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Molecular Physiological and Pathological Progression of Neurological 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 Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 25 July 2024 | Viewed by 7053

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Special Issue Editor

Dr. Daniele Bottai

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Guest Editor

Department of Pharmaceutical Sciences, Section of Pharmacology and Biosciences, University or Milan Assistant, Via Balzaretti 9, 20133 Milan, Italy
Interests: neural stem cells; glycosphingolipids; neurological diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The phrase "neurological diseases" is broad and encompasses a wide range of disorders that vary in terms of time of onset, affected gender, affected brain region, the type of affected neurons, spontaneous or genetic onset, and outcome in terms of curability.

Among common neurological diseases, we include cerebrovascular, neurodegenerative, psychiatric, autoimmune-related, and traumatic diseases.

These diseases affect many molecular pathways, undergo cellular changes that may disrupt several brain circuits, and exhibit distinctive pathophysiological characteristics. These features can now be explored not only in animal models, but also in cellular models such as human induced pluripotent stem cells; indeed, organoids and pluripotent stem cells can be utilized to evaluate several cellular and molecular characteristics that cannot be examined in patients.

It is essential to obtain a complete comprehension of the molecular, cellular, and physiological aspects of neurological illnesses in order to create new therapeutic treatments that might prevent or treat them. These therapies may be primarily focused on the numerous pathways leading to neuronal and glial restoration.

Dr. Daniele Bottai
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

neurological diseases
molecular pathways
spinal cord lesion
cognitive disabilities
epilepsy
stroke
motorneuron diseases
glioblastoma
autism
stem cells
organoids

Published Papers (6 papers)

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Research

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14 pages, 1430 KiB

Open AccessArticle

Patients with Chronic Spinal Cord Injury Display a Progressive Alteration over the Years of the Activation Stages of the T Lymphocyte Compartment

by Sergio Haro, Ana M. Gomez-Lahoz, Jorge Monserrat, Mar Atienza-Pérez, Oscar Fraile-Martinez, Miguel A. Ortega, Cielo García-Montero, David Díaz, Elisa Lopez-Dolado and Melchor Álvarez-Mon

Int. J. Mol. Sci. 2023, 24(24), 17596; https://doi.org/10.3390/ijms242417596 - 18 Dec 2023

Viewed by 725

Abstract

Spinal cord injury (SCI) is a serious medical condition associated with severe morbidities and disability. Chronic SCI patients present an enhanced susceptibility to infections and comorbidities with inflammatory pathogenesis. Chronic SCI appears to be associated with a systemic dysfunction of the immune system. We investigated the alteration of the pivotal CD4+ and CD8+ T lymphocytes in patients with chronic SCI at different years of evolution. A clinically homogenous population of 105 patients with chronic SCI (31 with time of evolution less than 5 years (SCI SP); 32 early chronic (SCI ECP) with time of evolution between 5 and 15 years; and 42 late chronic (SCI LCP) with time of evolution more than 15 years) and 38 healthy controls were enrolled. SCI ECP and SCI LCP patients showed significant CD4+ and CD8+ T lymphopenia, ascribed to a reduction in naïve and CM subsets. Furthermore, SCI ECP and SCI LCP patients showed a significant reduction in the expression of CD28 on CD8+ T lymphocytes. The expression of CCR6 by CD4+ T lymphocytes was decreased during the evolution of chronic SCI, but on CD8+ T lymphocytes, it was observed during the first 15 years of evolution. In conclusion, the chronic SCI course with severe damage to T lymphocytes mainly worsens over the years of disease evolution. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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17 pages, 2134 KiB

Open AccessArticle

Histamine H4 Receptor Antagonist Ameliorates the Progression of Experimental Autoimmune Encephalomyelitis via Regulation of T-Cell Imbalance

by Abdullah A. Aldossari, Mohammed A. Assiri, Mushtaq A. Ansari, Ahmed Nadeem, Sabry M. Attia, Saleh A. Bakheet, Thamer H. Albekairi, Hatun A. Alomar, Haneen A. Al-Mazroua, Taghreed N. Almanaa, Mohammed A. Al-Hamamah, Mohammad Y. Alwetaid and Sheikh F. Ahmad

Int. J. Mol. Sci. 2023, 24(20), 15273; https://doi.org/10.3390/ijms242015273 - 17 Oct 2023

Cited by 1 | Viewed by 1039

Abstract

Multiple sclerosis (MS) is a degenerative condition characterized by immune-mediated attacks on the central nervous system (CNS), resulting in demyelination and recurring T-cell responses. The histamine H4 receptor (H4R) is mainly expressed in cellular populations and plays a vital role in inflammation and immunological responses. The role of H4R in neurons of the CNS has recently been revealed. However, the precise role of H4R in neuronal function remains inadequately understood. The objective of this work was to investigate the impact of JNJ 10191584 (JNJ), a highly effective and specific H4R antagonist, on the development of experimental autoimmune encephalomyelitis (EAE) and to gain insight into the underlying mechanism involved. In this study, we examined the potential impact of JNJ therapy on the course of EAE in SJL/J mice. EAE mice were administered an oral dose of JNJ at a concentration of 6 mg/kg once a day, starting from day 10 and continuing until day 42. Afterward, the mice’s clinical scores were assessed. In this study, we conducted additional research to examine the impact of JNJ on several types of immune cells, specifically Th1 (IFN-γ and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A and RORγt), and regulatory T (Tregs; Foxp3 and TGF-β1) cells in the spleen. In this study, we further investigated the impact of JNJ on the mRNA expression levels of IFN-γ, T-bet, IL-9, IRF4, IL-17A, RORγt, Foxp3, and TGF-β1 in the brain. Daily treatment of JNJ effectively reduced the development of EAE in mice. The percentages of CD4⁺IFN-γ⁺, CD4⁺T-bet⁺, CD4⁺IL-9⁺, CD4⁺IRF4⁺, CD4⁺IL-17A⁺, and CD4⁺RORγt⁺ cells were shown to decrease, whereas the percentages of CD4⁺TGF-β1⁺ and CD4⁺Foxp3⁺ cells were observed to increase in EAE mice treated with JNJ. Therefore, the HR4 antagonist positively affected the course of EAE by modulating the signaling of transcription factors. The identified results include possible ramifications in the context of MS treatment. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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17 pages, 3439 KiB

Open AccessArticle

Diaphragm Fatigue in SMNΔ7 Mice and Its Molecular Determinants: An Underestimated Issue

by Francesca Cadile, Deborah Recchia, Massimiliano Ansaldo, Paola Rossi, Giorgia Rastelli, Simona Boncompagni, Lorenza Brocca, Maria Antonietta Pellegrino and Monica Canepari

Int. J. Mol. Sci. 2023, 24(19), 14953; https://doi.org/10.3390/ijms241914953 - 06 Oct 2023

Cited by 1 | Viewed by 1236

Abstract

Spinal muscular atrophy (SMA) is a genetic disorder characterized by the loss of spinal motor neurons leading to muscle weakness and respiratory failure. Mitochondrial dysfunctions are found in the skeletal muscle of patients with SMA. For obvious ethical reasons, the diaphragm muscle is poorly studied, notwithstanding the very important role that respiratory involvement plays in SMA mortality. The main goal of this study was to investigate diaphragm functionality and the underlying molecular adaptations in SMNΔ7 mice, a mouse model that exhibits symptoms similar to that of patients with intermediate type II SMA. Functional, biochemical, and molecular analyses on isolated diaphragm were performed. The obtained results suggest the presence of an intrinsic energetic imbalance associated with mitochondrial dysfunction and a significant accumulation of reactive oxygen species (ROS). In turn, ROS accumulation can affect muscle fatigue, cause diaphragm wasting, and, in the long run, respiratory failure in SMNΔ7 mice. Exposure to the antioxidant molecule ergothioneine leads to the functional recovery of the diaphragm, confirming the presence of mitochondrial impairment and redox imbalance. These findings suggest the possibility of carrying out a dietary supplementation in SMNΔ7 mice to preserve their diaphragm function and increase their lifespan. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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20 pages, 3888 KiB

Open AccessArticle

Novel Conformation-Dependent Tau Antibodies Are Modulated by Adjacent Phosphorylation Sites

by Giavanna Paterno, Jose Torrellas, Brach M. Bell, Kimberly-Marie M. Gorion, Stephan S. Quintin, Gabriela P. Hery, Stefan Prokop and Benoit I. Giasson

Int. J. Mol. Sci. 2023, 24(18), 13676; https://doi.org/10.3390/ijms241813676 - 05 Sep 2023

Viewed by 1103

Abstract

Tau proteins within the adult central nervous system (CNS) are found to be abnormally aggregated into heterogeneous filaments in neurodegenerative diseases, termed tauopathies. These tau inclusions are pathological hallmarks of Alzheimer’s disease (AD), Pick’s disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). The neuropathological hallmarks of these diseases burden several cell types within the CNS, and have also been shown to be abundantly phosphorylated. The mechanism(s) by which tau aggregates in the CNS is not fully known, but it is hypothesized that hyperphosphorylated tau may precede and further promote filament formation, leading to the production of these pathological inclusions. In the studies herein, we generated and thoroughly characterized two novel conformation-dependent tau monoclonal antibodies that bind to residues Pro218-Glu222, but are sensitive to denaturing conditions and highly modulated by adjacent downstream phosphorylation sites. These epitopes are present in the neuropathological hallmarks of several tauopathies, including AD, PiD, CBD, and PSP. These novel antibodies will further enable investigation of tau-dependent pathological inclusion formation and enhance our understanding of the phosphorylation signatures within tauopathies with the possibility of new biomarker developments. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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16 pages, 1499 KiB

Open AccessArticle

Histamine H4 Receptor Agonist, 4-Methylhistamine, Aggravates Disease Progression and Promotes Pro-Inflammatory Signaling in B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model

by Abdulaziz M. S. Alsaad, Mushtaq A. Ansari, Ahmed Nadeem, Sabry M. Attia, Saleh A. Bakheet, Hatun A. Alomar and Sheikh F. Ahmad

Int. J. Mol. Sci. 2023, 24(16), 12991; https://doi.org/10.3390/ijms241612991 - 20 Aug 2023

Viewed by 1075

Abstract

We sought to assess the impact of 4-Methylhistamine (4-MeH), a specific agonist targeting the Histamine H4 Receptor (H4R), on the progression of experimental autoimmune encephalomyelitis (EAE) and gain insight into the underlying mechanism. EAE is a chronic autoimmune, inflammatory, and neurodegenerative disease of the central nervous system (CNS) characterized by demyelination, axonal damage, and neurodegeneration. Over the past decade, pharmacological research into the H4R has gained significance in immune and inflammatory disorders. For this study, Swiss Jim Lambert EAE mice were treated with 4-MeH (30 mg/kg/day) via intraperitoneal administration from days 14 to 42, and the control group was treated with a vehicle. Subsequently, we evaluated the clinical scores. In addition, flow cytometry was employed to estimate the impact of 4-Methylhistamine (4-MeH) on NF-κB p65, GM-CSF, MCP-1, IL-6, and TNF-α within CD19⁺ and CXCR5⁺ spleen B cells. Additionally, we investigated the effect of 4-MeH on the mRNA expression levels of Nf-κB p65, Gmcsf, Mcp1, Il6, and Tnfα in the brain of mice using RT-PCR. Notably, the clinical scores of EAE mice treated with 4-MeH showed a significant increase compared with those treated with the vehicle. The percentage of cells expressing CD19⁺NF-κB p65⁺, CXCR5⁺NF-κB p65⁺, CD19⁺GM-CSF⁺, CXCR5⁺GM-CSF⁺, CD19⁺MCP-1⁺, CXCR5⁺MCP-1⁺, CD19⁺IL-6⁺, CXCR5⁺IL-6⁺, CD19⁺TNF-α⁺, and CXCR5⁺TNF-α⁺ exhibited was more pronounced in 4-MeH-treated EAE mice when compared to vehicle-treated EAE mice. Moreover, the administration of 4-MeH led to increased expression of NfκB p65, Gmcsf, Mcp1, Il6, and Tnfα mRNA in the brains of EAE mice. This means that the H4R agonist promotes pro-inflammatory mediators aggravating EAE symptoms. Our results indicate the harmful role of H4R agonists in the pathogenesis of MS in an EAE mouse model. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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Review

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27 pages, 3624 KiB

Open AccessReview

MicroRNAs as Potential Biomarkers of Post-Traumatic Epileptogenesis: A Systematic Review

by Anastasia A. Vasilieva, Elena E. Timechko, Kristina D. Lysova, Anastasia I. Paramonova, Alexey M. Yakimov, Elena A. Kantimirova and Diana V. Dmitrenko

Int. J. Mol. Sci. 2023, 24(20), 15366; https://doi.org/10.3390/ijms242015366 - 19 Oct 2023

Cited by 2 | Viewed by 1305

Abstract

Structural or post-traumatic epilepsy often develops after brain tissue damage caused by traumatic brain injury, stroke, infectious diseases of the brain, etc. Most often, between the initiating event and epilepsy, there is a period without seizures—a latent period. At this time, the process of restructuring of neural networks begins, leading to the formation of epileptiform activity, called epileptogenesis. The prediction of the development of the epileptogenic process is currently an urgent and difficult task. MicroRNAs are inexpensive and minimally invasive biomarkers of biological and pathological processes. The aim of this study is to evaluate the predictive ability of microRNAs to detect the risk of epileptogenesis. In this study, we conducted a systematic search on the MDPI, PubMed, ScienceDirect, and Web of Science platforms. We analyzed publications that studied the aberrant expression of circulating microRNAs in epilepsy, traumatic brain injury, and ischemic stroke in order to search for microRNAs—potential biomarkers for predicting epileptogenesis. Thus, 31 manuscripts examining biomarkers of epilepsy, 19 manuscripts examining biomarkers of traumatic brain injury, and 48 manuscripts examining biomarkers of ischemic stroke based on circulating miRNAs were analyzed. Three miRNAs were studied: miR-21, miR-181a, and miR-155. The findings showed that miR-21 and miR-155 are associated with cell proliferation and apoptosis, and miR-181a is associated with protein modifications. These miRNAs are not strictly specific, but they are involved in processes that may be indirectly associated with epileptogenesis. Also, these microRNAs may be of interest when they are studied in a cohort with each other and with other microRNAs. To further study the microRNA-based biomarkers of epileptogenesis, many factors must be taken into account: the time of sampling, the type of biological fluid, and other nuances. Currently, there is a need for more in-depth and prolonged studies of epileptogenesis. Full article

(This article belongs to the Special Issue Molecular Physiological and Pathological Progression of Neurological Diseases)

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