p75 Neurotrophin Receptor-mediated Apoptosis in Sympathetic Neurons Involves a Biphasic Activation of JNK and Up-regulation of Tumor Necrosis Factor-α-converting Enzyme/ADAM17

Abstract

During the development of the sympathetic nervous system, the p75 neurotrophin receptor (p75NTR) has a dual function: promoting survival together with TrkA in response to NGF, but inducing cell death upon binding pro or mature brain-derived neurotrophic factor (BDNF). Apoptotic signaling through p75NTR requires activation of the stress kinase, JNK. However, the receptor also undergoes regulated proteolysis, first by a metalloprotease, and then by ␥-secretase, in response to pro-apoptotic ligands and this is necessary for receptor mediated neuronal death (Kenchappa, R. S., Zampieri, N., Chao, M. V., Barker, P. A., Teng, H. K., Hempstead, B. L., and Carter, B. D. (2006) Neuron 50, 219 -232). Hence, the relationship between JNK activation and receptor proteolysis remains to be defined. Here, we report that JNK3 activation is necessary for p75NTR cleavage; however, following release of the intracellular domain, there is a secondary activation of JNK3 that is cleavage dependent. Receptor proteolysis and apoptosis were prevented in sympathetic neurons from jnk3 ؊/؊ mice, while activation of JNK by ectopic expression of MEKK1 induced p75NTR cleavage and cell death. Proteolysis of the receptor was not detected until 6 h after BDNF treatment, suggesting that JNK3 promotes cleavage through a transcriptional mechanism. In support of this hypothesis, BDNF up-regulated tumor necrosis factor-␣-converting enzyme (TACE)/ADAM17 mRNA and protein in wildtype, but not jnk3 ؊/؊ sympathetic neurons. Down-regulation of TACE by RNA interference blocked BDNF-induced p75NTR cleavage and apoptosis, indicating that this metalloprotease is responsible for the initial processing of the receptor. Together, these results demonstrate that p75NTR-mediated activation of JNK3 is required for up-regulation of TACE, which promotes receptor proteolysis, leading to prolonged activation of JNK3 and subsequent apoptosis in sympathetic neurons.

Structural Basis of p75 Transmembrane Domain Dimerization

“…Nanodiscs or bicelles are believed to better reflect the lipid bilayer characteristics (47,48). However, micelles provide the smallest particles, which is of great importance for solution NMR spectroscopy.…”

Mapping of the Interaction Site between Sortilin and the p75 Neurotrophin Receptor Reveals a Regulatory Role for the Sortilin Intracellular Domain in p75 Neurotrophin Receptor Shedding and Apoptosis

“…We found that the presence of the stalk region fully rescued binding of the p75 NTR extracellular domain with sortilin ecd -IL 2 R tm,icd (Fig. 4F) one function of p75 NTR relates to its ability to induce apoptosis, which requires RIP of p75 NTR (16,17). Because sortilin is essential for proNT-dependent apoptosis through p75 NTR (5-9), we measured the accumulation of p75 NTR ICD by Western blotting within HEK293 cells transfected with wild type sortilin, sortilin mut , and sortilin tailless in the presence of proteasome inhibitors.…”

Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats

“…It has been suggested that a reduction of p75 in early brain development could be quite detrimental due to the inability for neurotrophins, responsible for neurite outgrowth, to bind in a p75 dependent fashion, leading to an inability of axons to elongate throughout development 45 . Even though p75 expression is known to be associated with various apoptotic processes 46,47 , p75 neurotrophic factor also contributes to neuronal survival during development 40,46 . Tropomyosin receptor kinases (Trk), involved in p75-induced neuronal survival processes 40 , are also implicated in NMDA receptor activation and regulation 41 .…”