BDNF pro-peptide regulates dendritic spines via caspase-3

Guo, Jing; Ji, Youngmi; Ding, Yusheng; Jiang, Weiqin; Sun, Ying; Lu, Bai; Nagappan, Guhan

doi:10.1038/cddis.2016.166

Cited by 60 publications

(60 citation statements)

References 42 publications

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“…However, recent studies have reported that exposure of pro-BDNF to hippocampal neurons in culture dramatically reduces dendritic spine density. The cellular mechanism was reported as pro-BDNF increasing the number of “elongated” mitochondria and cytosolic cytochrome C, suggesting involvement of the mitochondrial caspase-3 pathway [27]. In the “learned helplessness” model of depression, the pro-BDNF level is increased while mBDNF declines in the prefrontal cortex; this is reversed by the BDNF TrkB receptor antagonist [28].…”

Section: Discussionmentioning

confidence: 99%

Astrocyte-Conditioned Medium Protects Prefrontal Cortical Neurons from Glutamate-Induced Cell Death by Inhibiting TNF-α Expression

Song

Yang

et al. 2019

Neuroimmunomodulation

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Objective: Both excitotoxicity and neurotrophin deficiency may contribute to the etiology of depression and neurodegeneration. Astrocytes not only regulate glutamate metabolism and clearance, they also produce neurotrophins in the brain. However, the direct interaction between neurons and astrocytes remains unknown. Methods: This study evaluated the cellular mechanisms by which astrocyte-conditioned medium (ACM) protects prefrontal cortical neurons from glutamate-induced death by measuring cell viability and morphology as well as mRNA and protein expression of brain-derived neurotrophic factor (BDNF), BDNF receptors, glial cell line-derived neurotrophic factor (GDNF), and the proinflammatory cytokine, tumor necrosis factor (TNF)-α. Neurons and astrocytes were purified from the brains of neonatal 1-day-old Sprague-Dawley rats. ACM was harvested after exposing astrocytes to culture medium containing 100 μM glutamate for 48 h. Results: Glutamate insult (100 μM for 6 h) significantly reduced neuronal cell viability and increased the mRNA expression of BDNF. Glutamate (24 h) decreased neuronal viability and the expression of BDNF, but increased mRNA expression of GFAP, p75 neurotrophin receptor (p75^NTR), and TNF-α. ACM pretreatment (2 h) reversed glutamate-decreased cell viability and increased BDNF, but reduced the expression of GDNF, P75^NTR, and TNF-α at the mRNA level. Western blotting generally confirmed the mRNA expression following 24 glutamate insults. Furthermore, the glutamate-induced decrease in the protein expression of BDNF and full-length TrkB receptor and increase in pro-BDNF, truncated TrkB isoform 1 receptor, p75^NTR, GDNF, and TNF-α were significantly attenuated by ACM pretreatment. Conclusions: The study demonstrates that ACM exerts neuroprotective effects on cell viability, and this effect is most likely mediated through the modulation of neurotrophin and TNF-α expression.

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Section: Discussionmentioning

confidence: 99%

Astrocyte-Conditioned Medium Protects Prefrontal Cortical Neurons from Glutamate-Induced Cell Death by Inhibiting TNF-α Expression

Song

Yang

et al. 2019

Neuroimmunomodulation

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“…The third report (3) found that the Val‐pBDNF reduces dendritic spine density in hippocampal neurons (Guo et al . ). The key findings of these three publications are analyzed below and summarized in Table .…”

Section: A Prodomain As An Independent Signaling Ligand: Pbdnfmentioning

confidence: 97%

“…f) (Guo et al . ). Notably, this effect was evident 24 h after the administration of the ligand, but not earlier.…”

Section: A Prodomain As An Independent Signaling Ligand: Pbdnfmentioning

confidence: 97%

“…Guo and collaborators generated an antibody specifically against pBDNF which recognizes an epitope in generated after furin processing of proBDNF (Guo et al . ). The authors claim that this antibody does not recognize proBDNF.…”

Section: A Prodomain As An Independent Signaling Ligand: Pbdnfmentioning

confidence: 97%

“…) and did not affect dendritic spines density in primary neuronal cultures (Guo et al . ). The significance of these findings is relative as the endogenous NGF prodomain has not been found yet in neural tissues or primary neurons.…”

Section: A Prodomain As An Independent Signaling Ligand: Pbdnfmentioning

confidence: 97%

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Growth factors and hormones pro‐peptides: the unexpected adventures of the BDNF prodomain

Zanin

Unsain

Anastasía

2017

Journal of Neurochemistry

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Most growth factors and hormones are synthesized as prepro-proteins which are processed to the biologically active mature protein. The pre-and prodomains are cleaved from the precursor protein in the secretory pathway or, in some cases, extracellularly. The canonical functions of these prodomains are to assist in folding and stabilization of the mature domain, to direct intra and extracellular localization, to facilitate storage, and to regulate bioavailability of their mature counterpart. Recently, exciting evidence has revealed that prodomains of certain growth factors, after cleaved from the precursor pro-protein, can act as independent active signaling molecules. In this review, we discuss the various classical functions of prodomains, and the biological consequences of these pro-peptides acting as ligands. We will focus our attention on the brain-derived neurotrophic factor prodomain (pBDNF), which has been recently described as a novel secreted ligand influencing neuronal morphology and physiology. Keywords: active prodomains, biosynthetic pathway, pBDNF, precursor cleavage peptides, proBDNF, Val66Met polymorphism. Most growth factors and hormones are synthetized as prepro-proteins. These prefixes are used to describe the intermediate processed forms of a protein before it is active and at the appropriate location. The prefix 'pre' indicates the presence of an N-terminal sequence that targets the precursor pro-protein to the secretory pathway or an intracellular compartment. For this reason, this sequence is referred to as 'signal peptide' or 'signal sequence'. Signal peptides, which are typically from 5 to 50 residues, are cleaved by signal peptidases and quickly degraded. Later, it was discovered that many proteins require additional proteolytic processing to become functional. This additional step involves cleavage of a subsequent N-terminal peptide, which is indicated by the prefix 'pro' accounting for prodomain (or pro-peptide; example in Fig. 1a). The processing of pro-proteins to remove their prodomains requires enzymes including proprotein convertases (or proconvertases), which are present in the Golgi apparatus or in secretory vesicles, or extracellular enzymes such as matrix metalloproteinases among others. For example, the pro-protein of the neurotrophin brainderived neurotrophic factor (proBDNF), can be cleaved by furin and other proconvertases in the trans-Golgi network or Received December 29, 2016; revised manuscript received February 8, 2017; accepted February 13, 2017. Address correspondence and reprint requests to Agustin Anastasia, Instituto de Investigaci on M edica Mercedes y Martin Ferreyra, (INIMEC-CONICET-Universidad Nacional de C ordoba), Friuli 2434, C ordoba, C ordoba 5016, Argentina. E-mail: aanastasia@immf.uncor.edu.Abbreviations used: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BMP, bone morphogenetic protein; CD, circular dichroism; DNSP, dopamine neuron-stimulating peptide; GDNF, glial cell line-derived neurotrophic factor; GPR146, G-prote...

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Differential effects of transient and sustained activation of BDNF‐TrkB signaling

Guo

Nagappan

2018

Developmental Neurobiology

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Brain-derived neurotrophic factor (BDNF) serves a pleiotropic role in the central nervous system, ranging from promoting neuronal survival and differentiation during development and synaptic modulation in the adult. An important, yet unanswered question is how BDNF could serve such diverse functions, sometimes in the same cell. At least two modes of BDNF actions have been elucidated so far based on BDNF signaling kinetics and/or the activity status of the responding neurons. Acute and gradual increases in extracellular BDNF concentrations elicit, respectively, transient and sustained activation of TrkB receptor and its downstream signaling, leading to differential molecular and cellular functions. In cultured neurons, sustained TrkB activation promotes neuronal dendritic arborization and spinogenesis, whereas transient TrkB activation facilitates dendritic growth and spine morphogenesis. In hippocampal slices, slow delivery of BDNF facilitates LTP, whereas fast application of BDNF enhances basal synaptic transmission in schaffer collateral synapses. High-frequency stimulation of neurons converts BDNF-induced TrkB signaling from a transient to a sustained mode. These initial insights lay the foundation for future investigation of the BDNF-TrkB pathway, and analogous signaling pathways to gain a comprehensive understanding to enable translational research. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 647-659, 2018.

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BDNF pro-peptide regulates dendritic spines via caspase-3

Cited by 60 publications

References 42 publications

Astrocyte-Conditioned Medium Protects Prefrontal Cortical Neurons from Glutamate-Induced Cell Death by Inhibiting TNF-α Expression

Astrocyte-Conditioned Medium Protects Prefrontal Cortical Neurons from Glutamate-Induced Cell Death by Inhibiting TNF-α Expression

Growth factors and hormones pro‐peptides: the unexpected adventures of the BDNF prodomain

Differential effects of transient and sustained activation of BDNF‐TrkB signaling

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