Publications by authors named "Assunta Virtuoso"

14 Publications

  • Page 1 of 1

The Spatiotemporal Coupling: Regional Energy Failure and Aberrant Proteins in Neurodegenerative Diseases.

Int J Mol Sci 2021 Oct 20;22(21). Epub 2021 Oct 20.

Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania ''Luigi Vanvitelli", 80138 Naples, Italy.

The spatial and temporal coordination of each element is a pivotal characteristic of systems, and the central nervous system (CNS) is not an exception. Glial elements and the vascular interface have been considered more recently, together with the extracellular matrix and the immune system. However, the knowledge of the single-element configuration is not sufficient to predict physiological or pathological long-lasting changes. Ionic currents, complex molecular cascades, genomic rearrangement, and the regional energy demand can be different even in neighboring cells of the same phenotype, and their differential expression could explain the region-specific progression of the most studied neurodegenerative diseases. We here reviewed the main nodes and edges of the system, which could be studied to develop a comprehensive knowledge of CNS plasticity from the neurovascular unit to the synaptic cleft. The future goal is to redefine the modeling of synaptic plasticity and achieve a better understanding of neurological diseases, pointing out cellular, subcellular, and molecular components that couple in specific neuroanatomical and functional regions.
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http://dx.doi.org/10.3390/ijms222111304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583302PMC
October 2021

Inhibition of plasminogen/plasmin system retrieves endogenous nerve growth factor and adaptive spinal synaptic plasticity following peripheral nerve injury.

Neurochem Int 2021 09 23;148:105113. Epub 2021 Jun 23.

Division of Human Anatomy, Laboratory of Morphology of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli, Naples, Italy. Electronic address:

Dysfunctions of the neuronal-glial crosstalk and/or impaired signaling of neurotrophic factors represent key features of the maladaptive changes in the central nervous system (CNS) in neuroinflammatory as neurodegenerative disorders. Tissue plasminogen activator (tPA)/plasminogen (PA)/plasmin system has been involved in either process of maturation and degradation of nerve growth factor (NGF), highlighting multiple potential targets for new therapeutic strategies. We here investigated the role of intrathecal (i.t.) delivery of neuroserpin (NS), an endogenous inhibitor of plasminogen activators, on neuropathic behavior and maladaptive synaptic plasticity in the rat spinal cord following spared nerve injury (SNI) of the sciatic nerve. We demonstrated that SNI reduced spinal NGF expression, induced spinal reactive gliosis, altering the expression of glial and neuronal glutamate and GABA transporters, reduced glutathione (GSH) levels and is associated to neuropathic behavior. Beside the increase of NGF expression, i.t. NS administration reduced reactive gliosis, restored synaptic homeostasis, GSH levels and reduced neuropathic behavior. Our results hereby highlight the essential role of tPA/PA system in the synaptic homeostasis and mechanisms of maladaptive plasticity, sustaining the beneficial effects of NGF-based approach in neurological disorders.
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http://dx.doi.org/10.1016/j.neuint.2021.105113DOI Listing
September 2021

The Glioblastoma Microenvironment: Morphology, Metabolism, and Molecular Signature of Glial Dynamics to Discover Metabolic Rewiring Sequence.

Int J Mol Sci 2021 Mar 24;22(7). Epub 2021 Mar 24.

Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania ''Luigi Vanvitelli", 80138 Naples, Italy.

Different functional states determine glioblastoma (GBM) heterogeneity. Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. This may be a possible reason for the lack of improvements in patients with high-grade gliomas therapies. Cell metabolism and bioenergetic fitness depend on the availability of nutrients and interactions in the microenvironment. It is strictly related to the cell location in the tumor mass, proximity to blood vessels, biochemical gradients, and tumor evolution, underlying the influence of the context and the timeline in anti-tumor therapeutic approaches. Besides the cancer metabolic strategies, here we review the modifications found in the GBM-associated glia, focusing on morphological, molecular, and metabolic features. We propose to analyze the GBM metabolic rewiring processes from a systems biology perspective. We aim at defining the crosstalk between GBM and the glial cells as modules. The complex networking may be expressed by metabolic modules corresponding to the GBM growth and spreading phases. Variation in the oxidative phosphorylation (OXPHOS) rate and regulation appears to be the most important part of the metabolic and functional heterogeneity, correlating with glycolysis and response to hypoxia. Integrated metabolic modules along with molecular and morphological features could allow the identification of key factors for controlling the GBM-stroma metabolism in multi-targeted, time-dependent therapies.
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http://dx.doi.org/10.3390/ijms22073301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036663PMC
March 2021

Roadmap for Stroke: Challenging the Role of the Neuronal Extracellular Matrix.

Int J Mol Sci 2020 Oct 13;21(20). Epub 2020 Oct 13.

SYSBIO Centre of Systems Biology ISBE.ITALY, University of Milano-Bicocca, 20126 Milano, Italy.

Stroke is a major challenge in modern medicine and understanding the role of the neuronal extracellular matrix (NECM) in its pathophysiology is fundamental for promoting brain repair. Currently, stroke research is focused on the neurovascular unit (NVU). Impairment of the NVU leads to neuronal loss through post-ischemic and reperfusion injuries, as well as coagulatory and inflammatory processes. The ictal core is produced in a few minutes by the high metabolic demand of the central nervous system. Uncontrolled or prolonged inflammatory response is characterized by leukocyte infiltration of the injured site that is limited by astroglial reaction. The metabolic failure reshapes the NECM through matrix metalloproteinases (MMPs) and novel deposition of structural proteins continues within months of the acute event. These maladaptive reparative processes are responsible for the neurological clinical phenotype. In this review, we aim to provide a systems biology approach to stroke pathophysiology, relating the injury to the NVU with the pervasive metabolic failure, inflammatory response and modifications of the NECM. The available data will be used to build a protein-protein interaction (PPI) map starting with 38 proteins involved in stroke pathophysiology, taking into account the timeline of damage and the co-expression scores of their RNA patterns The application of the proposed network could lead to a more accurate design of translational experiments aiming at improving both the therapy and the rehabilitation processes.
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http://dx.doi.org/10.3390/ijms21207554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589675PMC
October 2020

The Spinal Extracellular Matrix Modulates a Multi-level Protein Net and Epigenetic Inducers Following Peripheral Nerve Injury.

Neuroscience 2020 12 1;451:216-225. Epub 2020 Oct 1.

Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy; SYSBIO Centre of Systems Biology ISBE-IT, University of Milano-Bicocca, Milan, Italy.

The extracellular matrix (ECM) of the central nervous system (CNS) plays a pivotal role in the pathogenesis of several neurodegenerative and neuroinflammatory disorders. Among the major factors, matrix metalloproteinases (MMPs) are actively involved in ECM remodeling and directly affect neuro-glial interactions. Since disease-related functional alterations mostly rely on the proteome, modulation of MMPs activity may be a strategy to correct mechanisms behind neurological disorders. We here investigated modifications of signaling components related to the central pathways in spinal maladaptive plasticity following spared nerve injury (SNI) of the sciatic nerve, and after treatment with the MMPs inhibitor GM6001 for 3 or 8 days. We found that GM6001 reduced the massive astrocytic and microglial activation indicative of reactive gliosis. Functional activity of GM6001 was paralleled by its significant effect on expression levels of the purinergic P2X4 receptor (P2X4R), the transcription factors NFκB and RPBJ, as well as levels of the nerve growth factor (NGF) receptor TrkA. Moreover, we showed that histone deacetylases 1 and 2 (HDAC1, HDAC2) were differentially modulated after SNI and GM6001 treatments for 3 or 8 days. Our data suggest a multi-level network of interactions across ECM and the neuroglial network involving MMPs, the neurotrophin system, intracellular signaling, and epigenetic modifications.
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http://dx.doi.org/10.1016/j.neuroscience.2020.09.051DOI Listing
December 2020

First steps for the development of silk fibroin-based 3D biohybrid retina for age-related macular degeneration (AMD).

J Neural Eng 2020 10 31;17(5):055003. Epub 2020 Oct 31.

Neuro-computing & Neuro-robotics Research Group, Complutense University of Madrid, Spain. Innovation Research Group, Institute for Health Research San Carlos Clinical Hospital (IdISSC), Madrid, Spain. These authors equally contributed to this article.

Age-related macular degeneration is an incurable chronic neurodegenerative disease, causing progressive loss of the central vision and even blindness. Up-to-date therapeutic approaches can only slow down he progression of the disease.

Objective: Feasibility study for a multilayered, silk fibroin-based, 3D biohybrid retina.

Approach: Fabrication of silk fibroin-based biofilms; culture of different types of cells: retinal pigment epithelium, retinal neurons, Müller and mesenchymal stem cells ; creation of a layered structure glued with silk fibroin hydrogel.

Main Results: In vitro evidence for the feasibility of layered 3D biohybrid retinas; primary culture neurons grow and develop neurites on silk fibroin biofilms, either alone or in presence of other cells cultivated on the same biomaterial; cell organization and cellular phenotypes are maintained in vitro for the seven days of the experiment.

Significance: 3D biohybrid retina can be built using silk silkworm fibroin films and hydrogels to be used in cell replacement therapy for AMD and similar retinal neurodegenerative diseases.
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http://dx.doi.org/10.1088/1741-2552/abb9c0DOI Listing
October 2020

Neurons, Glia, Extracellular Matrix and Neurovascular Unit: A Systems Biology Approach to the Complexity of Synaptic Plasticity in Health and Disease.

Int J Mol Sci 2020 Feb 24;21(4). Epub 2020 Feb 24.

Laboratory of Morphology of Neuronal Network, Department of Public Medicine, University of Campania "Luigi Vanvitelli", 80138 Napoli, Italy.

The synaptic cleft has been vastly investigated in the last decades, leading to a novel and fascinating model of the functional and structural modifications linked to synaptic transmission and brain processing. The classic neurocentric model encompassing the neuronal pre- and post-synaptic terminals partly explains the fine-tuned plastic modifications under both pathological and physiological circumstances. Recent experimental evidence has incontrovertibly added oligodendrocytes, astrocytes, and microglia as pivotal elements for synapse formation and remodeling (tripartite synapse) in both the developing and adult brain. Moreover, synaptic plasticity and its pathological counterpart (maladaptive plasticity) have shown a deep connection with other molecular elements of the extracellular matrix (ECM), once considered as a mere extracellular structural scaffold altogether with the cellular glue (i.e., glia). The ECM adds another level of complexity to the modern model of the synapse, particularly, for the long-term plasticity and circuit maintenance. This model, called tetrapartite synapse, can be further implemented by including the neurovascular unit (NVU) and the immune system. Although they were considered so far as tightly separated from the central nervous system (CNS) plasticity, at least in physiological conditions, recent evidence endorsed these elements as structural and paramount actors in synaptic plasticity. This scenario is, as far as speculations and evidence have shown, a consistent model for both adaptive and maladaptive plasticity. However, a comprehensive understanding of brain processes and circuitry complexity is still lacking. Here we propose that a better interpretation of the CNS complexity can be granted by a systems biology approach through the construction of predictive molecular models that enable to enlighten the regulatory logic of the complex molecular networks underlying brain function in health and disease, thus opening the way to more effective treatments.
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http://dx.doi.org/10.3390/ijms21041539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073232PMC
February 2020

Regional brain susceptibility to neurodegeneration: what is the role of glial cells?

Neural Regen Res 2020 May;15(5):838-842

Human Anatomy and Laboratory of Morphology of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli, Naples, Italy.

The main pathological feature of the neurodegenerative diseases is represented by neuronal death that represents the final step of a cascade of adverse/hostile events. Early in the neurodegenerative process, glial cells (including astrocytes, microglial cells, and oligodendrocytes) activate and trigger an insidious neuroinflammatory reaction, metabolic decay, blood brain barrier dysfunction and energy impairment, boosting neuronal death. How these mechanisms might induce selective neuronal death in specific brain areas are far from being elucidated. The last two decades of neurobiological studies have provided evidence of the main role of glial cells in most of the processes of the central nervous system, from development to synaptogenesis, neuronal homeostasis and integration into, highly specific neuro-glial networks. In this mini-review, we moved from in vitro and in vivo models of neurodegeneration to analyze the putative role of glial cells in the early mechanisms of neurodegeneration. We report changes of transcriptional, genetic, morphological, and metabolic activity in astrocytes and microglial cells in specific brain areas before neuronal degeneration, providing evidence in experimental models of neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. Understanding these mechanisms might increase the insight of these processes and pave the way for new specific glia-targeted therapeutic strategies for neurodegenerative disorders.
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http://dx.doi.org/10.4103/1673-5374.268897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990768PMC
May 2020

Differential Modulation of NF-B in Neurons and Astrocytes Underlies Neuroprotection and Antigliosis Activity of Natural Antioxidant Molecules.

Oxid Med Cell Longev 2019 14;2019:8056904. Epub 2019 Aug 14.

Laboratory of Neuroscience "R. Levi-Montalcini," Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milano, Italy.

Neuroinflammation, a hallmark of chronic neurodegenerative disorders, is characterized by sustained glial activation and the generation of an inflammatory loop, through the release of cytokines and other neurotoxic mediators that cause oxidative stress and limit functional repair of brain parenchyma. Dietary antioxidants may protect against neurodegenerative diseases by counteracting chronic neuroinflammation and reducing oxidative stress. Here, we describe the effects of a number of natural antioxidants (polyphenols, carotenoids, and thiolic molecules) in rescuing astrocytic function and neuronal viability following glial activation by reducing astrocyte proliferation and restoring astrocytic and neuronal survival and basal levels of reactive oxygen species (ROS). All antioxidant molecules are also effective under conditions of oxidative stress and glutamate toxicity, two maladaptive components of neuroinflammatory processes. Moreover, it is remarkable that their antioxidant and anti-inflammatory activity occurs through differential modulation of NF-B binding activity in neurons and astrocytes. In fact, we show that inflammatory stimuli promote a significant induction of NF-B binding activity in astrocytes and its concomitant reduction in neurons. These changes are prevented in astrocytes and neurons pretreated with the antioxidant molecules, suggesting that NF-B plays a key role in the modulation of survival and anti-inflammatory responses. Finally, we newly demonstrate that effective antigliosis and neuroprotective activity is achieved with a defined cocktail of four natural antioxidants at very low concentrations, suggesting a promising strategy to reduce inflammatory and oxidative damage in neurodegenerative diseases with limited side effects.
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http://dx.doi.org/10.1155/2019/8056904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710787PMC
January 2020

Dependence of Neuroprosthetic Stimulation on the Sensory Modality of the Trigeminal Neurons Following Nerve Injury. Implications in the Design of Future Sensory Neuroprostheses for Correct Perception and Modulation of Neuropathic Pain.

Front Neurosci 2019 1;13:389. Epub 2019 May 1.

Neuro-computing & Neuro-robotics Research Group, Universidad Complutense de Madrid, Madrid, Spain.

Amputation of a sensory peripheral nerve induces severe anatomical and functional changes along the afferent pathway as well as perception alterations and neuropathic pain. In previous studies we showed that electrical stimulation applied to a transected infraorbital nerve protects the somatosensory cortex from the above-mentioned sensory deprivation-related changes. In the present study we focus on the initial tract of the somatosensory pathway and we investigate the way weak electrical stimulation modulates the neuroprotective-neuroregenerative and functional processes of trigeminal ganglia primary sensory neurons by studying the expression of neurotrophins (NTFs) and Glia-Derived Neurotrophic Factors (GDNFs) receptors. Neurostimulation was applied to the proximal stump of a transected left infraorbitary nerve using a neuroprosthetic micro-device 12 h/day for 4 weeks in freely behaving rats. Neurons were studied by hybridization and immunohistochemistry against RET (proto-oncogene tyrosine kinase "rearranged during transfection"), tropomyosin-related kinases (TrkA, TrkB, TrkC) receptors and IB4 (Isolectin B4 from Griffonia simplicifolia). Intra-group (left vs. right ganglia) and inter-group comparisons (between Control, Axotomization and Stimulation-after-axotomization groups) were performed using the mean percentage change of the number of positive cells per section [100(left-right)/right)]. Intra-group differences were studied by paired -tests. For inter-group comparisons ANOVA test followed by LSD test (when < 0.05) were used. Significance level (α) was set to 0.05 in all cases. Results showed that (i) neurostimulation has heterogeneous effects on primary nociceptive and mechanoceptive/proprioceptive neurons; (ii) neurostimulation affects RET-expressing small and large neurons which include thermo-nociceptors and mechanoceptors, as well as on the IB4- and TrkB-positive populations, which mainly correspond to non-peptidergic thermo-nociceptive cells and mechanoceptors respectively. Our results suggest (i) electrical stimulation differentially affects modality-specific primary sensory neurons (ii) artificial input mainly acts on specific nociceptive and mechanoceptive neurons (iii) neuroprosthetic stimulation could be used to modulate peripheral nerve injuries-induced neuropathic pain. These could have important functional implications in both, the design of effective clinical neurostimulation-based protocols and the development of neuroprosthetic devices, controlling primary sensory neurons through selective neurostimulation.
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http://dx.doi.org/10.3389/fnins.2019.00389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504809PMC
May 2019

Specific Expression of a New Bruton Tyrosine Kinase Isoform (p65BTK) in the Glioblastoma Gemistocytic Histotype.

Front Mol Neurosci 2019 24;12. Epub 2019 Jan 24.

School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

Bruton's tyrosine-kinase (BTK) is a non-receptor tyrosine kinase recently associated with glioma tumorigenesis and a novel prognostic marker for poor survival in patients with glioma. The p65BTK is a novel BTK isoform involved in different pathways of drug resistance of solid tumors, thus we aimed to investigate the expression and the putative role of p65BTK in tumors of the central nervous system (CNS). We selected a large cohort of patients with glial tumors ( = 71) and analyzed the expression of p65BTK in different histotypes and correlation with clinical parameters. Sections were stained with glial fibrillary acidic protein (GFAP), p53, epidermal growth factor receptor (EGFR), S100, vimentin, and epithelial membrane antigen (EMA) antibodies. Glioma stem cell (GSC) lines, isolated from glioblastoma multiforme (GBM), were treated with different concentrations of ibrutinib, a specific inhibitor of BTK, in order to evaluate their metabolic activity, mitotic index and mortality. Moreover, an orthotopic xenotransplant of GSC from human GBM was used to evaluate the expression of p65BTK in the brain of immunodeficient mice. p65BTK was expressed in GSC and in gemistocytes in human gliomas at different histological grade. We found a significant correlation between BTK expression and low-grade (LG) tumors ( ≤ 0.05) and overall survival (OS) of patients with grade III gliomas ( ≤ 0.05), suggestive of worst prognosis. Interestingly, the expression of p65BTK remained restricted exclusively to gemistocytic cells in the xenograft mouse model. Ibrutinib administration significantly reduced metabolic activity and mitotic index and increased mortality in GSC, highlighting the specific role of p65BTK in cell proliferation and survival. In conclusion, our data demonstrated that p65BTK is expressed in glioma tumors, restricted to gemistocytic cells, has a key role in GSC and has a bad prognostic value, thus highlighting the importance of future research for targeted therapy of human gliomas.
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http://dx.doi.org/10.3389/fnmol.2019.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353843PMC
January 2019

Selective Vulnerability of Basal Ganglia: Insights into the Mechanisms of Bilateral Striatal Necrosis.

J Neuropathol Exp Neurol 2019 02;78(2):123-129

Division of Human Anatomy - Neuronal Networks Morphology Lab, Department of Mental, Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli".

Selective neuronal death in neurodegenerative disorders represents the final step of a cascade of events, including neuroinflammation, regional-specific reactive gliosis, changes of brain-blood barrier structure and functions, metabolic failure and mitochondrial energy impairment. Bilateral striatal necrosis is usually reported in inherited mitochondrial disorders, suggesting a pathogenetic role of the energy impairment by mitochondrial dysfunction. We investigated mechanisms of the selective striatal degeneration, comparing clinical findings of a patient with an acquired bilateral striatal necrosis and experimental data of a selective basal ganglia degenerative model in rats. In a 70-year-old patient affected by severe parkinsonian syndrome triggered by persistent metabolic acidosis, brain MRI revealed bilateral cystic-lacunar necrosis of basal ganglia. Immunohistochemistry of rat brain sections after single intraperitoneal administration (60 mg/kg) of the mitochondrial toxin 3-nitropropionic acid (3-NP) revealed (i) selective bilateral striatal necrotic/cavitary lesions, (ii) degeneration of striatal medium spiny neurons, (iii) evidence of synaptic and transcriptional dysfunction, and (iv) reactive gliosis (activated microglia and astrocytes) in the striatum. Our data provide an intriguing hypothesis for the selective neuronal degeneration in the striatum, claiming that selective mitochondrial energy impairment associated to loco-regional neuroinflammation and reactive gliosis might contribute to synaptic dysfunction and excitotoxicity that ultimately lead to neuronal degeneration.
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http://dx.doi.org/10.1093/jnen/nly123DOI Listing
February 2019

Differentiation by nerve growth factor (NGF) involves mechanisms of crosstalk between energy homeostasis and mitochondrial remodeling.

Cell Death Dis 2018 03 9;9(3):391. Epub 2018 Mar 9.

Laboratory of Neuroscience "R. Levi-Montalcini", Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126, Milano, Italy.

Neuronal differentiation involves extensive modification of biochemical and morphological properties to meet novel functional requirements. Reorganization of the mitochondrial network to match the higher energy demand plays a pivotal role in this process. Mechanisms of neuronal differentiation in response to nerve growth factor (NGF) have been largely characterized in terms of signaling, however, little is known about its impact on mitochondrial remodeling and metabolic function. In this work, we show that NGF-induced differentiation requires the activation of autophagy mediated by Atg9b and Ambra1, as it is disrupted by their genetic knockdown and by autophagy blockers. NGF differentiation involves the induction of P-AMPK and P-CaMK, and is prevented by their pharmacological inhibition. These molecular events correlate with modifications of energy and redox homeostasis, as determined by ATP and NADPH changes, higher oxygen consumption (OCR) and ROS production. Our data indicate that autophagy aims to clear out exhausted mitochondria, as determined by enhanced localization of p62 and Lysotracker-red to mitochondria. In addition, we newly demonstrate that NGF differentiation is accompanied by increased mitochondrial remodeling involving higher levels of fission (P-Drp1) and fusion proteins (Opa1 and Mfn2), as well as induction of Sirt3 and the transcription factors mtTFA and PPARγ, which regulate mitochondria biogenesis and metabolism to sustain increased mitochondrial mass, potential, and bioenergetics. Overall, our data indicate a new NGF-dependent mechanism involving mitophagy and extensive mitochondrial remodeling, which plays a key role in both neurogenesis and nerve regeneration.
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http://dx.doi.org/10.1038/s41419-018-0429-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844953PMC
March 2018

Neuro-Coagulopathy: Blood Coagulation Factors in Central Nervous System Diseases.

Int J Mol Sci 2017 Oct 12;18(10). Epub 2017 Oct 12.

Laboratory of Neuronal Networks, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.

Blood coagulation factors and other proteins, with modulatory effects or modulated by the coagulation cascade have been reported to affect the pathophysiology of the central nervous system (CNS). The protease-activated receptors (PARs) pathway can be considered the central hub of this regulatory network, mainly through thrombin or activated protein C (aPC). These proteins, in fact, showed peculiar properties, being able to interfere with synaptic homeostasis other than coagulation itself. These specific functions modulate neuronal networks, acting both on resident (neurons, astrocytes, and microglia) as well as circulating immune system cells and the extracellular matrix. The pleiotropy of these effects is produced through different receptors, expressed in various cell types, in a dose- and time-dependent pattern. We reviewed how these pathways may be involved in neurodegenerative diseases (amyotrophic lateral sclerosis, Alzheimer's and Parkinson's diseases), multiple sclerosis, ischemic stroke and post-ischemic epilepsy, CNS cancer, addiction, and mental health. These data open up a new path for the potential therapeutic use of the agonist/antagonist of these proteins in the management of several central nervous system diseases.
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http://dx.doi.org/10.3390/ijms18102128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666810PMC
October 2017
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