Neuron-type-specific signaling by the p75NTR death receptor regulated by differential proteolytic cleavage

Vicario, Annalisa; Kisiswa, Lilian; Tann, Jason Y.; Kelly, Claire E.; Ibáñez, Carlos F.

doi:10.1242/jcs.161745

Cited by 48 publications

(62 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently mutation of the Val 264 impaired the cleavage by ␥-secretase, supporting this hypothesis (49). In p75-C257A, the AXXXG motif is participating in the homodimer formation and is less accessible to the ␥-secretase complex (Fig.…”

Section: Discussionmentioning

confidence: 72%

Structural Basis of p75 Transmembrane Domain Dimerization

Nadezhdin

Goncharuk

Mineev

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Dimerization of single span transmembrane receptors underlies their mechanism of activation. p75 neurotrophin receptor plays an important role in the nervous system, but the understanding of p75 activation mechanism is still incomplete. The transmembrane (TM) domain of p75 stabilizes the receptor dimers through a disulfide bond, essential for the NGF signaling. Here we solved by NMR the three-dimensional structure of the p75-TM-WT and the functionally inactive p75-TM-C257A dimers. Upon reconstitution in lipid micelles, p75-TM-WT forms the disulfide-linked dimers spontaneously. Under reducing conditions, p75-TM-WT is in a monomer-dimer equilibrium with the Cys 257 residue located on the dimer interface. In contrast, p75-TM-C257A forms dimers through the AXXXG motif on the opposite face of the ␣-helix. Biochemical and crosslinking experiments indicate that AXXXG motif is not on the dimer interface of p75-TM-WT, suggesting that the conformation of p75-TM-C257A may be not functionally relevant. However, rather than mediating p75 homodimerization, mutagenesis of the AXXXG motif reveals its functional role in the regulated intramembrane proteolysis of p75 catalyzed by the ␥-secretase complex. Our structural data provide an insight into the key role of the Cys 257 in stabilization of the weak transmembrane dimer in a conformation required for the NGF signaling.The neurotrophins (NTs) 6 are a family of neurotrophic factors that control multiple aspects of nervous system development and function. NTs interact with two distinct receptors, a cognate member of the Trk receptor tyrosine kinase family and the p75 neurotrophin receptor, a member of the tumor necrosis factor (TNF) receptor superfamily of death receptors (1). The most prominent biological function of p75 may be the induction of cell death, although it demonstrates several other activities, like survival, axonal growth, and cell migration (2-5).The precise mechanism as to how p75 transmits diverse signals in the normal or diseased nervous system remains elusive (3). Signal transduction by p75 is thought to proceed via the ligand-dependent recruitment and release of protein interactors to and from the receptor (6). Although different oligomer species have been recently described as the active receptor (7-10), several lines of evidence support the dimeric nature of p75 in neurotrophin signaling. NTs are homodimers in solution (11) that dimerize the extracellular domain of p75 upon binding as seen by in vivo cross-linking (12), by x-ray crystallography (13,14), and in solution (15). Engineered cysteine constructs activate p75 in the absence of NGF by inducing constitutive dimers (7), and the extracellular (16) and the intracellular domain (17, 18) form stable dimers in solution. In addition, the TM domain of p75 self-associates as measured by ToxCAT (8). All these data are supported by FRET (8,9) and by ␤-galactosidase protein-protein interaction assays (19), indicating that in the absence of NTs a significant fraction of p75 exists as preformed dimers on the plas...

show abstract

Section: Discussionmentioning

confidence: 72%

Structural Basis of p75 Transmembrane Domain Dimerization

Nadezhdin

Goncharuk

Mineev

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…NTR fragment signaling appears to be cell-type specific (Vicario et al, 2015), these studies indicate that the proteolytic cleavage of p75 NTR might be a key mechanism by which p75 NTR mediates death signaling after motor neuron injury and disease. We have previously shown that the juxtamembrane region of p75 NTR has the ability to induce cell death when bound to the cell membrane (Coulson et al, 2000;.…”

Section: Introductionmentioning

confidence: 79%

“…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: Discussionmentioning

confidence: 99%

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

“…More recently Vicario et al, (2015) has also reported CTF can mediate cell death when it accumulates, such that ICD is not produced. 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.…”

Section: C29 Peptide As An Enhancer Of Neurotrophic Signallingmentioning

confidence: 99%

“…Moreover, CTF has been found to activate G-protein-coupled inwardly rectifying potassium (GIRK) channels which mediate neuronal death through potassium efflux allowing for formation of apoptosomes and thus activation of caspases (Coulson et al, 2000). More recently Vicario et al, (2015) has also reported CTF can mediate cell death when it accumulates, such that ICD is not produced. 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.…”

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

Neuron-type-specific signaling by the p75NTR death receptor regulated by differential proteolytic cleavage

Abstract: BSTRACTSignaling by the p75 neurotrophin receptor (p75 NTR , also known as , can be tuned into narrower activity profiles by cell-type-specific differences in intracellular processes, such as proteolytic cleavage, leading to very different biological outcomes.

Cited by 48 publications

References 64 publications

Structural Basis of p75 Transmembrane Domain Dimerization

Structural Basis of p75 Transmembrane Domain Dimerization

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

Contact Info

Product

Resources

About