Different responses of PC12 cells to different pro-nerve growth factor protein variants

Soligo, Marzia; Albini, Martina; Bertoli, Federico Lorenzo; Marzano, Valeria; Protto, Virginia; Bracci-Laudiero, Luisa; Minnone, Gaetana; Benedetti, Fabrizio; Chiaretti, Antonio; Mantuano, Elide; Manni, Luigi

doi:10.1016/j.neuint.2019.104498

Cited by 11 publications

(10 citation statements)

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“…M2 selective activation with APE treatment results in a significant decrease of proNGF-B gene and protein expression in both dASCs and SCs; whilst proNGF-A gene expression is significantly downregulated in SCs and it is significantly upregulated in dASCs after both APE and muscarine treatments. Distinct proNGF isoforms are expressed in mouse tissues, resulting from alternative splicing and/or activation of different promoters 5,43,44 ; as recently reported, proNGF-A has a pro-survival and differentiative effects in vitro 6 , whereas proNGF-B isoform acts as an apoptotic signal 7 . The longer variant proNGF-A (32-34 kDa) and the shorter variant proNGF-B (25-27 kDa) are produced in both CNS and PNS [43][44][45][46] .…”

Section: Discussionmentioning

confidence: 90%

Muscarinic receptors modulate Nerve Growth Factor production in rat Schwann-like adipose-derived stem cells and in Schwann cells

Piovesana

Faroni

Taggi

et al. 2020

Sci Rep

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Regenerative capability of the peripheral nervous system after injury is enhanced by Schwann cells (Scs)producing several growth factors. the clinical use of Scs in nerve regeneration strategies is hindered by the necessity of removing a healthy nerve to obtain the therapeutic cells. Adipose-derived stem cells (ASCs) can be chemically differentiated towards a SC-like phenotype (dASCs), and represent a promising alternative to Scs. their physiology can be further modulated pharmacologically by targeting receptors for neurotransmitters such as acetylcholine (ACh). In this study, we compare the ability of rat dASCs and native SCs to produce NGF in vitro. We also evaluate the ability of muscarinic receptors, in particular the M2 subtype, to modulate NGF production and maturation from the precursor (proNGF) to the mature (mNGF) form. For the first time, we demonstrate that dASCs produce higher basal levels of proNGF and mature NGF compared to SCs. Moreover, muscarinic receptor activation, and in particular M2 subtype stimulation, modulates NGF production and maturation in both SCs and dASCs. Indeed, both cell types express both proNGF A and B isoforms, as well as mNGF. After M2 receptor stimulation, proNGF-B (25 kDa), which is involved in apoptotic processes, is strongly reduced at transcript and protein level. Thus, we demonstrate that dASCs possess a stronger neurotrophic potential compared to SCs. ACh, via M2 muscarinic receptors, contributes to the modulation and maturation of NGF, improving the regenerative properties of dASCs.Neurotrophins are a group of proteins that specifically stimulate neuronal activity during development, adult life and injury, supporting neuron survival, neurite outgrowth and controlling neuron and glial cell differentiation 1 .Nerve growth factor (NGF) has particular relevance for the survival and functional activity of sensory and sympathetic neurons 2,3 . NGF is synthesised as a precursor (proNGF) which is proteolytically cleaved to produce mature NGF (mNGF) 3,4 . In particular, two different isoforms of proNGF are described: proNGF-A (32 kDa) and proNGF-B (25 kDa) 5 . There are consistent clues that proNGF-A isoform may act as a modulator of cell survival 6 , whereas proNGF-B isoform acts as an apoptotic signal 7 . proNGF undergoes post-translational intracellular and extracellular processing at both amino-and carboxyl-terminal ends, thanks to the action of plasmin cleavage, to produce the mNGF form of 13.2kDa 4 . Both proNGF and mNGF can be secreted and have active functional roles 5,7,8 . In healthy peripheral nerves, NGF is produced by the target organs and retrogradely transported to the neuronal soma 1 binding two distinct receptors: the high-affinity Tropomyosin receptor kinase A (TrkA) and the low-affinity p75NTR 9,10 . After nerve injury, axons are dissociated from the source of neurotrophic support, and the Schwann cells (SCs) lose their contact with the axons before acquiring the repair phenotype. At this stage, open Scientific RepoRtS | (2020) 10:7159 | https://doi.org/10.1...

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Section: Discussionmentioning

confidence: 90%

Muscarinic receptors modulate Nerve Growth Factor production in rat Schwann-like adipose-derived stem cells and in Schwann cells

Piovesana

Faroni

Taggi

et al. 2020

Sci Rep

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“…However, one must take into account the short half-life of NGF (less than 1 h after ICV) ( Lapchak et al, 1993 ), and that the percentage of IN-NGF spreading by perivascular and perineural space into the subarachnoid space ( Dhuria et al, 2010 ) instead of in the parenchyma, may not be sufficient to reach the spinal cord neurons in relevant concentrations, especially after a delivery regimen limited to a few days. Nevertheless, in order to avoid potential development of side effects after IN-NGF, such as those related to pro-nociceptive function or loss of body weight, while inducing neurotrophic outcomes, the delivery of NGF-variants that target specifically the p75NTR ( Manni et al, 2019 ; Soligo et al, 2019 , 2020b ) or that do not promote the phosphorylation of residue Tyr490 on TrkA, with subsequent activation of PLC-1 ( Capsoni et al, 2011 ; Cattaneo and Capsoni, 2019 ), have been attempted. It should be noted, however, that these pharmacological approaches currently seem to be more suitable for systemic delivery of NGF, yet described as inducing side effects ( Apfel, 2002 ).…”

Section: Discussionmentioning

confidence: 99%

Intranasal Delivery of Nerve Growth Factor in Neurodegenerative Diseases and Neurotrauma

et al. 2021

Self Cite

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Since the 1980s, the development of a pharmacology based on nerve growth factor (NGF) has been postulated for the therapy of Alzheimer’s disease (AD). This hypothesis was based on the rescuing effect of the neurotrophin on the cholinergic phenotype of the basal forebrain neurons, primarily compromised during the development of AD. Subsequently, the use of NGF was put forward to treat a broader spectrum of neurological conditions affecting the central nervous system, such as Parkinson’s disease, degenerative retinopathies, severe brain traumas and neurodevelopmental dysfunctions. While supported by solid rational assumptions, the progress of a pharmacology founded on these hypotheses has been hampered by the difficulty of conveying NGF towards the brain parenchyma without resorting to invasive and risky delivery methods. At the end of the last century, it was shown that NGF administered intranasally to the olfactory epithelium was able to spread into the brain parenchyma. Notably, after such delivery, pharmacologically relevant concentration of exogenous NGF was found in brain areas located at considerable distances from the injection site along the rostral-caudal axis. These observations paved the way for preclinical characterization and clinical trials on the efficacy of intranasal NGF for the treatment of neurodegenerative diseases and of the consequences of brain trauma. In this review, a summary of the preclinical and clinical studies published to date will be attempted, as well as a discussion about the mechanisms underlying the efficacy and the possible development of the pharmacology based on intranasal conveyance of NGF to the brain.

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“…ProNGF-A promoted survival of neurons when TrkA was blocked, while ProNGF-B had the effect of causing the cells to differentiate when the p75NTR receptor was blocked. Therefore, the pro or anticancer signaling of these variants may be the result of the ratio of the different receptors on the cell surface, in combination with the different ratio of variants present [ 77 ]. Pro-NGF has the added ability to bind to a p75NTR-Sortilin receptor complex, allowing it to initiate pro-apoptotic signaling [ 78 , 79 ].…”

Section: Overview Of Tumor-nerves Interactions’ Main Componentsmentioning

confidence: 99%

Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination

Dlamini

Mathabe

Padayachy

et al. 2021

Cancers

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During development, as tissues expand and grow, they require circulatory, lymphatic, and nervous system expansion for proper function and support. Similarly, as tumors arise and develop, they also require the expansion of these systems to support them. While the contribution of blood and lymphatic systems to the development and progression of cancer is well known and is targeted with anticancer drugs, the contribution of the nervous system is less well studied and understood. Recent studies have shown that the interaction between neurons and a tumor are bilateral and promote metastasis on one hand, and the formation of new nerve structures (neoneurogenesis) on the other. Substances such as neurotransmitters and neurotrophins being the main actors in such interplay, it seems reasonable to expect that alternative splicing and the different populations of protein isoforms can affect tumor-derived neurogenesis. Here, we report the different, documented ways in which neurons contribute to the development and progression of cancer and investigate what is currently known regarding cancer-neuronal interaction in several specific cancer types. Furthermore, we discuss the incidence of alternative splicing that have been identified as playing a role in tumor-induced neoneurogenesis, cancer development and progression. Several examples of changes in alternative splicing that give rise to different isoforms in nerve tissue that support cancer progression, growth and development have also been investigated. Finally, we discuss the potential of our knowledge in alternative splicing to improve tumor diagnosis and treatment.

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Different responses of PC12 cells to different pro-nerve growth factor protein variants

Cited by 11 publications

References 50 publications

Muscarinic receptors modulate Nerve Growth Factor production in rat Schwann-like adipose-derived stem cells and in Schwann cells

Muscarinic receptors modulate Nerve Growth Factor production in rat Schwann-like adipose-derived stem cells and in Schwann cells

Intranasal Delivery of Nerve Growth Factor in Neurodegenerative Diseases and Neurotrauma

Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination

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Different responses of PC12 cells to different pro-nerve growth factor protein variants

Cited by 11 publications

References 50 publications

Muscarinic receptors modulate Nerve Growth Factor production in rat Schwann-like adipose-derived stem cells and in Schwann cells

Muscarinic receptors modulate Nerve Growth Factor production in rat Schwann-like adipose-derived stem cells and in Schwann cells

Intranasal Delivery of Nerve Growth Factor in Neurodegenerative Diseases and Neurotrauma

Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination

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Product

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Different responses of PC12 cells to different pro-nerve growth factor protein variants