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Neurotrophins: Roles and Function in Human Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 35673

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Prof. Dr. Marco Fiore

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Institute of Biochemistry and Cell Biology, Department of Sense Organs, Medical Faculty, Sapienza University of Rome, 00161 Rome, Italy
Interests: neurotrophins; addiction; toxicology; polyphenols; oxidative stress; neurobiology; behavior
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Dear Colleagues,

Neurotrophins are a family of proteins inducing the development, survival, and function of nerve cells. Neurotrophins belong to a class of growth factors, secreted proteins that signal selected cells to survive, differentiate or grow. Growth factors such as neurotrophins that promote the survival of neurons are also known as neurotrophic factors. Neurotrophic factors are produced by a specific target tissue and actively prevent the associated neuron from initiating apoptosis (programmed cell death), allowing the neurons to survive. Neurotrophins also elicit the differentiation of progenitor cells, to form neurons. Although most brain neurons are formed prenatally, brain limbic areas maintain the power to produce new neurons from neural stem cells, a process known as neurogenesis. Neurotrophins include polypeptides such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4/5. Neurotrophins and their receptors are also involved in many seemingly unrelated events, including neuronal disorders, aging-related disorders, cancer physiology, ocular diseases, autoimmune diseases, addiction, pregnancy, delivery and postpartum, oxidative-stress-related diseases, and cardiometabolic diseases such as type 2 diabetes mellitus, obesity, and metabolic syndrome.

This Special Issue focuses on the current understanding and future research directions regarding the neurotrophins and their receptors. We warmly welcome original research and review articles relating to this hot topic.

Prof. Dr. Marco Fiore
Guest Editor

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Keywords

neuroinflammation
brain
toxicology
cell growth
neurogenesis

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Neurotrophins: Roles and Function in Human Diseases 2.0 in International Journal of Molecular Sciences (3 articles)

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Research

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31 pages, 6176 KiB

Open AccessArticle

Closing the Gap between the Auditory Nerve and Cochlear Implant Electrodes: Which Neurotrophin Cocktail Performs Best for Axonal Outgrowth and Is Electrical Stimulation Beneficial?

by Dominik Schmidbauer, Stefan Fink, Francis Rousset, Hubert Löwenheim, Pascal Senn and Rudolf Glueckert

Int. J. Mol. Sci. 2023, 24(3), 2013; https://doi.org/10.3390/ijms24032013 - 19 Jan 2023

Cited by 6 | Viewed by 2876

Abstract

Neurotrophins promote neurite outgrowth of auditory neurons and may help closing the gap to cochlear implant (CI) electrodes to enhance electrical hearing. The best concentrations and mix of neurotrophins for this nerve regrowth are unknown. Whether electrical stimulation (ES) during outgrowth is beneficial or may direct axons is another open question. Auditory neuron explant cultures of distinct cochlear turns of 6–7 days old mice were cultured for four days. We tested different concentrations and combinations of BDNF and NT-3 and quantified the numbers and lengths of neurites with an advanced automated analysis. A custom-made 24-well electrical stimulator based on two bulk CIs served to test different ES strategies. Quantification of receptors trkB, trkC, p75^NTR, and histological analysis helped to analyze effects. We found 25 ng/mL BDNF to perform best, especially in basal neurons, a negative influence of NT-3 in combined BDNF/NT-3 scenarios, and tonotopic changes in trk and p75^NTR receptor stainings. ES largely impeded neurite outgrowth and glia ensheathment in an amplitude-dependent way. Apical neurons showed slight benefits in neurite numbers and length with ES at 10 and 500 µA. We recommend BDNF as a potent drug to enhance the man-machine interface, but CIs should be better activated after nerve regrowth. Full article

(This article belongs to the Special Issue Neurotrophins: Roles and Function in Human Diseases)

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18 pages, 1048 KiB

Open AccessArticle

NRN1 Gene as a Potential Marker of Early-Onset Schizophrenia: Evidence from Genetic and Neuroimaging Approaches

by Carmen Almodóvar-Payá, Maria Guardiola-Ripoll, Maria Giralt-López, Carme Gallego, Pilar Salgado-Pineda, Salvador Miret, Raymond Salvador, María J. Muñoz, Luisa Lázaro, Amalia Guerrero-Pedraza, Mara Parellada, María I. Carrión, Manuel J. Cuesta, Teresa Maristany, Salvador Sarró, Lourdes Fañanás, Luis F. Callado, Bárbara Arias, Edith Pomarol-Clotet and Mar Fatjó-Vilas

Int. J. Mol. Sci. 2022, 23(13), 7456; https://doi.org/10.3390/ijms23137456 - 5 Jul 2022

Cited by 2 | Viewed by 3057

Abstract

Included in the neurotrophins family, the Neuritin 1 gene (NRN1) has emerged as an attractive candidate gene for schizophrenia (SZ) since it has been associated with the risk for the disorder and general cognitive performance. In this work, we aimed to further investigate the association of NRN1 with SZ by exploring its role on age at onset and its brain activity correlates. First, we developed two genetic association analyses using a family-based sample (80 early-onset (EO) trios (offspring onset ≤ 18 years) and 71 adult-onset (AO) trios) and an independent case–control sample (120 healthy subjects (HS), 87 EO and 138 AO patients). Second, we explored the effect of NRN1 on brain activity during a working memory task (N-back task; 39 HS, 39 EO and 39 AO; matched by age, sex and estimated IQ). Different haplotypes encompassing the same three Single Nucleotide Polymorphisms(SNPs, rs3763180–rs10484320–rs4960155) were associated with EO in the two samples (GCT, TCC and GTT). Besides, the GTT haplotype was associated with worse N-back task performance in EO and was linked to an inefficient dorsolateral prefrontal cortex activity in subjects with EO compared to HS. Our results show convergent evidence on the NRN1 association with EO both from genetic and neuroimaging approaches, highlighting the role of neurotrophins in the pathophysiology of SZ. Full article

(This article belongs to the Special Issue Neurotrophins: Roles and Function in Human Diseases)

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14 pages, 1934 KiB

Open AccessArticle

Untangling the Conformational Plasticity of V66M Human proBDNF Polymorphism as a Modifier of Psychiatric Disorder Susceptibility

by Sonia Covaceuszach, Leticia Yamila Peche, Petr Valeryevich Konarev, Joze Grdadolnik, Antonino Cattaneo and Doriano Lamba

Int. J. Mol. Sci. 2022, 23(12), 6596; https://doi.org/10.3390/ijms23126596 - 13 Jun 2022

Cited by 2 | Viewed by 2187

Abstract

The human genetic variant BDNF (V66M) represents the first example of neurotrophin family member that has been linked to psychiatric disorders. In order to elucidate structural differences that account for the effects in cognitive function, this hproBDNF polymorph was expressed, refolded, purified, and compared directly to the WT variant for the first time for differences in their 3D structures by DSF, limited proteolysis, FT-IR, and SAXS measurements in solution. Our complementary studies revealed a deep impact of V66M polymorphism on hproBDNF conformations in solution. Although the mean conformation in solution appears to be more compact in the V66M variant, overall, we demonstrated a large increase in flexibility in solution upon V66M mutation. Thus, considering that plasticity in IDR is crucial for protein function, the observed alterations may be related to the functional alterations in hproBDNF binding to its receptors p75NTR, sortilin, HAP1, and SorCS2. These effects can provoke altered intracellular neuronal trafficking and/or affect proBDNF physiological functions, leading to many brain-associated diseases and conditions such as cognitive impairment and anxiety. The structural alterations highlighted in the present study may pave the way to the development of drug discovery strategies to provide greater therapeutic responses and of novel pharmacologic strategy in human populations with this common polymorphism, ultimately guiding personalized medicine for neuropsychiatric disorders. Full article

(This article belongs to the Special Issue Neurotrophins: Roles and Function in Human Diseases)

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13 pages, 1392 KiB

Open AccessArticle

Neurotrophic Factors in Experimental Cerebral Acanthamoebiasis

by Natalia Łanocha-Arendarczyk, Karolina Kot, Irena Baranowska-Bosiacka, Patrycja Kapczuk, Aleksandra Łanocha and Danuta Izabela Kosik-Bogacka

Int. J. Mol. Sci. 2022, 23(9), 4931; https://doi.org/10.3390/ijms23094931 - 29 Apr 2022

Cited by 2 | Viewed by 1999

Abstract

To date, no studies have addressed the role of neurotrophins (NTs) in Acanthamoeba spp. infections in the brain. Thus, to clarify the role of NTs in the cerebral cortex and hippocampus during experimental acanthamoebiasis in relation to the host immune status, the purpose of this study was to determine whether Acanthamoeba spp. may affect the concentration of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in brain structures. Our results suggest that at the beginning of infection in immunocompetent hosts, BDNF and NT-3 may reflect an endogenous attempt at neuroprotection against Acanthamoeba spp. infection. We also observed a pro-inflammatory effect of NGF during acanthamoebiasis in immunosuppressed hosts. This may provide important information for understanding the development of cerebral acanthamoebiasis related to the immunological status of the host. However, the pathogenesis of brain acanthamoebiasis is still poorly understood and documented and, therefore, requires further research. Full article

(This article belongs to the Special Issue Neurotrophins: Roles and Function in Human Diseases)

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15 pages, 1998 KiB

Open AccessArticle

NGF Modulates Cholesterol Metabolism and Stimulates ApoE Secretion in Glial Cells Conferring Neuroprotection against Oxidative Stress

by Mayra Colardo, Michele Petraroia, Letizia Lerza, Daniele Pensabene, Noemi Martella, Valentina Pallottini and Marco Segatto

Int. J. Mol. Sci. 2022, 23(9), 4842; https://doi.org/10.3390/ijms23094842 - 27 Apr 2022

Cited by 8 | Viewed by 3586

Abstract

Cholesterol plays a crucial role in the brain, where its metabolism is particularly regulated by astrocytic activity. Indeed, adult neurons suppress their own cholesterol biosynthesis and import this sterol through ApoE-rich particles secreted from astrocytes. Recent evidence suggests that nerve growth factor (NGF) may exert neurotrophic activity by influencing cell metabolism. Nevertheless, the effect of NGF on glial cholesterol homeostasis has still not been elucidated. Thus, the aim of this project is to assess whether NGF could influence cholesterol metabolism in glial cells. To reach this objective, the U373 astrocyte-derived cell line was used as an experimental model. Immunoblot and ELISA analysis showed that proteins and enzymes belonging to the cholesterol metabolism network were increased upon NGF treatment in glial cells. Furthermore, NGF significantly increased ApoE secretion and the amount of extracellular cholesterol in the culture medium. Co-culture and U373-conditioned medium experiments demonstrated that NGF treatment efficiently counteracted rotenone-mediated cytotoxicity in N1E-115 neuronal cells. Conversely, neuroprotection mediated by NGF treatment was suppressed when N1E-115 were co-cultured with ApoE-silenced U373 cells. Taken together, these data suggest that NGF controls cholesterol homeostasis in glial cells. More importantly, NGF exerts neuroprotection against oxidative stress, which is likely associated with the induction of glial ApoE secretion. Full article

(This article belongs to the Special Issue Neurotrophins: Roles and Function in Human Diseases)

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20 pages, 2673 KiB

Open AccessArticle

NGF Enhances CGRP Release Evoked by Capsaicin from Rat Trigeminal Neurons: Differential Inhibition by SNAP-25-Cleaving Proteases

by Mariia Belinskaia, Tomas Zurawski, Seshu Kumar Kaza, Caren Antoniazzi, J. Oliver Dolly and Gary W. Lawrence

Int. J. Mol. Sci. 2022, 23(2), 892; https://doi.org/10.3390/ijms23020892 - 14 Jan 2022

Cited by 8 | Viewed by 2628

Abstract

Nerve growth factor (NGF) is known to intensify pain in various ways, so perturbing pertinent effects without negating its essential influences on neuronal functions could help the search for much-needed analgesics. Towards this goal, cultured neurons from neonatal rat trigeminal ganglia—a locus for craniofacial sensory nerves—were used to examine how NGF affects the Ca²⁺-dependent release of a pain mediator, calcitonin gene-related peptide (CGRP), that is triggered by activating a key signal transducer, transient receptor potential vanilloid 1 (TRPV1) with capsaicin (CAP). Measurements utilised neurons fed with or deprived of NGF for 2 days. Acute re-introduction of NGF induced Ca²⁺-dependent CGRP exocytosis that was inhibited by botulinum neurotoxin type A (BoNT/A) or a chimera of/E and/A (/EA), which truncated SNAP-25 (synaptosomal-associated protein with Mr = 25 k) at distinct sites. NGF additionally caused a Ca²⁺-independent enhancement of the neuropeptide release evoked by low concentrations (<100 nM) of CAP, but only marginally increased the peak response to ≥100 nM. Notably, BoNT/A inhibited CGRP exocytosis evoked by low but not high CAP concentrations, whereas/EA effectively reduced responses up to 1 µM CAP and inhibited to a greater extent its enhancement by NGF. In addition to establishing that sensitisation of sensory neurons to CAP by NGF is dependent on SNARE-mediated membrane fusion, insights were gleaned into the differential ability of two regions in the C-terminus of SNAP-25 (181–197 and 198–206) to support CAP-evoked Ca²⁺-dependent exocytosis at different intensities of stimulation. Full article

(This article belongs to the Special Issue Neurotrophins: Roles and Function in Human Diseases)

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Review

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14 pages, 1322 KiB

Open AccessReview

Neurotrophins: Neuroimmune Interactions in Human Atopic Diseases

by Tobias Weihrauch, Maren M. Limberg, Natalie Gray, Martin Schmelz and Ulrike Raap

Int. J. Mol. Sci. 2023, 24(7), 6105; https://doi.org/10.3390/ijms24076105 - 24 Mar 2023

Cited by 13 | Viewed by 2210

Abstract

Allergic diseases are accompanied by a variety of symptoms such as pruritus, coughing, sneezing, and watery eyes, which can result in severe physiological and even psychological impairments. The exact mechanisms of these conditions are not yet completely understood. However, recent studies demonstrated a high relevance of neurotrophins in allergic inflammation, as they induce cytokine release, mediate interaction between immune cells and neurons, and exhibit different expression levels in health and disease. In this review, we aim to give an overview of the current state of knowledge concerning the role of neurotrophins in atopic disorders such as atopic dermatitis, allergic asthma, and allergic rhinitis. Full article

(This article belongs to the Special Issue Neurotrophins: Roles and Function in Human Diseases)

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19 pages, 2615 KiB

Open AccessReview

NGF and Its Role in Immunoendocrine Communication during Metabolic Syndrome

by Jazmín Samario-Román, Carlos Larqué, Pablo Pánico, Rosa Isela Ortiz-Huidobro, Myrian Velasco, Rene Escalona and Marcia Hiriart

Int. J. Mol. Sci. 2023, 24(3), 1957; https://doi.org/10.3390/ijms24031957 - 19 Jan 2023

Cited by 10 | Viewed by 3163

Abstract

Nerve growth factor (NGF) was the first neurotrophin described. This neurotrophin contributes to organogenesis by promoting sensory innervation and angiogenesis in the endocrine and immune systems. Neuronal and non-neuronal cells produce and secrete NGF, and several cell types throughout the body express the high-affinity neurotrophin receptor TrkA and the low-affinity receptor p75NTR. NGF is essential for glucose-stimulated insulin secretion and the complete development of pancreatic islets. Plus, this factor is involved in regulating lipolysis and thermogenesis in adipose tissue. Immune cells produce and respond to NGF, modulating their inflammatory phenotype and the secretion of cytokines, contributing to insulin resistance and metabolic homeostasis. This neurotrophin regulates the synthesis of gonadal steroid hormones, which ultimately participate in the metabolic homeostasis of other tissues. Therefore, we propose that this neurotrophin’s imbalance in concentrations and signaling during metabolic syndrome contribute to its pathophysiology. In the present work, we describe the multiple roles of NGF in immunoendocrine organs that are important in metabolic homeostasis and related to the pathophysiology of metabolic syndrome. Full article

(This article belongs to the Special Issue Neurotrophins: Roles and Function in Human Diseases)

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22 pages, 1689 KiB

Open AccessReview

NGF and the Male Reproductive System: Potential Clinical Applications in Infertility

by Giampiero Ferraguti, Francesca Fanfarillo, Luigi Tarani, Giovanna Blaconà, Francesca Tarani, Christian Barbato, Antonio Minni, Massimo Ralli, Silvia Francati, Antonio Greco, Carla Petrella and Marco Fiore

Int. J. Mol. Sci. 2022, 23(21), 13127; https://doi.org/10.3390/ijms232113127 - 28 Oct 2022

Cited by 10 | Viewed by 3651

Abstract

Infertility is a worldwide health issue defined by the World Health Organization (WHO) as the inability to establish a pregnancy after 12 months or more of regular and unprotected sexual intercourse. Male infertility etiology can be related to either congenital or acquired factors. The therapeutical approach to male infertility depends on the underlying causes and includes medical and surgical treatments. In recent studies, the potential role of nerve growth factor (NGF) in male reproductive physiology has been proposed. It has been hypothesized that neurotrophins might be involved in testis morphogenesis and regulation of several aspects of spermatogenesis. Moreover, it has been shown that NGF exerts its role on gonadotropin-releasing hormone (GnRH) neurons through the activation of the PKC/p–ERK1/2/p–CREB cascade, which leads to the activation of hypothalamic cells and the consequent activation of hypothalamus–pituitary–gonadal axis (HPG) with the secretion of GnRH. Lastly, it has been shown that the physiology of mature sperm is affected by both exogenous and endogenous NGF. The NGF impact on the HPG axis and its effect on GnRH neurons might be exploited in the therapy of male hypogonadism or used as a protective strategy against gonadal dysfunction related to chemotherapeutic agents. Moreover, the improving effect of NGF on sperm motility and vitality could be useful to enhance assisted reproduction outcomes. NGF could be supplemented to cryopreserved sperm samples to counteract the oxidative stress induced by the frozen and thawing processes. Indeed, the potential clinical applications of NGF in male infertility treatment have been discussed. Full article

(This article belongs to the Special Issue Neurotrophins: Roles and Function in Human Diseases)

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14 pages, 1184 KiB

Open AccessReview

Early Life Stress Affects Bdnf Regulation: A Role for Exercise Interventions

by Taylor S. Campbell, Katelyn M. Donoghue, Urmi Ghosh, Christina M. Nelson and Tania L. Roth

Int. J. Mol. Sci. 2022, 23(19), 11729; https://doi.org/10.3390/ijms231911729 - 3 Oct 2022

Cited by 14 | Viewed by 3263

Abstract

Early life stress (ELS) encompasses exposure to aversive experiences during early development, such as neglect or maltreatment. Animal and human studies indicate that ELS has maladaptive effects on brain development, leaving individuals more vulnerable to developing behavioral and neuropsychiatric disorders later in life. This result occurs in part to disruptions in Brain derived neurotrophic factor (Bdnf) gene regulation, which plays a vital role in early neural programming and brain health in adulthood. A potential treatment mechanism to reverse the effects of ELS on Bdnf expression is aerobic exercise due to its neuroprotective properties and positive impact on Bdnf expression. Aerobic exercise opens the door to exciting and novel potential treatment strategies because it is a behavioral intervention readily and freely available to the public. In this review, we discuss the current literature investigating the use of exercise interventions in animal models of ELS to reverse or mitigate ELS-induced changes in Bdnf expression. We also encourage future studies to investigate sensitive periods of exercise exposure, as well as sufficient duration of exposure, on epigenetic and behavioral outcomes to help lead to standardized practices in the exercise intervention field. Full article

(This article belongs to the Special Issue Neurotrophins: Roles and Function in Human Diseases)

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31 pages, 3479 KiB

Open AccessReview

New Frontiers in Neurodegeneration and Regeneration Associated with Brain-Derived Neurotrophic Factor and the rs6265 Single Nucleotide Polymorphism

by Carlye A. Szarowicz, Kathy Steece-Collier and Margaret E. Caulfield

Int. J. Mol. Sci. 2022, 23(14), 8011; https://doi.org/10.3390/ijms23148011 - 20 Jul 2022

Cited by 28 | Viewed by 4316

Abstract

Brain-derived neurotrophic factor is an extensively studied neurotrophin implicated in the pathology of multiple neurodegenerative and psychiatric disorders including, but not limited to, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, traumatic brain injury, major de-pressive disorder, and schizophrenia. Here we provide a brief summary of current knowledge on the role of BDNF and the common human single nucleotide polymorphism, rs6265, in driving the pathogenesis and rehabilitation in these disorders, as well as the status of BDNF-targeted therapies. A common trend has emerged correlating low BDNF levels, either detected within the central nervous system or peripherally, to disease states, suggesting that BDNF replacement therapies may hold clinical promise. In addition, we introduce evidence for a distinct role of the BDNF pro-peptide as a biologically active ligand and the need for continuing studies on its neurological function outside of that as a molecular chaperone. Finally, we highlight the latest research describing the role of rs6265 expression in mechanisms of neurodegeneration as well as paradoxical advances in the understanding of this genetic variant in neuroregeneration. All of this is discussed in the context of personalized medicine, acknowledging there is no “one size fits all” therapy for neurodegenerative or psychiatric disorders and that continued study of the multiple BDNF isoforms and genetic variants represents an avenue for discovery ripe with therapeutic potential. Full article

(This article belongs to the Special Issue Neurotrophins: Roles and Function in Human Diseases)

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