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Special Issue "Neurotrophic Factors—Historical Perspective and New Directions"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2016)

Special Issue Editors

Guest Editor
Prof. Margaret Fahnestock

Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
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Interests: regulation of neurotrophic factor expression; role of neurotrophins in neurological disease
Guest Editor
Dr. Keri Martinowich

Lieber Institute for Brain Development, Johns Hopkins Medical Center, Baltimore, MD, USA
Website | E-Mail
Interests: brain-derived neurotrophic factor (BDNF) signaling; neurodevelopment; regulation of the BDNF gene

Special Issue Information

Dear Colleagues,

The discovery of Nerve Growth Factor (NGF) by Drs. Rita Levi-Montalcini and Stanley Cohen in the mid-20th century ushered in a new field of research that has permeated, not only every aspect of neuroscience, but also all facets of human health and behavior. Thirty years ago, in 1986, a meeting was held in Monterey, California in honor of Rita Levi-Montalcini’s birthday and to bring together researchers and their new ideas in the field that she pioneered. Since then, the “NGF meetings” have continued to provide a venue for neurotrophic factor scientists to present exciting new findings and novel research directions. In April, 2016, a meeting was held in Asilomar, California, to mark the 30th anniversary of that original meeting and to celebrate her legacy (available online: http://www.ngfmeetings.com/2016-meeting.html)

In this Special Issue, “Neurotrophic Factors—Historical Perspective and New Directions”, we bring together a selection of articles representing the NGF 2016 meeting. This Special Issue will include a historical retrospective by three eminent colleagues of Dr. Levi-Montalcini’s: Drs. Ralph Bradshaw, Robert Rush and William Mobley. The issue will also continue the tradition of the “NGF meetings” by publishing recent research directions and current review articles about neurotrophic factors, particularly NGF and brain-derived neurotrophic factor (BDNF).

Prof. Margaret Fahnestock
Dr. Keri Martinowich
Guest Editors

Manuscript Submission Information

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Keywords

  • Neurotrophins
  • Receptors
  • Synapse
  • Signal transduction
  • Developmental biology
  • Human health
  • Neurological disease
  • Molecular mechanisms
  • Cell biology

Published Papers (17 papers)

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Editorial

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Open AccessEditorial Nerve Growth Factor and Related Substances: A Brief History and an Introduction to the International NGF Meeting Series
Int. J. Mol. Sci. 2017, 18(6), 1143; https://doi.org/10.3390/ijms18061143
Received: 12 April 2017 / Revised: 10 May 2017 / Accepted: 10 May 2017 / Published: 26 May 2017
Cited by 2 | PDF Full-text (3532 KB) | HTML Full-text | XML Full-text
Abstract
Nerve growth factor (NGF) is a protein whose importance to research and its elucidation of fundamental mechanisms in cell and neurobiology far outstrips its basic physiological roles. It was the first of a broad class of cell regulators, largely acting through autocrine and
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Nerve growth factor (NGF) is a protein whose importance to research and its elucidation of fundamental mechanisms in cell and neurobiology far outstrips its basic physiological roles. It was the first of a broad class of cell regulators, largely acting through autocrine and paracrine interactions which will be described herein. It was of similar significance in establishing the identity and unique roles of neurotrophic factors in the development and maintenance of the peripheral and central nervous systems. Finally, it contributed to many advances in the elaboration of cell surface receptor mechanisms and intracellular cell signaling. As such, it can be considered to be a “molecular Rosetta Stone”. In this brief review, the highlights of these various studies are summarized, particularly as illustrated by their coverage in the 13 NGF international meetings that have been held since 1986. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Research

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Open AccessArticle BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction
Int. J. Mol. Sci. 2017, 18(5), 1042; https://doi.org/10.3390/ijms18051042
Received: 7 April 2017 / Revised: 6 May 2017 / Accepted: 8 May 2017 / Published: 12 May 2017
Cited by 4 | PDF Full-text (1402 KB) | HTML Full-text | XML Full-text
Abstract
Most growth factors are initially synthesized as precursors then cleaved into bioactive mature domains and pro-domains, but the biological roles of pro-domains are poorly understood. In the present study, we investigated the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which promotes neuronal
[...] Read more.
Most growth factors are initially synthesized as precursors then cleaved into bioactive mature domains and pro-domains, but the biological roles of pro-domains are poorly understood. In the present study, we investigated the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which promotes neuronal survival, differentiation and synaptic plasticity. The BDNF pro-peptide is a post-processing product of the precursor BDNF. Using surface plasmon resonance and biochemical experiments, we first demonstrated that the BDNF pro-peptide binds to mature BDNF with high affinity, but not other neurotrophins. This interaction was more enhanced at acidic pH than at neutral pH, suggesting that the binding is significant in intracellular compartments such as trafficking vesicles rather than the extracellular space. The common Val66Met BDNF polymorphism results in a valine instead of a methionine in the pro-domain, which affects human brain functions and the activity-dependent secretion of BDNF. We investigated the influence of this variation on the interaction between BDNF and the pro-peptide. Interestingly, the Val66Met polymorphism stabilized the heterodimeric complex of BDNF and its pro-peptide. Furthermore, compared with the Val-containing pro-peptide, the complex with the Met-type pro-peptide was more stable at both acidic and neutral pH, suggesting that the Val66Met BDNF polymorphism forms a more stable complex. A computational modeling provided an interpretation to the role of the Val66Met mutation in the interaction of BDNF and its pro-peptide. Lastly, we performed electrophysiological experiments, which indicated that the BDNF pro-peptide, when pre-incubated with BDNF, attenuated the ability of BDNF to inhibit hippocampal long-term depression (LTD), suggesting a possibility that the BDNF pro-peptide may interact directly with BDNF and thereby inhibit its availability. It was previously reported that the BDNF pro-domain exerts a chaperone-like function and assists the folding of the BDNF protein. However, our results suggest a new role for the BDNF pro-domain (or pro-peptide) following proteolytic cleave of precursor BDNF, and provide insight into the Val66Met polymorphism. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessArticle Nerve Growth Factor Signaling from Membrane Microdomains to the Nucleus: Differential Regulation by Caveolins
Int. J. Mol. Sci. 2017, 18(4), 693; https://doi.org/10.3390/ijms18040693
Received: 29 December 2016 / Revised: 8 March 2017 / Accepted: 13 March 2017 / Published: 24 March 2017
Cited by 2 | PDF Full-text (4533 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Membrane microdomains or “lipid rafts” have emerged as essential functional modules of the cell, critical for the regulation of growth factor receptor-mediated responses. Herein we describe the dichotomy between caveolin-1 and caveolin-2, structural and regulatory components of microdomains, in modulating proliferation and differentiation.
[...] Read more.
Membrane microdomains or “lipid rafts” have emerged as essential functional modules of the cell, critical for the regulation of growth factor receptor-mediated responses. Herein we describe the dichotomy between caveolin-1 and caveolin-2, structural and regulatory components of microdomains, in modulating proliferation and differentiation. Caveolin-2 potentiates while caveolin-1 inhibits nerve growth factor (NGF) signaling and subsequent cell differentiation. Caveolin-2 does not appear to impair NGF receptor trafficking but elicits prolonged and stronger activation of MAPK (mitogen-activated protein kinase), Rsk2 (ribosomal protein S6 kinase 2), and CREB (cAMP response element binding protein). In contrast, caveolin-1 does not alter initiation of the NGF signaling pathway activation; rather, it acts, at least in part, by sequestering the cognate receptors, TrkA and p75NTR, at the plasma membrane, together with the phosphorylated form of the downstream effector Rsk2, which ultimately prevents CREB phosphorylation. The non-phosphorylatable caveolin-1 serine 80 mutant (S80V), no longer inhibits TrkA trafficking or subsequent CREB phosphorylation. MC192, a monoclonal antibody towards p75NTR that does not block NGF binding, prevents exit of both NGF receptors (TrkA and p75NTR) from lipid rafts. The results presented herein underline the role of caveolin and receptor signaling complex interplay in the context of neuronal development and tumorigenesis. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessArticle ProNGF, but Not NGF, Switches from Neurotrophic to Apoptotic Activity in Response to Reductions in TrkA Receptor Levels
Int. J. Mol. Sci. 2017, 18(3), 599; https://doi.org/10.3390/ijms18030599
Received: 1 February 2017 / Revised: 3 March 2017 / Accepted: 7 March 2017 / Published: 9 March 2017
Cited by 6 | PDF Full-text (935 KB) | HTML Full-text | XML Full-text
Abstract
Nerve growth factor (NGF) promotes the survival and differentiation of neurons. NGF is initially synthesized as a precursor, proNGF, which is the predominant form in the central nervous system. NGF and proNGF bind to TrkA/p75NTR to mediate cell survival and to sortilin/p75NTR to
[...] Read more.
Nerve growth factor (NGF) promotes the survival and differentiation of neurons. NGF is initially synthesized as a precursor, proNGF, which is the predominant form in the central nervous system. NGF and proNGF bind to TrkA/p75NTR to mediate cell survival and to sortilin/p75NTR to promote apoptosis. The ratio of TrkA to p75NTR affects whether proNGF and mature NGF signal cell survival or apoptosis. The purpose of this study was to determine whether the loss of TrkA influences p75NTR or sortilin expression levels, and to establish whether proNGF and mature NGF have a similar ability to switch between cell survival and cell death. We systematically altered TrkA receptor levels by priming cells with NGF, using small interfering RNA, and using the mutagenized PC12nnr5 cell line. We found that both NGF and proNGF can support cell survival in cells expressing TrkA, even in the presence of p75NTR and sortilin. However, when TrkA is reduced, proNGF signals cell death, while NGF exhibits no activity. In the absence of TrkA, proNGF-induced cell death occurs, even when p75NTR and sortilin levels are reduced. These results show that proNGF can switch between neurotrophic and apoptotic activity in response to changes in TrkA receptor levels, whereas mature NGF cannot. These results also support the model that proNGF is neurotrophic under normal circumstances, but that a loss in TrkA in the presence of p75NTR and sortilin, as occurs in neurodegenerative disease or injury, shifts proNGF, but not NGF, signalling from cell survival to cell death. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessArticle Time-Dependent Nerve Growth Factor Signaling Changes in the Rat Retina During Optic Nerve Crush-Induced Degeneration of Retinal Ganglion Cells
Int. J. Mol. Sci. 2017, 18(1), 98; https://doi.org/10.3390/ijms18010098
Received: 25 July 2016 / Revised: 20 December 2016 / Accepted: 24 December 2016 / Published: 5 January 2017
Cited by 4 | PDF Full-text (3817 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Nerve growth factor (NGF) is suggested to be neuroprotective after nerve injury; however, retinal ganglion cells (RGC) degenerate following optic-nerve crush (ONC), even in the presence of increased levels of endogenous NGF. To further investigate this apparently paradoxical condition, a time-course study was
[...] Read more.
Nerve growth factor (NGF) is suggested to be neuroprotective after nerve injury; however, retinal ganglion cells (RGC) degenerate following optic-nerve crush (ONC), even in the presence of increased levels of endogenous NGF. To further investigate this apparently paradoxical condition, a time-course study was performed to evaluate the effects of unilateral ONC on NGF expression and signaling in the adult retina. Visually evoked potential and immunofluorescence staining were used to assess axonal damage and RGC loss. The levels of NGF, proNGF, p75NTR, TrkA and GFAP and the activation of several intracellular pathways were analyzed at 1, 3, 7 and 14 days after crush (dac) by ELISA/Western Blot and PathScan intracellular signaling array. The progressive RGC loss and nerve impairment featured an early and sustained activation of apoptotic pathways; and GFAP and p75NTR enhancement. In contrast, ONC-induced reduction of TrkA, and increased proNGF were observed only at 7 and 14 dac. We propose that proNGF and p75NTR contribute to exacerbate retinal degeneration by further stimulating apoptosis during the second week after injury, and thus hamper the neuroprotective effect of the endogenous NGF. These findings might aid in identifying effective treatment windows for NGF-based strategies to counteract retinal and/or optic-nerve degeneration. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessArticle Preferential Enhancement of Sensory and Motor Axon Regeneration by Combining Extracellular Matrix Components with Neurotrophic Factors
Int. J. Mol. Sci. 2017, 18(1), 65; https://doi.org/10.3390/ijms18010065
Received: 5 October 2016 / Revised: 28 November 2016 / Accepted: 24 December 2016 / Published: 29 December 2016
Cited by 7 | PDF Full-text (7307 KB) | HTML Full-text | XML Full-text
Abstract
After peripheral nerve injury, motor and sensory axons are able to regenerate but inaccuracy of target reinnervation leads to poor functional recovery. Extracellular matrix (ECM) components and neurotrophic factors (NTFs) exert their effect on different neuronal populations creating a suitable environment to promote
[...] Read more.
After peripheral nerve injury, motor and sensory axons are able to regenerate but inaccuracy of target reinnervation leads to poor functional recovery. Extracellular matrix (ECM) components and neurotrophic factors (NTFs) exert their effect on different neuronal populations creating a suitable environment to promote axonal growth. Here, we assessed in vitro and in vivo the selective effects of combining different ECM components with NTFs on motor and sensory axons regeneration and target reinnervation. Organotypic cultures with collagen, laminin and nerve growth factor (NGF)/neurotrophin-3 (NT3) or collagen, fibronectin and brain-derived neurotrophic factor (BDNF) selectively enhanced sensory neurite outgrowth of DRG neurons and motor neurite outgrowth from spinal cord slices respectively. For in vivo studies, the rat sciatic nerve was transected and repaired with a silicone tube filled with a collagen and laminin matrix with NGF/NT3 encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres (MP) (LM + MP.NGF/NT3), or a collagen and fibronectin matrix with BDNF in PLGA MPs (FN + MP.BDNF). Retrograde labeling and functional tests showed that LM + MP.NGF/NT3 increased the number of regenerated sensory neurons and improved sensory functional recovery, whereas FN + MP.BDNF preferentially increased regenerated motoneurons and enhanced motor functional recovery. Therefore, combination of ECM molecules with NTFs may be a good approach to selectively enhance motor and sensory axons regeneration and promote appropriate target reinnervation. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessArticle Altered Episodic Memory in Introverted Young Adults Carrying the BDNFMet Allele
Int. J. Mol. Sci. 2016, 17(11), 1886; https://doi.org/10.3390/ijms17111886
Received: 11 August 2016 / Revised: 8 November 2016 / Accepted: 8 November 2016 / Published: 12 November 2016
Cited by 2 | PDF Full-text (424 KB) | HTML Full-text | XML Full-text
Abstract
While most studies have been interested in the distinct, predisposing roles of the common BDNF Val66Met variant and extraversion personality traits on episodic memory, very few studies have looked at the synergistic effects of genetic and personality factors to account for cognitive variance.
[...] Read more.
While most studies have been interested in the distinct, predisposing roles of the common BDNF Val66Met variant and extraversion personality traits on episodic memory, very few studies have looked at the synergistic effects of genetic and personality factors to account for cognitive variance. This is surprising considering recent reports challenging the long-held belief that the BDNFMet variant negatively impacts cognitive function. A total of 75 young healthy adults (26 of them carried at least one copy of the BDNFMet allele) took part in this study consisting of genetic profiling from saliva, personality assessment using the Revised NEO Personality Inventory (NEO PI-R) and a short battery of neuropsychological tests. An ANOVA revealed that BDNFMet carriers were significantly less extraverted than BDNFVal carriers (F1,73 = 9.54; p < 0.01; ηp2 = 0.126). Moreover, extraversion was found to significantly moderate the relationship between the BDNF genotype and episodic memory performance (p = 0.03). Subsequent correlational analyses yielded a strong and significant correlation (r = 0.542; p < 0.005) between introversion and delayed episodic memory specific to BDNFMet individuals. The present study suggests that introversion and the BDNFMet variant synergistically interact to reduce episodic memory performance in healthy, young adults. These findings reaffirm that a more accurate explanation of cognitive variance can be achieved by looking at the synergistic effects of genotype and phenotype factors. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Review

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Open AccessReview The Intersection of NGF/TrkA Signaling and Amyloid Precursor Protein Processing in Alzheimer’s Disease Neuropathology
Int. J. Mol. Sci. 2017, 18(6), 1319; https://doi.org/10.3390/ijms18061319
Received: 19 May 2017 / Revised: 8 June 2017 / Accepted: 16 June 2017 / Published: 20 June 2017
Cited by 3 | PDF Full-text (656 KB) | HTML Full-text | XML Full-text
Abstract
Dysfunction of nerve growth factor (NGF) and its high-affinity Tropomyosin receptor kinase A (TrkA) receptor has been suggested to contribute to the selective degeneration of basal forebrain cholinergic neurons (BFCN) associated with the progressive cognitive decline in Alzheimer's disease (AD). The aim of
[...] Read more.
Dysfunction of nerve growth factor (NGF) and its high-affinity Tropomyosin receptor kinase A (TrkA) receptor has been suggested to contribute to the selective degeneration of basal forebrain cholinergic neurons (BFCN) associated with the progressive cognitive decline in Alzheimer's disease (AD). The aim of this review is to describe our progress in elucidating the molecular mechanisms underlying the dynamic interplay between NGF/TrkA signaling and amyloid precursor protein (APP) metabolism within the context of AD neuropathology. This is mainly based on the finding that TrkA receptor binding to APP depends on a minimal stretch of ~20 amino acids located in the juxtamembrane/extracellular domain of APP that carries the α- and β-secretase cleavage sites. Here, we provide evidence that: (i) NGF could be one of the “routing” proteins responsible for modulating the metabolism of APP from amyloidogenic towards non-amyloidogenic processing via binding to the TrkA receptor; (ii) the loss of NGF/TrkA signaling could be linked to sporadic AD contributing to the classical hallmarks of the neuropathology, such as synaptic loss, β-amyloid peptide (Aβ) deposition and tau abnormalities. These findings will hopefully help to design therapeutic strategies for AD treatment aimed at preserving cholinergic function and anti-amyloidogenic activity of the physiological NGF/TrkA pathway in the septo-hippocampal system. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessReview Neurotrauma: The Crosstalk between Neurotrophins and Inflammation in the Acutely Injured Brain
Int. J. Mol. Sci. 2017, 18(5), 1082; https://doi.org/10.3390/ijms18051082
Received: 31 January 2017 / Revised: 25 April 2017 / Accepted: 11 May 2017 / Published: 18 May 2017
Cited by 8 | PDF Full-text (3353 KB) | HTML Full-text | XML Full-text
Abstract
Traumatic brain injury (TBI) is a major cause of morbidity and mortality among young individuals worldwide. Understanding the pathophysiology of neurotrauma is crucial for the development of more effective therapeutic strategies. After the trauma occurs, immediate neurologic damage is produced by the traumatic
[...] Read more.
Traumatic brain injury (TBI) is a major cause of morbidity and mortality among young individuals worldwide. Understanding the pathophysiology of neurotrauma is crucial for the development of more effective therapeutic strategies. After the trauma occurs, immediate neurologic damage is produced by the traumatic forces; this primary injury triggers a secondary wave of biochemical cascades together with metabolic and cellular changes, called secondary neural injury. In the scenario of the acutely injured brain, the ongoing secondary injury results in ischemia and edema culminating in an uncontrollable increase in intracranial pressure. These areas of secondary injury progression, or areas of “traumatic penumbra”, represent crucial targets for therapeutic interventions. Neurotrophins are a class of signaling molecules that promote survival and/or maintenance of neurons. They also stimulate axonal growth, synaptic plasticity, and neurotransmitter synthesis and release. Therefore, this review focuses on the role of neurotrophins in the acute post-injury response. Here, we discuss possible endogenous neuroprotective mechanisms of neurotrophins in the prevailing environment surrounding the injured areas, and highlight the crosstalk between neurotrophins and inflammation with focus on neurovascular unit cells, particularly pericytes. The perspective is that neurotrophins may represent promising targets for research on neuroprotective and neurorestorative processes in the short-term following TBI. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessReview NGF and Its Receptors in the Regulation of Inflammatory Response
Int. J. Mol. Sci. 2017, 18(5), 1028; https://doi.org/10.3390/ijms18051028
Received: 17 February 2017 / Revised: 31 March 2017 / Accepted: 3 May 2017 / Published: 11 May 2017
Cited by 10 | PDF Full-text (10200 KB) | HTML Full-text | XML Full-text
Abstract
There is growing interest in the complex relationship between the nervous and immune systems and how its alteration can affect homeostasis and result in the development of inflammatory diseases. A key mediator in cross-talk between the two systems is nerve growth factor (NGF),
[...] Read more.
There is growing interest in the complex relationship between the nervous and immune systems and how its alteration can affect homeostasis and result in the development of inflammatory diseases. A key mediator in cross-talk between the two systems is nerve growth factor (NGF), which can influence both neuronal cell function and immune cell activity. The up-regulation of NGF described in inflamed tissues of many diseases can regulate innervation and neuronal activity of peripheral neurons, inducing the release of immune-active neuropeptides and neurotransmitters, but can also directly influence innate and adaptive immune responses. Expression of the NGF receptors tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptor (p75NTR) is dynamically regulated in immune cells, suggesting a varying requirement for NGF depending on their state of differentiation and functional activity. NGF has a variety of effects that can be either pro-inflammatory or anti-inflammatory. This apparent contradiction can be explained by considering NGF as part of an endogenous mechanism that, while activating immune responses, also activates pathways necessary to dampen the inflammatory response and limit tissue damage. Decreases in TrkA expression, such as that recently demonstrated in immune cells of arthritis patients, might prevent the activation by NGF of regulatory feed-back mechanisms, thus contributing to the development and maintenance of chronic inflammation. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessReview Targeting Neurotrophins to Specific Populations of Neurons: NGF, BDNF, and NT-3 and Their Relevance for Treatment of Spinal Cord Injury
Int. J. Mol. Sci. 2017, 18(3), 548; https://doi.org/10.3390/ijms18030548
Received: 21 December 2016 / Revised: 23 February 2017 / Accepted: 24 February 2017 / Published: 3 March 2017
Cited by 16 | PDF Full-text (890 KB) | HTML Full-text | XML Full-text
Abstract
Neurotrophins are a family of proteins that regulate neuronal survival, synaptic function, and neurotransmitter release, and elicit the plasticity and growth of axons within the adult central and peripheral nervous system. Since the 1950s, these factors have been extensively studied in traumatic injury
[...] Read more.
Neurotrophins are a family of proteins that regulate neuronal survival, synaptic function, and neurotransmitter release, and elicit the plasticity and growth of axons within the adult central and peripheral nervous system. Since the 1950s, these factors have been extensively studied in traumatic injury models. Here we review several members of the classical family of neurotrophins, the receptors they bind to, and their contribution to axonal regeneration and sprouting of sensory and motor pathways after spinal cord injury (SCI). We focus on nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), and their effects on populations of neurons within diverse spinal tracts. Understanding the cellular targets of neurotrophins and the responsiveness of specific neuronal populations will allow for the most efficient treatment strategies in the injured spinal cord. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessReview Role of Nerve Growth Factor (NGF) and miRNAs in Epithelial Ovarian Cancer
Int. J. Mol. Sci. 2017, 18(3), 507; https://doi.org/10.3390/ijms18030507
Received: 28 December 2016 / Revised: 12 February 2017 / Accepted: 20 February 2017 / Published: 26 February 2017
Cited by 4 | PDF Full-text (1293 KB) | HTML Full-text | XML Full-text
Abstract
Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types
[...] Read more.
Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types of cancer, including EOC; both NGF and TRKA levels are elevated in this pathology. EOC presents high angiogenesis and several molecules have been reported to induce this process. NGF increases angiogenesis through its TRKA receptor on endothelial cells, and by indirectly inducing vascular endothelial growth factor expression. Other molecules controlled by NGF include ciclooxigenase-2, disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) and calreticulin (CRT), proteins involved in crucial processes needed for EOC progression. These molecules could be modified through microRNA regulation, which could be regulated by NGF. MicroRNAs are the widest family of non-coding RNAs; they bind to 3′-UTR of mRNAs to inhibit their translation, to deadenilate or to degraded them. In EOC, a deregulation in microRNA expression has been described, including alterations of miR-200 family, cluster-17-92, and miR-23b, among others. Since the NGF-microRNA relationship in pathologies has not been studied, this review proposes that some microRNAs could be associated with NGF/TRKA activation, modifying protein levels needed for EOC progression. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessReview The Role of Nerve Growth Factor (NGF) and Its Precursor Forms in Oral Wound Healing
Int. J. Mol. Sci. 2017, 18(2), 386; https://doi.org/10.3390/ijms18020386
Received: 7 December 2016 / Revised: 17 January 2017 / Accepted: 6 February 2017 / Published: 11 February 2017
Cited by 1 | PDF Full-text (4306 KB) | HTML Full-text | XML Full-text
Abstract
Nerve growth factor (NGF) and its different precursor forms are secreted into human saliva by salivary glands and are also produced by an array of cells in the tissues of the oral cavity. The major forms of NGF in human saliva are forms
[...] Read more.
Nerve growth factor (NGF) and its different precursor forms are secreted into human saliva by salivary glands and are also produced by an array of cells in the tissues of the oral cavity. The major forms of NGF in human saliva are forms of pro-nerve growth factor (pro-NGF) and not mature NGF. The NGF receptors tropomyosin-related kinase A (TrkA) and p75 neurotrophin receptor (p75NTR) are widely expressed on cells in the soft tissues of the human oral cavity, including keratinocytes, endothelial cells, fibroblasts and leukocytes, and in ductal and acinar cells of all types of salivary glands. In vitro models show that NGF can contribute at most stages in the oral wound healing process: restitution, cell survival, apoptosis, cellular proliferation, inflammation, angiogenesis and tissue remodeling. NGF may therefore take part in the effective wound healing in the oral cavity that occurs with little scarring. As pro-NGF forms appear to be the major form of NGF in human saliva, efforts should be made to study its function, specifically in the process of wound healing. In addition, animal and clinical studies should be initiated to examine if topical application of pro-NGF or NGF can be a therapy for chronic oral ulcerations and wounds. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessReview Charcot Marie Tooth 2B Peripheral Sensory Neuropathy: How Rab7 Mutations Impact NGF Signaling?
Int. J. Mol. Sci. 2017, 18(2), 324; https://doi.org/10.3390/ijms18020324
Received: 5 December 2016 / Revised: 10 January 2017 / Accepted: 15 January 2017 / Published: 4 February 2017
Cited by 3 | PDF Full-text (1041 KB) | HTML Full-text | XML Full-text
Abstract
Charcot-Marie-Tooth 2B peripheral sensory neuropathy (CMT2B) is a debilitating autosomal dominant hereditary sensory neuropathy. Patients with this disease lose pain sensation and frequently need amputation. Axonal dysfunction and degeneration of peripheral sensory neurons is a major clinical manifestation of CMT2B. However, the cellular
[...] Read more.
Charcot-Marie-Tooth 2B peripheral sensory neuropathy (CMT2B) is a debilitating autosomal dominant hereditary sensory neuropathy. Patients with this disease lose pain sensation and frequently need amputation. Axonal dysfunction and degeneration of peripheral sensory neurons is a major clinical manifestation of CMT2B. However, the cellular and molecular pathogenic mechanisms remain undefined. CMT2B is caused by missense point mutations (L129F, K157N, N161T/I, V162M) in Rab7 GTPase. Strong evidence suggests that the Rab7 mutation(s) enhances the cellular levels of activated Rab7 proteins, thus resulting in increased lysosomal activity and autophagy. As a consequence, trafficking and signaling of neurotrophic factors such as nerve growth factor (NGF) in the long axons of peripheral sensory neurons are particularly vulnerable to premature degradation. A “gain of toxicity” model has, thus, been proposed based on these observations. However, studies of fly photo-sensory neurons indicate that the Rab7 mutation(s) causes a “loss of function”, resulting in haploinsufficiency. In the review, we summarize experimental evidence for both hypotheses. We argue that better models (rodent animals and human neurons) of CMT2B are needed to precisely define the disease mechanisms. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessReview Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer’s Disease
Int. J. Mol. Sci. 2016, 17(12), 2122; https://doi.org/10.3390/ijms17122122
Received: 23 November 2016 / Revised: 5 December 2016 / Accepted: 12 December 2016 / Published: 17 December 2016
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Abstract
The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological
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The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer’s disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer’s disease. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessReview Functional Diversity of Neurotrophin Actions on the Oculomotor System
Int. J. Mol. Sci. 2016, 17(12), 2016; https://doi.org/10.3390/ijms17122016
Received: 6 October 2016 / Revised: 24 November 2016 / Accepted: 25 November 2016 / Published: 1 December 2016
Cited by 4 | PDF Full-text (2879 KB) | HTML Full-text | XML Full-text
Abstract
Neurotrophins play a principal role in neuronal survival and differentiation during development, but also in the maintenance of appropriate adult neuronal circuits and phenotypes. In the oculomotor system, we have demonstrated that neurotrophins are key regulators of developing and adult neuronal properties, but
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Neurotrophins play a principal role in neuronal survival and differentiation during development, but also in the maintenance of appropriate adult neuronal circuits and phenotypes. In the oculomotor system, we have demonstrated that neurotrophins are key regulators of developing and adult neuronal properties, but with peculiarities depending on each neurotrophin. For instance, the administration of NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor) or NT-3 (neurotrophin-3) protects neonatal extraocular motoneurons from cell death after axotomy, but only NGF and BDNF prevent the downregulation in ChAT (choline acetyltransferase). In the adult, in vivo recordings of axotomized extraocular motoneurons have demonstrated that the delivery of NGF, BDNF or NT-3 recovers different components of the firing discharge activity of these cells, with some particularities in the case of NGF. All neurotrophins have also synaptotrophic activity, although to different degrees. Accordingly, neurotrophins can restore the axotomy-induced alterations acting selectively on different properties of the motoneuron. In this review, we summarize these evidences and discuss them in the context of other motor systems. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Open AccessReview Neuroprotection, Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration
Int. J. Mol. Sci. 2016, 17(9), 1584; https://doi.org/10.3390/ijms17091584
Received: 27 July 2016 / Revised: 1 September 2016 / Accepted: 14 September 2016 / Published: 20 September 2016
Cited by 37 | PDF Full-text (2008 KB) | HTML Full-text | XML Full-text
Abstract
Neurotrophic factors play key roles in the development and survival of neurons. The potent neuroprotective effects of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF) and nerve growth factor (NGF), suggest that they are
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Neurotrophic factors play key roles in the development and survival of neurons. The potent neuroprotective effects of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF) and nerve growth factor (NGF), suggest that they are good therapeutic candidates for neurodegenerative diseases. Glaucoma is a neurodegenerative disease of the eye that causes irreversible blindness. It is characterized by damage to the optic nerve, usually due to high intraocular pressure (IOP), and progressive degeneration of retinal neurons called retinal ganglion cells (RGCs). Current therapy for glaucoma focuses on reduction of IOP, but neuroprotection may also be beneficial. BDNF is a powerful neuroprotective agent especially for RGCs. Exogenous application of BDNF to the retina and increased BDNF expression in retinal neurons using viral vector systems are both effective in protecting RGCs from damage. Furthermore, induction of BDNF expression by agents such as valproic acid has also been beneficial in promoting RGC survival. In this review, we discuss the therapeutic potential of neurotrophic factors in retinal diseases and focus on the differential roles of glial and neuronal TrkB in neuroprotection. We also discuss the role of neurotrophic factors in neuroregeneration. Full article
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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