Death domain signaling by disulfide-linked dimers of the p75 neurotrophin receptor mediates neuronal death in the CNS
Date
2016-05-18
Journal Title
Journal ISSN
Volume Title
Publisher
Society for Neuroscience
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 (Cys 259) 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 p75NTRDD, or just Cys 259
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 Cys 259were identical
tothose of p75NTR knock-out mice eventhoughthe Cys 259mutant differedfromthe wild-type receptorin only one amino acid residue.We
conclude that, both in vitro and in vivo, neuronal death induced by p75NTR requires the DD and TM Cys 259, supporting the physiological
relevance of DD signaling by disulfide-linked dimers of p75NTR in the CNS.
Description
CITATION: Tanaka, K. et al. 2016. Death domain signaling by disulfide-linked dimers of the p75 neurotrophin receptor mediates neuronal death in the CNS. Journal of Neuroscience, 36(20):5587-5595, doi:10.1523/JNEUROSCI.4536-15.2016.
The original publication is available at http://www.jneurosci.org
The original publication is available at http://www.jneurosci.org
Keywords
Apoptosis, Neurons -- Growth, Epilepsy, Neurotrophic functions, Seizures, Death receptors, Nervous system -- Degeneration, P75NTR, Dimers
Citation
Tanaka, K. et al. 2016. Death domain signaling by disulfide-linked dimers of the p75 neurotrophin receptor mediates neuronal death in the CNS. Journal of Neuroscience, 36(20):5587-5595, doi:10.1523/JNEUROSCI.4536-15.2016.