Teng Henry K, Teng Kenneth K, Lee Ramee, Wright Saundrene, Tevar Seema, Almeida Ramiro D, Kermani Pouneh, Torkin Risa, Chen Zhe-Yu, Lee Francis S, Kraemer Rosemary T, Nykjaer Anders, Hempstead Barbara L
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
J Neurosci. 2005 Jun 1;25(22):5455-63. doi: 10.1523/JNEUROSCI.5123-04.2005.
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.
脑源性神经营养因子（BDNF）在由TrkB受体酪氨酸激酶介导的神经元存活、分化和突触调节中发挥关键作用，这一特性最为显著。BDNF在发育过程中通过激活p75NTR调节死亡信号也已得到证实。由于最近的研究表明，神经生长因子（NGF）的前体形式proNGF在与p75NTR和共受体sortilin结合后诱导细胞凋亡方面比成熟的NGF更具活性，我们不禁要问，BDNF的前体（proBDNF）在神经系统中是否也是一种促凋亡配体。proBDNF由培养的神经元分泌，重组proBDNF可与sortilin结合。在共表达sortilin和p75NTR的交感神经元中，我们发现proBDNF是一种凋亡配体，在亚纳摩尔浓度下就能诱导细胞死亡。相比之下，成熟的BDNF而非proBDNF能有效诱导TrkB磷酸化。proBDNF的作用依赖于p75NTR和sortilin在细胞中的共表达，因为缺乏p75NTR的神经元对proBDNF诱导的细胞凋亡具有抗性，并且sortilin的竞争性拮抗剂可阻止交感神经元死亡。此外，添加预先形成的可溶性sortilin和proBDNF复合物未能诱导共表达sortilin和p75NTR的细胞凋亡，这表明proBDNF与细胞表面的两种受体相互作用对于启动细胞死亡是必需的。结合我们过去的研究结果，这些数据表明神经营养因子家族能够通过对前体神经营养因子的不同加工来调节多种生物学过程。
