Characterization of a p75NTR Apoptotic Signaling Pathway Using a Novel Cellular Model

Wang, Xin; Bauer, Johannes H.; Li, Yong; Shao, Zhihong; Zetoune, Firas S.; Cattaneo, Elena; Vincenz, Claudius

doi:10.1074/jbc.m010548200

Cited by 98 publications

(84 citation statements)

References 70 publications

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“…Furthermore, overexpression of p-Akt in the SNc DA neurons provides potent protection against 6-OHDA-induced cellular damages and function of DA neurons (23), consistent with our neuroprotection data. In addition to EGFR, inhibition of LINGO-1 may reduce p75 NTR activity that has been linked to cell death (33). Because LINGO-1 is also expressed by non-DA cells, those cells may also have positive influences on the DA neuronal function when LINGO-1 activity is inhibited.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models

Inoue

Li²,

Lee³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

148

182

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The nervous system-specific leucine-rich repeat Ig-containing protein LINGO-1 is associated with the Nogo-66 receptor complex and is endowed with a canonical EGF receptor (EGFR)-like tyrosine phosphorylation site. Our studies indicate that LINGO-1 expression is elevated in the substantia nigra of Parkinson's disease (PD) patients compared with age-matched controls and in animal models of PD after neurotoxic lesions. LINGO-1 expression is present in midbrain dopaminergic (DA) neurons in the human and rodent brain. Therefore, the role of LINGO-1 in cell damage responses of DA neurons was examined in vitro and in experimental models of PD induced by either oxidative (6-hydroxydopamine) or mitochondrial (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity. In LINGO-1 knockout mice, DA neuron survival was increased and behavioral abnormalities were reduced compared with WT. dopamine neuron ͉ substantia nigra ͉ degeneration ͉ neuroprotection ͉ axon N ew therapeutics are required that simultaneously preserve dopamine (DA) neurons and their functional connections to limit or eliminate the progression of the movement disorder of Parkinson's disease (PD) (1, 2). Several growth factors normally active in cell growth and survival during brain development have been shown to provide protection against cell death in animal models of PD (1-5). The phosphoinositide 3-kinases (PI3-Ks) and Akt (protein kinase B) signaling pathways have been shown to participate in such growth factor actions (1, 2, 5, 6). Recent studies also suggest that some leucine-rich repeat (LRR) Ig-containing proteins can influence growth factors by modulating EGF receptor (EGFR) signaling-related pathways (7,8). LINGO-1 is a LRR-Ig protein first identified as a critical component of the NogoR1-p75NTR complex in RhoA activation, and it is responsible for some inhibition of axonal regeneration by myelin-associated factors (9, 10). Unlike NogoR1, LINGO-1 gene expression is increased when adult nerve cells are exposed to traumatic injuries (9), indicating that LINGO-1 may be involved in cell injury responses. LRRK2, another LRR protein, was recently genetically linked to PD and Lewy body disease (11, 12). As we describe here, LINGO-1 appears to regulate neurite growth and the structural integrity of neurons, in analogy with LRRK2 (9, 13).In this study, elevated LINGO-1 levels were found after selective experimental damage to DA nerve terminals in the striatum of mice, and increased expressed levels of LINGO-1 were found in the substantia nigra (SN) of some PD patients. Using methods that reduced or eliminated the negative actions of LINGO-1, we demonstrate that midbrain DA neuron survival, growth, and function improve in primary in vitro cultures and in vivo experimental models of parkinsonism in mice. We also show that LINGO-1 normally binds to EGFR and negatively regulates the EGFR/Akt signaling pathway in cells and tissues relevant to these studies. Fig. 4 B and C). LINGO-1 is expressed in remaining DA neurons in the SN of PD patients (SI Fig. 4 A and B)....

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Section: Discussionmentioning

confidence: 99%

Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models

Inoue

Li²,

Lee³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

148

182

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“…NTR was found to induce apoptosis without the participation of TRADD as an adaptor protein (28). Whether or not the interaction of TRADD with p75…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Receptor-associated Death Domain Protein Is Involved in the Neurotrophin Receptor-mediated Antiapoptotic Activity of Nerve Growth Factor in Breast Cancer Cells

Yazidi‐Belkoura¹,

Adriaenssens²,

Dollé³

et al. 2003

Journal of Biological Chemistry

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The common neurotrophin receptor p75NTR has been shown to initiate intracellular signaling that leads either to cell survival or to apoptosis depending on the cell type examined; however, the mechanism by which p75 NTR initiates its intracellular transduction remains unclear. We show here that the tumor necrosis factor receptor-associated death domain protein (TRADD) interacts with p75 NTR upon nerve growth factor (NGF) stimulation. TRADD could be immunodetected after p75NTR immunoprecipitation from MCF-7 breast cancer cells stimulated by nerve growth factor. In addition, confocal microscopy indicated that NGF stimulation induced the plasma membrane localization of TRADD. Using a dominant negative form of TRADD, we also show that interactions between p75 NTR and TRADD are dependent on the death domain of TRADD, thus demonstrating its requirement for binding. Furthermore, the p75 NTR -mediated activation of NF-B was inhibited by transfection with a dominant negative TRADD, resulting in an inhibition of NGF antiapoptotic activity. These results thus demonstrate that TRADD is involved in the p75 NTR -mediated antiapoptotic activity of NGF in breast cancer cells.

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“…P75-expressing mouse vascular smooth-muscle cells (11) were plated at 10,000 per well in media containing 0.1% serum, and the temperature was shifted to 39.5°C to induce differentiation. Purified, recombinant cleavage-resistant proNGF (4) or diluent controls were added to cultures in the presence or absence of protein A column-purified IgG from rabbit antiprodomain polyclonal antibody or comparably protein A column-purified IgG from nonimmune rabbit serum.…”

Section: Analysis Of Cerebrospinal Fluid (Csf)mentioning

confidence: 99%

Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury

Harrington

Leiner

Blechschmitt

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

252

234

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The unprocessed precursor of the neurotrophin nerve growth factor (NGF), proNGF, has been suggested to be a death-inducing ligand for the neurotrophin receptor p75. Whether proNGF is a true pathophysiological ligand that is secreted, binds p75, and activates cell death in vivo, however, has remained unknown. Here, we report that after brain injury, proNGF was induced and secreted in an active form capable of triggering apoptosis in culture. We further demonstrate that proNGF binds p75 in vivo and that disruption of this binding results in complete rescue of injured adult corticospinal neurons. These data together suggest that proNGF binding to p75 is responsible for the death of adult corticospinal neurons after lesion, and they help to establish proNGF as the pathophysiological ligand that activates the celldeath program by means of p75 after brain injury. Interference in the binding of proNGF to p75 may provide a therapeutic approach for the treatment of disorders involving neuronal loss.

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Characterization of a p75NTR Apoptotic Signaling Pathway Using a Novel Cellular Model

Cited by 98 publications

References 70 publications

Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models

Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models

Tumor Necrosis Factor Receptor-associated Death Domain Protein Is Involved in the Neurotrophin Receptor-mediated Antiapoptotic Activity of Nerve Growth Factor in Breast Cancer Cells

Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury

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