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Death domain signaling by disulfide-linked dimers of the p75 neurotrophin receptor mediates neuronal death in the CNS

Tanaka, Kazuhiro ; Kelly, Claire E. ; Goh, Ket Yin ; Lim, Kim Buay ; Ibanez, Carlos F. (2016-05-18)

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

Article

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.

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