ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of p75NTR and Sortilin

By Henry K Teng, K. Teng, Ramee Lee, S. Wright, Seema Tevar, Ramiro D. Almeida, P. Kermani, Risa Torkin, Zhe-Yu Chen, F. Lee and 3 more. Journal of Neuroscience, 2005

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Brain-derived neurotrophic factor (BDNF) is best characterized for critical roles in neuronal survival, differentiation, and synaptic modulation mediated by the TrkB receptor tyrosine kinase. Developmentally regulated death signaling by BDNF has also been demonstrated via activation of p75NTR. Because recent studies suggest that proNGF, the precursor form of NGF, is more active than mature NGF in inducing apoptosis after binding to p75NTR and a coreceptor, sortilin, we asked whether the precursor of BDNF (proBDNF) is also a proapoptotic ligand in the nervous system. proBDNF is secreted by cultured neurons, and recombinant proBDNF binds to sortilin. In sympathetic neurons coexpressing sortilin and p75NTR, we found that proBDNF is an apoptotic ligand that induces death at subnanomolar concentrations. In contrast, mature BDNF, but not proBDNF, is effective in inducing TrkB phosphorylation. proBDNF effects are dependent on cellular coexpression of both p75NTR and sortilin, because neurons deficient in p75NTR are resistant to proBDNF-induced apoptosis, and competitive antagonists of sortilin block sympathetic neuron death. Moreover, addition of preformed complexes of soluble sortilin and proBDNF failed to induce apoptosis of cells coexpressing both sortilin and p75NTR, suggesting that interaction of proBDNF with both receptors on the cell surface is required to initiate cell death. Together with our past findings, these data suggest that the neurotrophin family is capable of modulating diverse biological processes via differential processing of the proneurotrophins.

Subfields: Cellular and Molecular Neuroscience, Developmental Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/07d9e557f4ed316b34c78176990a4529b6c5e395

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Citations in the corpus

BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity (2017, background): “inhibition of growth, or even apoptotic death (Teng et al. 2005).”
The yin and yang of neurotrophin action (2005, background): “A recent study showed that proBDNF also induces neuronal apoptosis by activating p75 NTR (Ref”
Activation of p75NTR by proBDNF facilitates hippocampal long-term depression (2005, result): “Indeed, a number of recent studies showed that pro-neurotrophins, by activating p75 NTR , promote apoptosis in the peripheral nervous syste”
Mouse and rat BDNF gene structure and expression revisited (2006, background): “Secreted proBDNF activates a heteromeric receptor complex of p75 and sortilin to initiate cell death (Teng et al., 2005) and binds to p75 in hippocampal neurons to enhance longterm depression (Woo et al., 2005).”
New insights in the biology of BDNF synthesis and release: implications in CNS function (2009, neutral): “Proneurotrophins, including proBDNF, bind and activate the p75 NTR receptor (Teng et al., 2005).”
Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer (2020, background): “This pathway i involved in neuronal apoptosis [82,83].”
New insights into BDNF function in depression and anxiety (2007, background): “A large proportion of neuronal BDNF is secreted in the pro-form, which is subsequently converted to mBDNF by extracellular proteases such as plasmin or matrix metalloproteinase”
Interaction between BDNF and Serotonin: Role in Mood Disorders (2008, background): “…functions have been attributed to signaling through TrkB. Pro-BDNF, which preferentially binds p75NTR, activates a different set of intracellular signaling cascades including nuclear factor-kappa B (NFkB), c-jun kinase and sphingomyelin hydrolysis (Gentry et al, 2004; Teng et al, 2005).”