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The Journal of Neuroscience, June 1, 2005, 25(22):5455-5463; doi:10.1523/JNEUROSCI.5123-04.2005

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Cellular/Molecular
ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of p75^NTR and Sortilin

Henry K. Teng,¹ Kenneth K. Teng,¹ Ramee Lee,¹ Saundrene Wright,¹ Seema Tevar,¹ Ramiro D. Almeida,¹ Pouneh Kermani,¹ Risa Torkin,^1,5 Zhe-Yu Chen,² Francis S. Lee,² Rosemary T. Kraemer,³ Anders Nykjaer,⁴ and Barbara L. Hempstead¹

Departments of ¹Medicine, ²Psychiatry, and ³Pathology, Weill Medical College of Cornell University, New York, New York 10021, ⁴Department of Medical Biochemistry, Aarhus University, DK-8000 Aarhus C, Denmark, and ⁵Cancer Research Program, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8

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 p75^NTR. Because recent studies suggest that proNGF, the precursor form of NGF, is more active than mature NGF in inducing apoptosis after binding to p75^NTR 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 p75^NTR, 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 p75^NTR and sortilin, because neurons deficient in p75^NTR 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 p75^NTR, 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.

Key words: proBDNF; apoptosis; p75 receptor; sortilin; neuron; neurotrophin

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Received Dec 15, 2004; revised April 19, 2005; accepted April 27, 2005.

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