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.

https://www.jneurosci.org/content/jneuro/25/22/5455.full.pdf

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

In the year 2003 there was a 17% increase in the number of publications citing work performed using optical biosensor technology compared with the previous year. We collated the 962 total papers for 2003, identified the geographical regions where the work was performed, highlighted the instrument types on which it was carried out, and segregated the papers by biological system. In this overview, we spotlight 13 papers that should be on everyone's 'must read' list for 2003 and provide examples of how to identify and interpret high-quality biosensor data. Although we still find that the literature is replete with poorly performed experiments, over-interpreted results and a general lack of understanding of data analysis, we are optimistic that these shortcomings will be addressed as biosensor technology continues to mature.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jmr.753

Survey of the year 2003 commercial optical biosensor literature

VPS10P-domain receptors, such as SORLA and sortilin, constitute a recently identified class of type-1 receptors that are expressed in neurons. Family members are multifunctional proteins that target a range of ligands, including trophic factors and neuropeptides but also other transmembrane proteins. New findings have revealed unexpected roles for VPS10P-domain receptors as regulators of neuronal viability and function through the regulation of both protein transport and signal transduction. Loss of these activities might contribute to the pathophysiology of devastating disorders of the nervous system, including Alzheimer's disease, affective disorders and post-traumatic neuronal cell death.

VPS10P-domain receptors — regulators of neuronal viability and function

Proteins are essential elements for life. They are building blocks of all organisms and the operators of cellular functions. Humans produce a repertoire of at least 30,000 different proteins, each with a different role. Each protein has its own unique sequence and shape (native conformation) to fulfill its specific function. The appearance of incorrectly shaped (misfolded) proteins occurs on exposure to environmental changes. Protein misfolding and the subsequent aggregation is associated with various, often highly debilitating, diseases for which no sufficient cure is available yet. In the first part of this review we summarize the structural composition of proteins and the current knowledge of underlying forces that lead proteins to lose their native structure. In the second and third parts we describe the molecular and cellular mechanisms that are associated with protein misfolding in disease. Finally, in the last part we portray recent efforts to develop treatments for protein misfolding diseases.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.07-099671

Molecular and cellular aspects of protein misfolding and disease

The trans-Golgi network (TGN) is an important cargo sorting station within the cell where newly synthesized proteins are packaged into distinct transport carriers that are targeted to various destinations. To maintain the fidelity of protein transport, elaborate protein sorting machinery is employed to mediate sorting of specific cargo proteins into distinct transport carriers. Protein sorting requires assembly of the cytosolic sorting machinery onto the TGN membrane and capture of cargo proteins. We review the cytosolic and transmembrane sorting machinery that function at the TGN and describe molecular interactions and regulatory mechanisms that enable accurate protein sorting. In addition, we highlight the importance of TGN sorting in physiology and disease.

Protein Sorting at the trans-Golgi Network

Functional Organization of the Sortilin Vps10p Domain

SorCS1, a member of the novel sorting receptor family, is localized in somata and dendrites of neurons throughout the murine brain.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.febslet.2004.12.088

SorCS3 does not require propeptide cleavage to bind nerve growth factor

In the search for new ligands for the plasminogen kringle 4 binding-protein tetranectin, it has been found by ligand blot analysis and ELISA that tetranectin specifically bound to the plasminogen-like hepatocyte growth factor and tissue-type plasminogen activator. The dissociation constants of these complexes were found to be within the same order of magnitude as the one for the plasminogen-tetranectin complex. The study also revealed that tetranectin did not interact with the kindred proteins: macrophage-stimulating protein, urokinase-type plasminogen activator and prothrombin. In order to examine the function of tetranectin, a kinetic analysis of the tPA-catalysed plasminogen activation was performed. The kinetic parameters of the tetranectin-stimulated enhancement of tPA were comparable to fibrinogen fragments, which are so far the best inducer of tPA-catalysed plasminogen activation. The enhanced activation was suggested to be caused by tetranectin's ability to bind and accumulate tPA in an active conformation.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1432-1033.2003.03549.x

Tetranectin binds hepatocyte growth factor and tissue-type plasminogen activator

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.febslet.2005.03.068

Uffe B. Westergaard

Papers

Functional Organization of the Sortilin Vps10p Domain

SorCS1, a member of the novel sorting receptor family, is localized in somata and dendrites of neurons throughout the murine brain.

SorCS3 does not require propeptide cleavage to bind nerve growth factor

Tetranectin binds hepatocyte growth factor and tissue-type plasminogen activator

Corrigendum to: SorCS3 does not require propeptide cleavage to bind nerve growth factor (FEBS 29259) [FEBS Letters 579 (2005) 1172–1176]☆