The p75NTR intracellular domain generated by neurotrophin-induced receptor cleavage potentiates Trk signaling

Ceni, Claire; Kommaddi, Reddy Peera; Thomas, Rhalena A.; Vereker, Emily; Liu, Xiaoyang; McPherson, Peter S.; Ritter, Brigitte; Barker, Philip A.

doi:10.1242/jcs.062612

Cited by 68 publications

(79 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the precise mechanism responsible for this outcome remains elusive (Barker, 2007), the transmembrane and juxtamembrane regions of p75 NTR have been implicated in this interaction (Hempstead et al, 1991;Bibel et al, 1999;Esposito et al, 2001;Iacaruso et al, 2011), and more recent studies also suggest that cleavage of p75 NTR plays an important role in this process (Ceni et al, 2010;Kommaddi et al, 2011;Matusica et al, 2013). Our observation that a soluble peptide mimicking the juxtamembrane region of p75 NTR is able to enhance the function of TrkA (Matusica et al, 2013) and TrkB (herein) accords with the previous studies.…”

Section: Role Of the P75 Ntr Juxtamembrane (C29) Region In Trk Signalingsupporting

confidence: 89%

“…There is also emerging evidence that regulated intramembrane proteolysis might be important for p75 NTR functions, including induction of cell death signaling pathways and promotion of cell survival in vitro, although reports of ligand activation of p75 NTR cleavage are inconsistent (Kenchappa et al, 2006;Skeldal et al, 2011;Vicario et al, 2015). Our in vitro experiments measuring cleavage of endogenous p75 NTR in response to exogenous ligand application established that cell death ligands increase the production of the C-terminal fragment, which is associated with increased death signaling (Coulson et al, 1999;Vicario et al, 2015), whereas cell survival ligands result in greater production of the intracellular domain fragment, consistent with Trk-mediated cleavage of p75 NTR facilitating survival through this fragment (Ceni et al, 2010;Kommaddi et al, 2011;Matusica et al, 2013).…”

Section: Discussionsupporting

confidence: 66%

“…One characterized role of p75 NTR is its ability to increase ligandbinding affinity for the TrkA receptor and increase neuronal survival (Hempstead et al, 1991;Lee et al, 1994;Horton et al, 1997;Esposito et al, 2001), and it is widely accepted that p75 NTR also interacts with other Trk receptors with equivalent effect (Hempstead et al, 1991;Davies et al, 1993;Huber and Chao, 1995;Bibel et al, 1999;Vesa et al, 2000;Ceni et al, 2010;Kommaddi et al, 2011). Although the precise mechanism responsible for this outcome remains elusive (Barker, 2007), the transmembrane and juxtamembrane regions of p75 NTR have been implicated in this interaction (Hempstead et al, 1991;Bibel et al, 1999;Esposito et al, 2001;Iacaruso et al, 2011), and more recent studies also suggest that cleavage of p75 NTR plays an important role in this process (Ceni et al, 2010;Kommaddi et al, 2011;Matusica et al, 2013).…”

Section: Role Of the P75 Ntr Juxtamembrane (C29) Region In Trk Signalingmentioning

confidence: 99%

“…An important mechanism in this process appears to be the generation of biologically active receptor fragments following enzymatic cleavage of p75 NTR (Ceni et al, 2010;Kommaddi et al, 2011;Matusica et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment

Matusica

Alfonsi

Turner

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

The p75 neurotrophin receptor ( p75 NTR ; also known as NGFR) can mediate neuronal apoptosis in disease or following trauma, and facilitate survival through interactions with Trk receptors. Here we tested the ability of a p75NTR -derived trophic cell-permeable peptide, c29, to inhibit p75 NTR -mediated motor neuron death. Acute c29 application to axotomized motor neuron axons decreased cell death, and systemic c29 treatment of SOD1 G93A mice, a common model of amyotrophic lateral sclerosis, resulted in increased spinal motor neuron survival mid-disease as well as delayed disease onset. Coincident with this, c29 treatment of these mice reduced the production of p75 NTR cleavage products. Although c29 treatment inhibited mature-and pro-nerve-growth-factor-induced death of cultured motor neurons, and these ligands induced the cleavage of p75 NTR in motor-neuron-like NSC-34 cells, there was no direct effect of c29 on p75 NTR cleavage. Rather, c29 promoted motor neuron survival in vitro by enhancing the activation of TrkB-dependent signaling pathways, provided that low levels of brain-derived neurotrophic factor (BDNF) were present, an effect that was replicated in vivo in SOD1 G93A mice. We conclude that the c29 peptide facilitates BDNF-dependent survival of motor neurons in vitro and in vivo.

show abstract

Section: Role Of the P75 Ntr Juxtamembrane (C29) Region In Trk Signalingsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 66%

Section: Role Of the P75 Ntr Juxtamembrane (C29) Region In Trk Signalingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment

Matusica

Alfonsi

Turner

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…The ICD has been associated with mediating both neuronal survival and death signalling (Casademunt et al, 1999, Kenchappa et al, 2006, Coulson et al, 2009, Ceni et al, 2010, Matusica et al, 2013, Vicario et al, 2015, Matusica et al, 2016. Survival signalling of the ICD fragment has been reported to occur through formation of a signalling complex with a member of the Trk receptor family and initiation of neurotrophin-induced ERK and Akt signalling and thus enhancement of Trk survival signalling (Ceni et al, 2010, Matusica et al, 2013, Matusica et al, 2016. It is from this ICD fragment that the soluble peptide mimic, c29, was derived.…”

Section: C29 Peptide As An Enhancer Of Neurotrophic Signallingmentioning

confidence: 99%

Neurotrophin regulation of Alzheimer's disease pathology

Turnbull¹

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized histopathologically by the accumulation of amyloid-β (Aβ) and hyperphosphorylation of tau protein. These two key proteins are major contributors to neuronal toxicity and disease progression; however, the causal factors initiating this toxic cascade in sporadic disease are unknown. We hypothesize that the specific degeneration of basal forebrain cholinergic neurons (BFCNs) and a decrease in neurotrophin availability -which occur coincidentally with the disease -are key regulators of aberrant Aβ accumulation and tau hyperphosphorylation, and could constitute the molecular basis of AD pathology in sporadic disease. Here we show that loss of BFCN innervation to the hippocampus of two pre-symptomatic mouse lines modelling the disease (APP/PS1 and pR5 (P301L) mice) causes a reduction in hippocampal and nerve growth factor (NGF) protein and/or brain-derived neurotrophic factor (BDNF). In APP/PS1 mice this correlates with memory and learning deficits in a Morris water maze task, which is not observed in unlesioned transgenic controls and wildtype littermates -indicating an exacerbation of the disease. Loss of BFCN hippocampal innervation in APP/PS1 mice also increases the amount of total Aβ in the hippocampus, but has no additional effects on levels of tau hyperphosphorylation. In contrast, memory deficits are not observed in pR5 tau transgenic mice following an equivalent loss of BFCN hippocampal innervation and reduction of neurotrophin levels. Moreover, hippocampal levels of tau and hyperphosphorylated tau were comparable to that of control pR5 tau transgenic mice. The role of neurotrophins in Aβ pathology in APP/PS1 mice was further assessed through viral knockdown of BDNF protein in the hippocampus, and treatment with a neurotrophic c29 peptide following loss of basal forebrain cholinergic neurons. Although reduction of BDNF did not cause increased Aβ levels, and treatment with c29 peptide did not reduce Aβ load in the hippocampus of APP/PS1 mice following loss of BFCN, c29 peptide was able to rescue behavioural deficits of aged unlesioned APP/PS1 mice.This work demonstrates that early cholinergic denervation of the hippocampus can trigger some features of Alzheimer's disease, namely reduced neurotrophin expression and increased Aβ production, but does not alone cause tau hyperphosphorylation and aggregation. These results are consistent with the idea that tau pathology in AD may be downstream of Aβ pathology, and highlights the possibility that cholinergic dysfunction might be a major upstream contributing factor of sporadic Alzheimer's disease. Although we show that neurotrophin dysfunction is insufficient by itself to induce or prevent Aβ accumulation, enhancing neurotrophic signalling to provide cognitive benefit may be a viable treatment strategy.

show abstract

Proteolytic processing of the p75 neurotrophin receptor: A prerequisite for signalling?

et al. 2011

View full text Add to dashboard Cite

The common neurotrophin receptor (p75(NTR) ) regulates various functions in the developing and adult nervous system. Cell survival, cell death, axonal and growth cone retraction, and regulation of the cell cycle can be regulated by p75(NTR) -mediated signals following activation by either mature or pro-neurotrophins and in combination with various co-receptors, including Trk receptors and sortilin. Here, we review the known functions of p75(NTR) by cell type, receptor-ligand combination, and whether regulated intra-membrane proteolysis of p75(NTR) is required for signalling. We highlight that the generation of the intracellular domain fragment of p75(NTR) is associated with many of the receptor functions, regardless of its ligand and co-receptor interactions.

show abstract

The p75NTR intracellular domain generated by neurotrophin-induced receptor cleavage potentiates Trk signaling

Cited by 68 publications

References 49 publications

Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment

Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment

Neurotrophin regulation of Alzheimer's disease pathology

Proteolytic processing of the p75 neurotrophin receptor: A prerequisite for signalling?

Contact Info

Product

Resources

About