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Cell Signaling in Neurodegeneration 2.0

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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 (31 December 2021) | Viewed by 41388

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Dr. Jose Luis Zugaza

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Guest Editor

Achucarro Basque Center for Neuroscience, Barrio de Sarriena, s/n, 48940 Leioa, Spain
Interests: small GTPases; glycogen metabolism; PTMs; neurodegeneration and signaling pathways
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cellular communication and signaling are keys to coordinate the functions of the different cell types that constitute organisms. These systems control processes such as inter- and intracellular transport, changes in cell morphology, energy consumption, and accumulation, cell differentiation, cell migration, cell proliferation or cell death. These controls are established through gene regulation and the function of small and macromolecules, such as proteins. It is estimated that more than 20% of the genes of the human genome encode proteins are involved in the signal transduction pathways that regulate changes in localization, trafficking, degradation, of molecules or functional intermolecular interactions. Understanding how cells receive and coordinate signals from the environment and/or other cells to finally emit a physiological response is the basis for correcting dysfunctionalities that cause unregulated modifications of these signaling systems and result in multiple pathologies, including neurodegenerative diseases.

The purpose of this Special Issue of IJMS is to explore this paradigm of cell signaling in neurodegeneration in order to understand the molecular mechanisms that lead to these neurodegenerative processes. Therefore, this Special Issue provides an excellent opportunity to cover studies and reports on cell cultures and animal models and to reveal new knowledge about the underlying pathophysiology/pathogenesis or other aspects that could affect positively the progressive development of efficient molecules to fight those neurodegenerative diseases effectively.

Prof. Dr. José Zugaza
Guest Editor

Manuscript Submission Information

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Keywords

Small GTPases
Post-translational modification (PTM)
Enzyme activity
Cytoskeleton
Gene expression
Epigenetic modifications
Glia
Neuron
Neurodegeneration

Published Papers (11 papers)

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Research

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15 pages, 2540 KiB

Open AccessArticle

The Tyrosine Phosphatase hPTPRβ Controls the Early Signals and Dopaminergic Cells Viability via the P2X₇ Receptor

by Francisco Llavero Bernal, Miriam Luque Montoro, Alazne Arrazola Sastre, Hadriano M. Lacerda and José Luis Zugaza

Int. J. Mol. Sci. 2021, 22(23), 12936; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312936 - 29 Nov 2021

Cited by 3 | Viewed by 1802

Abstract

ATP, one of the signaling molecules most commonly secreted in the nervous system and capable of stimulating multiple pathways, binds to the ionotropic purinergic receptors, in particular, the P2X₇ receptor (P2X₇R) and stimulates neuronal cell death. Given this effect of purinergic receptors on the viability of dopaminergic neurons model cells and that Ras GTPases control Erk1/2-regulated mitogen-activated cell proliferation and survival, we have investigated the role of the small GTPases of the Ras superfamily, together with their regulatory and effector molecules as the potential molecular intermediates in the P2X₇R-regulated cell death of SN4741 dopaminergic neurons model cells. Here, we demonstrate that the neuronal response to purinergic stimulation involves the Calmodulin/RasGRF1 activation of the small GTPase Ras and Erk1/2. We also demonstrate that tyrosine phosphatase PTPRβ and other tyrosine phosphatases regulate the small GTPase activation pathway and neuronal viability. Our work expands the knowledge on the intracellular responses of dopaminergic cells by identifying new participating molecules and signaling pathways. In this sense, the study of the molecular circuitry of these neurons is key to understanding the functional effects of ATP, as well as considering the importance of these cells in Parkinson’s Disease. Full article

(This article belongs to the Special Issue Cell Signaling in Neurodegeneration 2.0)

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17 pages, 1839 KiB

Open AccessArticle

Involvement of the miR-363-5p/P2RX4 Axis in Regulating Schwann Cell Phenotype after Nerve Injury

by Eun-Jung Sohn, Yun-Kyeong Nam and Hwan-Tae Park

Int. J. Mol. Sci. 2021, 22(21), 11601; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111601 - 27 Oct 2021

Cited by 7 | Viewed by 3143

Abstract

Although microRNAs (miRNAs or miRs) have been studied in the peripheral nervous system, their function in Schwann cells remains elusive. In this study, we performed a microRNA array analysis of cyclic adenosine monophosphate (cAMP)-induced differentiated primary Schwann cells. KEGG pathway enrichment analysis of the target genes showed that upregulated miRNAs (mR212-5p, miR335, miR20b-5p, miR146b-3p, and miR363-5p) were related to the calcium signaling pathway, regulation of actin cytoskeleton, retrograde endocannabinoid signaling, and central carbon metabolism in cancer. Several key factors, such as purinergic receptors (P2X), guanine nucleotide-binding protein G(olf) subunit alpha (GNAL), P2RX5, P2RX3, platelet-derived growth factor receptor alpha (PDGFRA), and inositol 1,4,5-trisphosphate receptor type 2 (ITPR2; calcium signaling pathway) are potential targets of miRNAs regulating cAMP. Our analysis revealed that miRNAs were differentially expressed in cAMP-treated Schwann cells; miRNA363-5p was upregulated and directly targeted the P2X purinoceptor 4 (P2RX4)-UTR, reducing the luciferase activity of P2RX4. The expression of miRNA363-5p was inhibited and the expression of P2RX4 was upregulated in sciatic nerve injury. In contrast, miRNA363-5p expression was upregulated and P2RX4 expression was downregulated during postnatal development. Of note, a P2RX4 antagonist counteracted myelin degradation after nerve injury and increased pERK and c-Jun expression. Interestingly, a P2RX4 antagonist increased the levels of miRNA363-5p. This study suggests that a double-negative feedback loop between miRNA363-5p and P2RX4 contributes to the dedifferentiation and migration of Schwann cells after nerve injury. Full article

(This article belongs to the Special Issue Cell Signaling in Neurodegeneration 2.0)

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15 pages, 3940 KiB

Open AccessArticle

The Effects of Aβ_1-42 Binding to the SARS-CoV-2 Spike Protein S1 Subunit and Angiotensin-Converting Enzyme 2

by John Tsu-An Hsu, Chih-Feng Tien, Guann-Yi Yu, Santai Shen, Yi-Hsuan Lee, Pei-Chien Hsu, Yun Wang, Po-Kuan Chao, Huey-Jen Tsay and Feng-Shiun Shie

Int. J. Mol. Sci. 2021, 22(15), 8226; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158226 - 30 Jul 2021

Cited by 35 | Viewed by 3926

Abstract

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer’s disease (AD), the major form of dementia, β-amyloid (Aβ) levels in the blood are increased; however, the impact of elevated Aβ levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aβ_1-42, but not Aβ_1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aβ_1-42. Furthermore, Aβ_1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aβ_1-42 show that the clearance of Aβ_1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aβ antibody. In conclusion, these findings suggest that the binding of Aβ_1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aβ_1-42 in the blood is beneficial to the fight against COVID-19 and AD. Full article

(This article belongs to the Special Issue Cell Signaling in Neurodegeneration 2.0)

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15 pages, 24106 KiB

Open AccessArticle

EBI2 Is Temporarily Upregulated in MO3.13 Oligodendrocytes during Maturation and Regulates Remyelination in the Organotypic Cerebellar Slice Model

by Maria Velasco-Estevez, Nina Koch, Ilona Klejbor, Stephane Laurent, Kumlesh K. Dev, Andrzej Szutowicz, Andreas W. Sailer and Aleksandra Rutkowska

Int. J. Mol. Sci. 2021, 22(9), 4342; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094342 - 21 Apr 2021

Cited by 8 | Viewed by 3073

Abstract

The EBI2 receptor regulates the immune system and is expressed in various immune cells including B and T lymphocytes. It is also expressed in astrocytes in the central nervous system (CNS) where it regulates pro-inflammatory cytokine release, cell migration and protects from chemically induced demyelination. Its signaling and expression are implicated in various diseases including multiple sclerosis, where its expression is increased in infiltrating immune cells in the white matter lesions. Here, for the first time, the EBI2 protein in the CNS cells in the human brain was examined. The function of the receptor in MO3.13 oligodendrocytes, as well as its role in remyelination in organotypic cerebellar slices, were investigated. Human brain sections were co-stained for EBI2 receptor and various markers of CNS-specific cells and the human oligodendrocyte cell line MO3.13 was used to investigate changes in EBI2 expression and cellular migration. Organotypic cerebellar slices prepared from wild-type and cholesterol 25-hydroxylase knock-out mice were used to study remyelination following lysophosphatidylcholine (LPC)-induced demyelination. The data showed that EBI2 receptor is present in OPCs but not in myelinating oligodendrocytes in the human brain and that EBI2 expression is temporarily upregulated in maturing MO3.13 oligodendrocytes. Moreover, we show that migration of MO3.13 cells is directly regulated by EBI2 and that its signaling is necessary for remyelination in cerebellar slices post-LPC-induced demyelination. The work reported here provides new information on the expression and role of EBI2 in oligodendrocytes and myelination and provides new tools for modulation of oligodendrocyte biology and therapeutic approaches for demyelinating diseases. Full article

(This article belongs to the Special Issue Cell Signaling in Neurodegeneration 2.0)

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15 pages, 1850 KiB

Open AccessArticle

Pigment Epithelium-Derived Factor (PEDF) Receptors Are Involved in Survival of Retinal Neurons

by Susanne Bürger, Jie Meng, Annette Zwanzig, Mike Beck, Maik Pankonin, Peter Wiedemann, Wolfram Eichler and Jan Darius Unterlauft

Int. J. Mol. Sci. 2021, 22(1), 369; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010369 - 31 Dec 2020

Cited by 14 | Viewed by 2571

Abstract

The demise of retinal ganglion cells (RGCs) is characteristic of diseases of the retina such as glaucoma and diabetic or ischemic retinopathies. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted protein that mediates neuroprotection and inhibition of angiogenesis in the retina. We have studied expression and regulation of two of several receptors for PEDF, patatin-like phospholipase 2 gene product/PEDF-R and laminin receptor (LR), in serum-starved RGC under normoxia and hypoxia and investigated their involvement in the survival of retinal neuronal cells. We show that PEDF-R and LR are co-expressed in RGC and R28 retinal precursor cells. Expression of both receptors was enhanced in the presence of complex secretions from retinal glial (Müller) cells and upregulated by VEGF and under hypoxic conditions. PEDF-R- and LR-knocked-down cells demonstrated a markedly attenuated expression of anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-xL) and neuroprotective mediators (PEDF, VEGF, BDNF) suggesting that both PEDF-R and LR mediate pro-survival effects of PEDF on RGC. While this study does not provide evidence for a differential survival-promoting influence of either PEDF-R or LR, it nevertheless highlights the importance of both PEDF receptors for the viability of retinal neurons. Full article

(This article belongs to the Special Issue Cell Signaling in Neurodegeneration 2.0)

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21 pages, 8273 KiB

Open AccessArticle

Neural Tissue Degeneration in Rosenthal’s Canal and Its Impact on Electrical Stimulation of the Auditory Nerve by Cochlear Implants: An Image-Based Modeling Study

by Kiran Kumar Sriperumbudur, Revathi Appali, Anthony W. Gummer and Ursula van Rienen

Int. J. Mol. Sci. 2020, 21(22), 8511; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228511 - 12 Nov 2020

Cited by 3 | Viewed by 2819

Abstract

Sensorineural deafness is caused by the loss of peripheral neural input to the auditory nerve, which may result from peripheral neural degeneration and/or a loss of inner hair cells. Provided spiral ganglion cells and their central processes are patent, cochlear implants can be used to electrically stimulate the auditory nerve to facilitate hearing in the deaf or severely hard-of-hearing. Neural degeneration is a crucial impediment to the functional success of a cochlear implant. The present, first-of-its-kind two-dimensional finite-element model investigates how the depletion of neural tissues might alter the electrically induced transmembrane potential of spiral ganglion neurons. The study suggests that even as little as 10% of neural tissue degeneration could lead to a disproportionate change in the stimulation profile of the auditory nerve. This result implies that apart from encapsulation layer formation around the cochlear implant electrode, tissue degeneration could also be an essential reason for the apparent inconsistencies in the functionality of cochlear implants. Full article

(This article belongs to the Special Issue Cell Signaling in Neurodegeneration 2.0)

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Review

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23 pages, 4074 KiB

Open AccessReview

Should We Open Fire on Microglia? Depletion Models as Tools to Elucidate Microglial Role in Health and Alzheimer’s Disease

by Carmen Romero-Molina, Victoria Navarro, Sebastian Jimenez, Clara Muñoz-Castro, Maria V. Sanchez-Mico, Antonia Gutierrez, Javier Vitorica and Marisa Vizuete

Int. J. Mol. Sci. 2021, 22(18), 9734; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189734 - 08 Sep 2021

Cited by 7 | Viewed by 4053

Abstract

Microglia play a critical role in both homeostasis and disease, displaying a wide variety in terms of density, functional markers and transcriptomic profiles along the different brain regions as well as under injury or pathological conditions, such as Alzheimer’s disease (AD). The generation of reliable models to study into a dysfunctional microglia context could provide new knowledge towards the contribution of these cells in AD. In this work, we included an overview of different microglial depletion approaches. We also reported unpublished data from our genetic microglial depletion model, Cx3cr1^CreER/Csf1r^flx/flx, in which we temporally controlled microglia depletion by either intraperitoneal (acute model) or oral (chronic model) tamoxifen administration. Our results reported a clear microglial repopulation, then pointing out that our model would mimic a context of microglial replacement instead of microglial dysfunction. Next, we evaluated the origin and pattern of microglial repopulation. Additionally, we also reviewed previous works assessing the effects of microglial depletion in the progression of Aβ and Tau pathologies, where controversial data are found, probably due to the heterogeneous and time-varying microglial phenotypes observed in AD. Despite that, microglial depletion represents a promising tool to assess microglial role in AD and design therapeutic strategies. Full article

(This article belongs to the Special Issue Cell Signaling in Neurodegeneration 2.0)

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26 pages, 2438 KiB

Open AccessReview

Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

by Joanna A. Motyl, Joanna B. Strosznajder, Agnieszka Wencel and Robert P. Strosznajder

Int. J. Mol. Sci. 2021, 22(12), 6277; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126277 - 11 Jun 2021

Cited by 11 | Viewed by 4450

Abstract

Molecular studies have provided increasing evidence that Parkinson’s disease (PD) is a protein conformational disease, where the spread of alpha-synuclein (ASN) pathology along the neuraxis correlates with clinical disease outcome. Pathogenic forms of ASN evoke oxidative stress (OS), neuroinflammation, and protein alterations in neighboring cells, thereby intensifying ASN toxicity, neurodegeneration, and neuronal death. A number of evidence suggest that homeostasis between bioactive sphingolipids with opposing function—e.g., sphingosine-1-phosphate (S1P) and ceramide—is essential in pro-survival signaling and cell defense against OS. In contrast, imbalance of the “sphingolipid biostat” favoring pro-oxidative/pro-apoptotic ceramide-mediated changes have been indicated in PD and other neurodegenerative disorders. Therefore, we focused on the role of sphingolipid alterations in ASN burden, as well as in a vast range of its neurotoxic effects. Sphingolipid homeostasis is principally directed by sphingosine kinases (SphKs), which synthesize S1P—a potent lipid mediator regulating cell fate and inflammatory response—making SphK/S1P signaling an essential pharmacological target. A growing number of studies have shown that S1P receptor modulators, and agonists are promising protectants in several neurological diseases. This review demonstrates the relationship between ASN toxicity and alteration of SphK-dependent S1P signaling in OS, neuroinflammation, and neuronal death. Moreover, we discuss the S1P receptor-mediated pathways as a novel promising therapeutic approach in PD. Full article

(This article belongs to the Special Issue Cell Signaling in Neurodegeneration 2.0)

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27 pages, 1140 KiB

Open AccessReview

Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

by Niccolò Candelise, Silvia Scaricamazza, Illari Salvatori, Alberto Ferri, Cristiana Valle, Valeria Manganelli, Tina Garofalo, Maurizio Sorice and Roberta Misasi

Int. J. Mol. Sci. 2021, 22(11), 6016; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116016 - 02 Jun 2021

Cited by 27 | Viewed by 4483

Abstract

Intrinsic disorder is a natural feature of polypeptide chains, resulting in the lack of a defined three-dimensional structure. Conformational changes in intrinsically disordered regions of a protein lead to unstable β-sheet enriched intermediates, which are stabilized by intermolecular interactions with other β-sheet enriched molecules, producing stable proteinaceous aggregates. Upon misfolding, several pathways may be undertaken depending on the composition of the amino acidic string and the surrounding environment, leading to different structures. Accumulating evidence is suggesting that the conformational state of a protein may initiate signalling pathways involved both in pathology and physiology. In this review, we will summarize the heterogeneity of structures that are produced from intrinsically disordered protein domains and highlight the routes that lead to the formation of physiological liquid droplets as well as pathogenic aggregates. The most common proteins found in aggregates in neurodegenerative diseases and their structural variability will be addressed. We will further evaluate the clinical relevance and future applications of the study of the structural heterogeneity of protein aggregates, which may aid the understanding of the phenotypic diversity observed in neurodegenerative disorders. Full article

(This article belongs to the Special Issue Cell Signaling in Neurodegeneration 2.0)

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15 pages, 1404 KiB

Open AccessReview

Brain-Derived Neurotrophic Factor Signaling in the Pathophysiology of Alzheimer’s Disease: Beneficial Effects of Flavonoids for Neuroprotection

by Tadahiro Numakawa and Haruki Odaka

Int. J. Mol. Sci. 2021, 22(11), 5719; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115719 - 27 May 2021

Cited by 48 | Viewed by 4800

Abstract

The function of the brain-derived neurotrophic factor (BDNF) via activation through its high-affinity receptor Tropomyosin receptor kinase B (TrkB) has a pivotal role in cell differentiation, cell survival, synaptic plasticity, and both embryonic and adult neurogenesis in central nervous system neurons. A number of studies have demonstrated the possible involvement of altered expression and action of the BDNF/TrkB signaling in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). In this review, we introduce an essential role of the BDNF and its downstream signaling in neural function. We also review the current evidence on the deregulated the BDNF signaling in the pathophysiology of AD at gene, mRNA, and protein levels. Further, we discuss a potential usefulness of small compounds, including flavonoids, which can stimulate BDNF-related signaling as a BDNF-targeting therapy. Full article

(This article belongs to the Special Issue Cell Signaling in Neurodegeneration 2.0)

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24 pages, 1586 KiB

Open AccessReview

Small GTPases of the Rab and Arf Families: Key Regulators of Intracellular Trafficking in Neurodegeneration

by Alazne Arrazola Sastre, Miriam Luque Montoro, Hadriano M. Lacerda, Francisco Llavero and José L. Zugaza

Int. J. Mol. Sci. 2021, 22(9), 4425; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094425 - 23 Apr 2021

Cited by 17 | Viewed by 4939

Abstract

Small guanosine triphosphatases (GTPases) of the Rab and Arf families are key regulators of vesicle formation and membrane trafficking. Membrane transport plays an important role in the central nervous system. In this regard, neurons require a constant flow of membranes for the correct distribution of receptors, for the precise composition of proteins and organelles in dendrites and axons, for the continuous exocytosis/endocytosis of synaptic vesicles and for the elimination of dysfunctional proteins. Thus, it is not surprising that Rab and Arf GTPases have been associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Both pathologies share characteristics such as the presence of protein aggregates and/or the fragmentation of the Golgi apparatus, hallmarks that have been related to both Rab and Arf GTPases functions. Despite their relationship with neurodegenerative disorders, very few studies have focused on the role of these GTPases in the pathogenesis of neurodegeneration. In this review, we summarize their importance in the onset and progression of Alzheimer’s and Parkinson’s diseases, as well as their emergence as potential therapeutical targets for neurodegeneration. Full article

(This article belongs to the Special Issue Cell Signaling in Neurodegeneration 2.0)

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