VO 36
IS 20
A1 Kazuhiro Tanaka
A1 Claire E. Kelly
A1 Ket Yin Goh
A1 Kim Buay Lim
A1 Carlos F. Ibáñez
YR 2016
UL http://www.jneurosci.org/content/36/20/5587.abstract
AB 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.