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

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dc.contributor.authorTanaka, Kazuhiroen_ZA
dc.contributor.authorKelly, Claire E.en_ZA
dc.contributor.authorGoh, Ket Yinen_ZA
dc.contributor.authorLim, Kim Buayen_ZA
dc.contributor.authorIbanez, Carlos F.en_ZA
dc.date.accessioned2017-07-10T13:51:06Z
dc.date.available2017-07-10T13:51:06Z
dc.date.issued2016-05-18
dc.descriptionCITATION: 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.
dc.descriptionThe original publication is available at http://www.jneurosci.org
dc.description.abstractThe 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.en_ZA
dc.description.urihttp://www.jneurosci.org/content/36/20/5587
dc.description.versionPublisher's version
dc.format.extent9 pages
dc.identifier.citationTanaka, 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.
dc.identifier.issn1529-2401 (online)
dc.identifier.issn0270-6474 (print)
dc.identifier.otherdoi:10.1523/JNEUROSCI.4536-15.2016
dc.identifier.urihttp://hdl.handle.net/10019.1/101934
dc.language.isoen_ZAen_ZA
dc.publisherSociety for Neuroscience
dc.rights.holderAuthors retain copyright
dc.subjectApoptosisen_ZA
dc.subjectNeurons -- Growthen_ZA
dc.subjectEpilepsyen_ZA
dc.subjectNeurotrophic functionsen_ZA
dc.subjectSeizuresen_ZA
dc.subjectDeath receptorsen_ZA
dc.subjectNervous system -- Degenerationen_ZA
dc.subjectP75NTRen_ZA
dc.subjectDimersen_ZA
dc.titleDeath domain signaling by disulfide-linked dimers of the p75 neurotrophin receptor mediates neuronal death in the CNSen_ZA
dc.typeArticleen_ZA
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