Pro-domain in precursor nerve growth factor mediates cell death

Armugam, Arunmozhiarasi; Koh, Dow Rhoon; Ching, Chai Siaw; Chandrasekaran, Karthikeyan; Kaur, Prameet; Jeyaseelan, Kandiah

doi:10.1016/j.neuint.2012.03.006

Cited by 12 publications

(9 citation statements)

References 46 publications

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“…In addition, recombinant human NGF pro-peptide (similar in molecular size to BDNF pro-peptide) was purified to be used in experiments to evaluate whether the biological activities of BDNF pro-peptide, if any, are specific to the pro-domain of BDNF or are they generic across the pro-domain of the NGF family of neurotrophins. 18, 19 …”

Section: Resultsmentioning

confidence: 99%

BDNF pro-peptide regulates dendritic spines via caspase-3

Guo

Ding

et al. 2016

Cell Death Dis

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The precursor of brain-derived neurotrophic factor (BDNF) (proBDNF) is enzymatically cleaved, by either intracellular (furin/PC1) or extracellular proteases (tPA/plasmin/MMP), to generate mature BDNF (mBDNF) and its pro-peptide (BDNF pro-peptide). Little is known about the function of BDNF pro-peptide. We have developed an antibody that specifically detects cleaved BDNF pro-peptide, but not proBDNF or mBDNF. Neuronal depolarization elicited a marked increase in extracellular BDNF pro-peptide, suggesting activity-dependent regulation of its extracellular levels. Exposure of BDNF pro-peptide to mature hippocampal neurons in culture dramatically reduced dendritic spine density. This effect was mediated by caspase-3, as revealed by studies with pharmacological inhibitors and genetic knockdown. BDNF pro-peptide also increased the number of ‘elongated' mitochondria and cytosolic cytochrome c, suggesting the involvement of mitochondrial-caspase-3 pathway. These results, along with BDNF pro-peptide effects recently reported on growth cones and long-term depression (LTD), suggest that BDNF pro-peptide is a negative regulator of neuronal structure and function.

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Section: Resultsmentioning

confidence: 99%

BDNF pro-peptide regulates dendritic spines via caspase-3

Guo

Ding

et al. 2016

Cell Death Dis

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“…Furthermore, proNGF has been reported to promote apoptosis via its interaction with p75NTR and sortilin receptor [7,28]. Both proNGF and mature NGF exhibited neurotrophic activity on PC12 cells, while the pro-domain itself promotes cell death [29]. NGF and proNGF co-exist in vivo [9].…”

Section: Discussionmentioning

confidence: 99%

proNGF/NGF mixtures induce gene expression changes in PC12 cells that neither singly produces

et al. 2014

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BackgroundGrowing evidence shows that, in vivo, the precursor of Nerve Growth Factor (NGF), proNGF, displays biological activities different from those of its mature NGF counterpart, mediated by distinct, and somewhat complementary, receptor binding properties. NGF and proNGF induce distinct transcriptional signatures in target cells, highlighting their different bioactivities. In vivo, proNGF and mature NGF coexist. It was proposed that the relative proNGF/NGF ratio is important for their biological outcomes, especially in pathological conditions, since proNGF, the principal form of NGF in Central Nervous System (CNS), is increased in Alzheimer’s disease brains. These observations raise a relevant question: does proNGF, in the presence of NGF, influence the NGF transcriptional response and viceversa? In order to understand the specific proNGF effect on NGF activity, depending on the relative proNGF/NGF concentration, we investigated whether proNGF affects the pattern of well-known NGF-regulated mRNAs.ResultsTo test any influence of proNGF on pure NGF expression fingerprinting, the expression level of a set of candidate genes was analysed by qReal-Time PCR in rat adrenal pheochromocytoma cell line PC12, treated with a mixture of NGF and proNGF recombinant proteins, in different stoichiometric ratios. These candidates were selected amongst a set of genes well-known as being rapidly induced by NGF treatment. We found that, when PC12 cells are treated with proNGF/NGF mixtures, a unique pattern of gene expression, which does not overlap with that deriving from treatment with either proNGF or NGF alone, is induced. The specific effect is also dependent on the stoichiometric composition of the mixture. The proNGF/NGF equimolar mixture seems to partially neutralize the specific effects of the proNGF or NGF individual treatments, showing a weaker overall response, compared to the individual contributions of NGF and proNGF alone.ConclusionsUsing gene expression as a functional read-out, our data demonstrate that the relative availability of NGF and proNGF in vivo might modulate the biological outcome of these ligands.

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“…The NGF maturation in neuronal cells requires the furin-induced endoproteolytic processing of the precursor protein proNGF to b-NGF [88]. Besides, ProNGF and b-NGF can exert opposite biological effects by binding to different neurotrophinreceptors, resulting in sortilin-mediated apoptosis or neurotrophic tyrosine kinase receptor type-1 (TrkA)-induced cell survival, respectively [89]. Additionally, NGF and furin can be detected in rodent arteries and human proliferating VSMCs [90].…”

Section: Furin Promotes Cell Proliferation and Ecm Synthesis By Activmentioning

confidence: 99%