Retrograde Degenerative Signaling Mediated by the p75 Neurotrophin Receptor Requires p150Glued Deacetylation by Axonal HDAC1

Pathak, Amrita; Stanley, Emily M.; Hickman, F. Edward; Wallace, Natalie; Brewer, Bryson M.; Li, Deyu; Gluska, Shani; Perlson, Eran; Fuhrmann, Sabine; Akassoglou, Katerina; Bronfman, Francisca C.; Casaccia, Patrizia; Burnette, Dylan T.; Carter, Bruce D.

doi:10.1016/j.devcel.2018.07.001

Cited by 26 publications

(30 citation statements)

References 64 publications

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“…Consistent with the notion of a transcriptional feedback loop, this pathway has been shown to up-regulate TNFα-converting enzyme (TACE), which is necessary for p75NTR cleavage (Kenchappa et al, 2010). Liberation of the p75NTR ICD retrograde degenerative signal is accompanied by secondary activation of JNK and up-regulation of proapoptotic factors like p53upregulated modulator of apoptosis (Puma) (Kenchappa et al, 2010;Simon et al, 2016;Pathak et al, 2018). The time it takes to engage this transcriptional program and cleave p75NTR by TACE and γ-secretase may represent a molecular timer governing the duration of the latency window (Pathak and Carter, 2017).…”

Section: Discussionmentioning

confidence: 75%

p75NTR and DR6 regulate distinct phases of axon degeneration demarcated by spheroid rupture

Gamage

Cheng

et al. 2019

Preprint

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The regressive events associated with trophic deprivation are critical for sculpting a functional nervous system. After nerve growth factor withdrawal, sympathetic axons maintain their structural integrity for roughly 18 hours (latent phase) followed by a rapid and near unison disassembly of axons over the next 3 hours (catastrophic phase). Here we examine the molecular basis by which axons transition from latent to catastrophic phases of degeneration following trophic withdrawal. Prior to catastrophic degeneration, we observed an increase in intra-axonal calcium. This calcium flux is accompanied by p75 neurotrophic factor receptor (NTR)-Rho-actin dependent expansion of calcium rich axonal spheroids that eventually rupture, releasing their contents to the extracellular space. Conditioned media derived from degenerating axons is capable of hastening transition into the catastrophic phase of degeneration. We also found that death receptor 6 (DR6) but not p75NTR is required for transition into the catastrophic phase in response to conditioned media but not for the intra-axonal calcium flux, spheroid formation, or rupture that occurs toward the end of latency. Our results support the existence of an inter-axonal degenerative signal that promotes catastrophic degeneration among trophically deprived axons.Similar intra-axonal calcium waves have been observed prior to catastrophic fragmentation in injured zebrafish peripheral sensory axons (Vargas et al., 2015). Moreover, it was recently shown that axoplasmic calcium increases before the emergence of gross morphological changes in NGF deprived DRG cultures (Johnstone et al., 2019) suggesting that intra-axonal calcium signaling could play a role in all phases of degeneration.We sought to identify the signaling events that occur during the transition between latent and catastrophic phases of degeneration induced by trophic withdrawal. To this end, we asked the following questions: 1. What is the role of calcium in the latent and catastrophic phase in response to NGF deprivation? It may be that flux in intra-axonal calcium acts as a trigger for trophically deprived axons to exit the latent phase and enter the catastrophic phase. 2. What are the signaling events that regulate the commitment to irreversible fragmentation? The engagement of calcium is well established in the execution phase of injury induced axon degeneration (Conforti et al., 2014), however whether other signaling pathways act permissively to allow calcium dependent irreversible fragmentation in response to trophic withdrawal remains an open question. 3. What are the relative contributions of receptors p75NTR and DR6 to latent and catastrophic phases of degeneration? Because loss of p75NTR and DR6 showed different kinetics of axon degeneration after NGF deprivation (Gamage et al., 2017), we hypothesize that these death receptors may be required for different phases of degeneration.Similar to injury paradigms, we demonstrate that after trophic deprivation, intra-axonal calcium increases prior to catastrophic ...

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Section: Discussionmentioning

confidence: 75%

p75NTR and DR6 regulate distinct phases of axon degeneration demarcated by spheroid rupture

Gamage

Cheng

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…This pathway has been shown to upregulate TNF␣-converting enzyme, which is necessary for p75NTR cleavage (Kenchappa et al, 2010). Liberation of the p75NTR intracellular domain retrograde degenerative signal is accompanied by secondary activation of JNK and upregulation of proapoptotic factors, such as p53upregulated modulator of apoptosis (Kenchappa et al, 2010;Simon et al, 2016;Pathak et al, 2018). The time it takes to engage this transcriptional program and cleave p75NTR by TNF␣converting enzyme and ␥-secretase may represent a molecular timer governing the duration of the latency window (Pathak and Carter, 2017).…”

Section: Discussionmentioning

confidence: 99%

p75NTR and DR6 Regulate Distinct Phases of Axon Degeneration Demarcated by Spheroid Rupture

Yu¹,

Gamage²,

Cheng³

et al. 2019

J. Neurosci.

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The regressive events associated with trophic deprivation are critical for sculpting a functional nervous system. After nerve growth factor withdrawal, sympathetic axons derived from male and female neonatal mice maintain their structural integrity for ϳ18 h (latent phase) followed by a rapid and near unison disassembly of axons over the next 3 h (catastrophic phase). Here we examine the molecular basis by which axons transition from latent to catastrophic phases of degeneration following trophic withdrawal. Before catastrophic degeneration, we observed an increase in intra-axonal calcium. This calcium flux is accompanied by p75 neurotrophic factor receptor-Rho-actindependent expansion of calcium-rich axonal spheroids that eventually rupture, releasing their contents to the extracellular space. Conditioned media derived from degenerating axons are capable of hastening transition into the catastrophic phase of degeneration. We also found that death receptor 6, but not p75 neurotrophic factor receptor, is required for transition into the catastrophic phase in response to conditioned media but not for the intra-axonal calcium flux, spheroid formation, or rupture that occur toward the end of latency. Our results support the existence of an interaxonal degenerative signal that promotes catastrophic degeneration among trophically deprived axons.

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“…However, p75 NTR also can signal retrogradely from the axon terminus to the soma to induce neuronal cell death. Although Trk activation promotes release of the p75 NTR ICD, loss of NGF-dependent TrkA activation in sympathetic neurons causes enhanced production of the ICD fragment and HDAC1-dependent retrograde trafficking of this fragment mediates retrograde axonal conveyance of the p75 NTR cell death signal 44 . Similarly, enhanced release of the p75 NTR ICD fragment has been implicated as a mechanism responsible for neuronal cell death promoted by unliganded TrkA and TrkC in the developing peripheral nervous system 20 .…”

Section: Control Of Anterograde and Retrograde Receptor Traffickingmentioning

confidence: 99%

Recent advances in understanding context-dependent mechanisms controlling neurotrophin signaling and function

Bothwell

2019

F1000Res

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Complex mechanisms control the signaling of neurotrophins through p75NTR and Trk receptors, allowing cellular responses that are highly context dependent, particularly in the nervous system and particularly with regard to the neurotrophin brain-derived neurotrophic factor (BDNF). Recent reports describe a variety of sophisticated regulatory mechanisms that contribute to such functional flexibility. Mechanisms described include regulation of trafficking of alternative BDNF transcripts, regulation of post-translational processing and secretion of BDNF, engagement of co-receptors that influence localization and signaling of p75NTR and Trk receptors, and control of trafficking of receptors in the endocytic pathway and during anterograde and retrograde axonal transport.

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Retrograde Degenerative Signaling Mediated by the p75 Neurotrophin Receptor Requires p150Glued Deacetylation by Axonal HDAC1

Cited by 26 publications

References 64 publications

p75NTR and DR6 regulate distinct phases of axon degeneration demarcated by spheroid rupture

p75NTR and DR6 regulate distinct phases of axon degeneration demarcated by spheroid rupture

p75NTR and DR6 Regulate Distinct Phases of Axon Degeneration Demarcated by Spheroid Rupture

Recent advances in understanding context-dependent mechanisms controlling neurotrophin signaling and function

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