Reducing p75 nerve growth factor receptor levels using antisense oligonucleotides prevents the loss of axotomized sensory neurons in the dorsal root ganglia of newborn rats

Cheema, Surindar S.; Barrett, Graham L.; Bartlett, Perry F.

doi:10.1002/(sici)1097-4547(19961015)46:2<239::aid-jnr12>3.0.co;2-y

Cited by 70 publications

(62 citation statements)

References 24 publications

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“…The rat 5Ј p75ntr antisense was also purchased with a 5Ј 56-FAM fluorescent label so that uptake by the neurons could be monitored. The antisense sequence used has been characterized previously and has been shown to be effective at inhibiting p75ntr-mediated cell death both in vitro and in vivo (Barrett and Bartlett, 1994;Cheema et al, 1996;Lowry et al, 2001).…”

Section: Methodsmentioning

confidence: 92%

“…This antisense sequence has been shown to be effective at preventing the NGF withdrawal or axotomy-induced death of dorsal root ganglion neurons (Barrett and Bartlett, 1994;Cheema et al, 1996) and the axotomy-induced death of spinal motor neurons (Lowry et al, 2001), which are mediated by p75ntr. Dissociated cerebellar tissue was triturated with 5 M 56-FAM-labeled antisense or missense phosphorothioate oligonucleotides at the time of plating.…”

Section: In the Presence Of Trophic Factors The P75ntr Supports Purkmentioning

confidence: 99%

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The p75 Neurotrophin Receptor Can Induce Autophagy and Death of Cerebellar Purkinje Neurons

Florez-McClure

Linseman²,

Chu³

et al. 2004

J. Neurosci.

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The cellular mechanisms underlying Purkinje neuron death in various neurodegenerative disorders of the cerebellum are poorly understood. Here we investigate an in vitro model of cerebellar neuronal death. We report that cerebellar Purkinje neurons, deprived of trophic factors, die by a form of programmed cell death distinct from the apoptotic death of neighboring granule neurons. Purkinje neuron death was characterized by excessive autophagic-lysosomal vacuolation. Autophagy and death of Purkinje neurons were inhibited by nerve growth factor (NGF) and were activated by NGF-neutralizing antibodies. Although treatment with antisense oligonucleotides to the p75 neurotrophin receptor (p75ntr) decreased basal survival of cultured cerebellar neurons, p75ntr-antisense decreased autophagy and completely inhibited death of Purkinje neurons induced by trophic factor withdrawal. Moreover, adenoviral expression of a p75ntr mutant lacking the ligand-binding domain induced vacuolation and death of Purkinje neurons. These results suggest that p75ntr is required for Purkinje neuron survival in the presence of trophic support; however, during trophic factor withdrawal, p75ntr contributes to Purkinje neuron autophagy and death. The autophagic morphology resembles that found in neurodegenerative disorders, suggesting a potential role for this pathway in neurological disease.

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Section: Methodsmentioning

confidence: 92%

Section: In the Presence Of Trophic Factors The P75ntr Supports Purkmentioning

confidence: 99%

The p75 Neurotrophin Receptor Can Induce Autophagy and Death of Cerebellar Purkinje Neurons

Florez-McClure

Linseman²,

Chu³

et al. 2004

J. Neurosci.

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“…Multiple studies have indicated a possible role of this receptor in acute neuronal injuries and progressive neurodegenerative disorders. p75 NTR expression is up-regulated after axotomy or neuronal injury, and p75 NTR antisense oligonucleotides have been shown to reduce the damage (67)(68)(69). The ␤-amyloid peptide that is accumulating as extracellular deposits during the progression of Alzheimer's disease has been shown to bind and activate p75 NTR (70,71).…”

Section: Discussionmentioning

confidence: 99%

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

Wang¹,

Bauer²,

Li³

et al. 2001

Journal of Biological Chemistry

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The p75 neurotrophin receptor (p75 NTR ) belongs to the tumor necrosis factor receptor/nerve growth factor receptor superfamily. In some cells derived from neuronal tissues it causes cell death through a poorly characterized pathway. We developed a neuronal system using conditionally immortalized striatal neurons, in which the expression of p75 NTR is inducibly controlled by the ecdysone receptor. In these cells p75 NTR induces apoptosis through its death domain in a nerve growth factor-independent manner. Caspases 9, 6, and 3 are activated by receptor expression indicating the activation of the common effector pathway of apoptosis. Cell death is blocked by a dominant negative form of caspase 9 and Bcl-X L consistent with a pathway that involves mitochondria. Significantly, the viral flice inhibitory protein E8 protects from p75 NTR -induced cell death indicating that death effector domains are involved. A p75 NTR construct with a deleted death domain dominantly interferes with p75 NTR signaling, implying that receptor multimerization is required. However, in contrast to the other receptors of the family, p75 NTR -mediated apoptosis does not involve the adaptor proteins Fas-associated death domain protein or tumor necrosis factor-associated death domain protein, and the apical caspase 8 is not activated. We conclude that p75 NTR signals apoptosis by similar mechanisms as other death receptors but uses different adaptors and apical caspases.

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“…This novel profile suggested that p75 NTR creates a state of cellular dependence, or addiction, on neurotrophins (Figure 1). This concept has been supported by data from p75 null (`knockout') mice (Sauer et al, 1996;Yeo et al, 1997), as well as by in vivo antisense experiments (Cheema et al, 1996). Sauer et al (1996) found that mice deficient in NGF display atrophy and hypoplasia of medial septal cholinergic neurons, but that crossing those NGF hemizygous mice with p75 NTR null mice restored cell size and number to that of the p75 NTR null mice, i.e., to supranormal.…”

Section: Apoptosis and Negative Signal Transductionmentioning

confidence: 99%

“…Perry Bartlett and Graham Barrett, along with their colleagues, found that the use of antisense oligonucleotides to decrease p75 expression also blocks neuronal apoptosis in another paradigm of neurotrophin-withdrawal-induced death, that of axotomy-induced neuronal cell death (Cheema et al, 1996).…”

Section: Apoptosis and Negative Signal Transductionmentioning

confidence: 99%

p75NTR and the concept of cellular dependence: seeing how the other half die

Bredesen

Tasinato

et al. 1998

Cell Death Differ

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Cells depend on specific stimuli, such as trophic factors, for survival and in the absence of such stimuli, undergo apoptosis. How do cells initiate apoptosis in response to the withdrawal of trophic factors or other dependent stimuli? Recent studies of apoptosis induction by neurotrophin withdrawal argue for a novel form of pro-apoptotic signal transduction ±`negative signal transduction' ± in which the absence of ligand-receptor interaction induces cell death. We have found that the prototype for this form of signaling ± the common neurotrophin receptor, p75 NTR ± creates a state of cellular dependence (or addiction) on neurotrophins, and that this effect requires an`addiction/dependence domain' (ADD) in the intracytoplasmic region of p75 NTR . We have recently found other receptors that include dependence domains, arguing that dependence receptors, and their associated dependence domains, may be involved in a rather general mechanism to create cellular states of dependence on trophic factors, cytokines, adhesion, electrical activity and other dependent stimuli.

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Reducing p75 nerve growth factor receptor levels using antisense oligonucleotides prevents the loss of axotomized sensory neurons in the dorsal root ganglia of newborn rats

Cited by 70 publications

References 24 publications

The p75 Neurotrophin Receptor Can Induce Autophagy and Death of Cerebellar Purkinje Neurons

The p75 Neurotrophin Receptor Can Induce Autophagy and Death of Cerebellar Purkinje Neurons

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

p75NTR and the concept of cellular dependence: seeing how the other half die

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