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Molecular Mechanisms and Therapies in Neurological Diseases 2022
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Molecular Mechanisms and Therapies in Neurological Diseases 2022

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 June 2023) | Viewed by 12952

Special Issue Editor

Dr. Ashu Johri

E-Mail Website
Guest Editor
Independent Researcher, New York, NY 10021, USA
Interests: neurological diseases; pathophysiology; therapeutics; animal models; molecular mechanisms; drug development; mitochondria; biomarker; posttranslational modification; transcription factor; gut-brain axis; Huntington’s disease; Parkinson’s disease; Alzheimer’s disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As you are aware, neurological diseases exert a major societal and financial burden worldwide and remain a major cause of disability. With population expansion and greater life expectancies, the overall burden of neurological diseases is increasing. Promising strides have been made in solving the jigsaw puzzle of the molecular mechanisms on many of them providing insights into the etiopathology of the diseases, how the disease progresses, etc. This knowledge furthers our overarching goal of how to best tackle the disease pathogenesis producing symptom alleviation or in best case scenario, the magic word, a cure. This special issue focuses on new and fast developing knowledge base about the disease mechanisms and therapeutic approaches for neurological diseases.

This issue intends to highlight the advances made in our understanding of the disease processes as well as provide a cumulative summary of the new and existing therapies for neurological diseases. With this issue we hope to provide a comprehensive roadmap of the landscape in neurological diseases for the broad readership of the journal.

Dr. Ashu Johri
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
  • neurodegeneration
  • pathophysiology
  • therapeutics
  • animal models
  • molecular mechanisms
  • drug development
  • mitochondria
  • biomarker
  • posttranslational modification
  • transcription factors

Published Papers (7 papers)

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Research

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24 pages, 6211 KiB  
Article
Thrombin-Induced Microglia Activation Modulated through Aryl Hydrocarbon Receptors
by Meei-Ling Sheu, Liang-Yi Pan, Cheng-Ning Yang, Jason Sheehan, Liang-Yu Pan, Weir-Chiang You, Chien-Chia Wang and Hung-Chuan Pan
Int. J. Mol. Sci. 2023, 24(14), 11416; https://doi.org/10.3390/ijms241411416 - 13 Jul 2023
Cited by 2 | Viewed by 1100
Abstract
Thrombin is a multifunctional serine protein which is closely related to neurodegenerative disorders. The Aryl hydrocarbon receptor (AhR) is well expressed in microglia cells involving inflammatory disorders of the brain. However, it remains unclear as to how modulation of AhR expression by thrombin [...] Read more.
Thrombin is a multifunctional serine protein which is closely related to neurodegenerative disorders. The Aryl hydrocarbon receptor (AhR) is well expressed in microglia cells involving inflammatory disorders of the brain. However, it remains unclear as to how modulation of AhR expression by thrombin is related to the development of neurodegeneration disorders. In this study, we investigated the role of AhR in the development of thrombin-induced neurodegenerative processes, especially those concerning microglia. The primary culture of either wild type or AhR deleted microglia, as well as BV-2 cell lines, was used for an in vitro study. Hippocampal slice culture and animals with either wild type or with AhR deleted were used for the ex vivo and in vivo studies. Simulations of ligand protein docking showed a strong integration between the thrombin and AhR. In thrombin-triggered microglia cells, deleting AhR escalated both the NO release and iNOS expression. Such effects were abolished by the administration of the AhR agonist. In thrombin-activated microglia cells, downregulating AhR increased the following: vascular permeability, pro-inflammatory genetic expression, MMP-9 activity, and the ratio of M1/M2 phenotype. In the in vivo study, thrombin induced the activation of microglia and their volume, thereby contributing to the deterioration of neurobehavior. Deleting AhR furthermore aggravated the response in terms of impaired neurobehavior, increasing brain edema, aggregating microglia, and increasing neuronal death. In conclusion, thrombin caused the activation of microglia through increased vessel permeability, expression of inflammatory response, and phenotype of M1 microglia, as well the MMP activity. Deleting AhR augmented the above detrimental effects. These findings indicate that the modulation of AhR is essential for the regulation of thrombin-induced brain damages and that the AhR agonist may harbor the potentially therapeutic effect in thrombin-induced neurodegenerative disorder. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies in Neurological Diseases 2022)
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33 pages, 14779 KiB  
Article
Distribution of Cleaved SNAP-25 in the Rat Brain, following Unilateral Injection of Botulinum Neurotoxin-A into the Striatum
by Friederike Schümann, Oliver Schmitt, Andreas Wree and Alexander Hawlitschka
Int. J. Mol. Sci. 2023, 24(2), 1685; https://doi.org/10.3390/ijms24021685 - 14 Jan 2023
Viewed by 1548
Abstract
In Parkinson’s disease, hypercholinism in the striatum occurs, with the consequence of disturbed motor functions. Direct application of Botulinum neurotoxin-A in the striatum of hemi-Parkinsonian rats might be a promising anticholinergic therapeutic option. Here, we aimed to determine the spread of intrastriatally injected [...] Read more.
In Parkinson’s disease, hypercholinism in the striatum occurs, with the consequence of disturbed motor functions. Direct application of Botulinum neurotoxin-A in the striatum of hemi-Parkinsonian rats might be a promising anticholinergic therapeutic option. Here, we aimed to determine the spread of intrastriatally injected BoNT-A in the brain as well as the duration of its action based on the distribution of cleaved SNAP-25. Rats were injected with 1 ng of BoNT-A into the right striatum and the brains were examined at different times up to one year after treatment. In brain sections immunohistochemically stained for BoNT-A, cleaved SNAP-25 area-specific densitometric analyses were performed. Increased immunoreactivity for cleaved SNAP-25 was found in brain regions other than the unilaterally injected striatum. Most cleaved SNAP-25-ir was found in widespread areas ipsilateral to the BoNT-A injection, in some regions, however, immunoreactivity was also measured in the contralateral hemisphere. There was a linear relationship between the distance of a special area from the injected striatum and the time until its maximum averaged immunoreactivity was reached. Moreover, we observed a positive relationship for the area-specific distance from the injected striatum and its maximum immunoreactivity as well as for the connection density with the striatum and its maximum immunoreactivity. The results speak for a bidirectional axonal transport of BoNT-A after its application into the striatum to its widespread connected parts of the brain. Even one year after BoNT-A injection, cleaved SNAP-25 could still be detected. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies in Neurological Diseases 2022)
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Review

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17 pages, 2641 KiB  
Review
The Genetics of Primary Familial Brain Calcification: A Literature Review
by Shih-Ying Chen, Chen-Jui Ho, Yan-Ting Lu, Chih-Hsiang Lin, Min-Yu Lan and Meng-Han Tsai
Int. J. Mol. Sci. 2023, 24(13), 10886; https://doi.org/10.3390/ijms241310886 - 29 Jun 2023
Cited by 5 | Viewed by 1810
Abstract
Primary familial brain calcification (PFBC), also known as Fahr’s disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among [...] Read more.
Primary familial brain calcification (PFBC), also known as Fahr’s disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among the diverse clinical phenotypes, the most common manifestations are movement disorders, cognitive deficits, and psychiatric disturbances. Although patients with PFBC always exhibit brain calcification, nearly one-third of cases remain clinically asymptomatic. Due to advances in the genetics of PFBC, the diagnostic criteria of PFBC may need to be modified. Hitherto, seven genes have been associated with PFBC, including four dominant inherited genes (SLC20A2, PDGFRB, PDGFB, and XPR1) and three recessive inherited genes (MYORG, JAM2, and CMPK2). Nevertheless, around 50% of patients with PFBC do not have pathogenic variants in these genes, and further PFBC-associated genes are waiting to be identified. The function of currently known genes suggests that PFBC could be caused by the dysfunction of the neurovascular unit, the dysregulation of phosphate homeostasis, or mitochondrial dysfunction. An improved understanding of the underlying pathogenic mechanisms for PFBC may facilitate the development of novel therapies. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies in Neurological Diseases 2022)
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60 pages, 1276 KiB  
Review
Systematic Review of Molecular Targeted Therapies for Adult-Type Diffuse Glioma: An Analysis of Clinical and Laboratory Studies
by Logan Muzyka, Nicolas K. Goff, Nikita Choudhary and Michael T. Koltz
Int. J. Mol. Sci. 2023, 24(13), 10456; https://doi.org/10.3390/ijms241310456 - 21 Jun 2023
Cited by 2 | Viewed by 1964
Abstract
Gliomas are the most common brain tumor in adults, and molecularly targeted therapies to treat gliomas are becoming a frequent topic of investigation. The current state of molecular targeted therapy research for adult-type diffuse gliomas has yet to be characterized, particularly following the [...] Read more.
Gliomas are the most common brain tumor in adults, and molecularly targeted therapies to treat gliomas are becoming a frequent topic of investigation. The current state of molecular targeted therapy research for adult-type diffuse gliomas has yet to be characterized, particularly following the 2021 WHO guideline changes for classifying gliomas using molecular subtypes. This systematic review sought to characterize the current state of molecular target therapy research for adult-type diffuse glioma to better inform scientific progress and guide next steps in this field of study. A systematic review was conducted in accordance with PRISMA guidelines. Studies meeting inclusion criteria were queried for study design, subject (patients, human cell lines, mice, etc.), type of tumor studied, molecular target, respective molecular pathway, and details pertaining to the molecular targeted therapy—namely the modality, dose, and duration of treatment. A total of 350 studies met the inclusion criteria. A total of 52 of these were clinical studies, 190 were laboratory studies investigating existing molecular therapies, and 108 were laboratory studies investigating new molecular targets. Further, a total of 119 ongoing clinical trials are also underway, per a detailed query on clinicaltrials.gov. GBM was the predominant tumor studied in both ongoing and published clinical studies as well as in laboratory analyses. A few studies mentioned IDH-mutant astrocytomas or oligodendrogliomas. The most common molecular targets in published clinical studies and clinical trials were protein kinase pathways, followed by microenvironmental targets, immunotherapy, and cell cycle/apoptosis pathways. The most common molecular targets in laboratory studies were also protein kinase pathways; however, cell cycle/apoptosis pathways were the next most frequent target, followed by microenvironmental targets, then immunotherapy pathways, with the wnt/β-catenin pathway arising in the cohort of novel targets. In this systematic review, we examined the current evidence on molecular targeted therapy for adult-type diffuse glioma and discussed its implications for clinical practice and future research. Ultimately, published research falls broadly into three categories—clinical studies, laboratory testing of existing therapies, and laboratory identification of novel targets—and heavily centers on GBM rather than IDH-mutant astrocytoma or oligodendroglioma. Ongoing clinical trials are numerous in this area of research as well and follow a similar pattern in tumor type and targeted pathways as published clinical studies. The most common molecular targets in all study types were protein kinase pathways. Microenvironmental targets were more numerous in clinical studies, whereas cell cycle/apoptosis were more numerous in laboratory studies. Immunotherapy pathways are on the rise in all study types, and the wnt/β-catenin pathway is increasingly identified as a novel target. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies in Neurological Diseases 2022)
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19 pages, 2021 KiB  
Review
Paraoxonases at the Heart of Neurological Disorders
by Fatimah K. Khalaf, Jacob Connolly, Bella Khatib-Shahidi, Abdulsahib Albehadili, Iman Tassavvor, Meghana Ranabothu, Noha Eid, Prabhatchandra Dube, Samer J. Khouri, Deepak Malhotra, Steven T. Haller and David J. Kennedy
Int. J. Mol. Sci. 2023, 24(8), 6881; https://doi.org/10.3390/ijms24086881 - 07 Apr 2023
Cited by 3 | Viewed by 1467
Abstract
Paraoxonase enzymes serve as an important physiological redox system that participates in the protection against cellular injury caused by oxidative stress. The PON enzymes family consists of three members (PON-1, PON-2, and PON-3) that share a similar structure and location as a cluster [...] Read more.
Paraoxonase enzymes serve as an important physiological redox system that participates in the protection against cellular injury caused by oxidative stress. The PON enzymes family consists of three members (PON-1, PON-2, and PON-3) that share a similar structure and location as a cluster on human chromosome 7. These enzymes exhibit anti-inflammatory and antioxidant properties with well-described roles in preventing cardiovascular disease. Perturbations in PON enzyme levels and their activity have also been linked with the development and progression of many neurological disorders and neurodegenerative diseases. The current review summarizes the available evidence on the role of PONs in these diseases and their ability to modify risk factors for neurological disorders. We present the current findings on the role of PONs in Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative and neurological diseases. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies in Neurological Diseases 2022)
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28 pages, 1133 KiB  
Review
Roles of Fatty Acids in Microglial Polarization: Evidence from In Vitro and In Vivo Studies on Neurodegenerative Diseases
by Sanjay, Miey Park and Hae-Jeung Lee
Int. J. Mol. Sci. 2022, 23(13), 7300; https://doi.org/10.3390/ijms23137300 - 30 Jun 2022
Cited by 10 | Viewed by 3357
Abstract
Microglial polarization to the M1 phenotype (classically activated) or the M2 phenotype (alternatively activated) is critical in determining the fate of immune responses in neurodegenerative diseases (NDs). M1 macrophages contribute to neurotoxicity, neuronal and synaptic damage, and oxidative stress and are the first [...] Read more.
Microglial polarization to the M1 phenotype (classically activated) or the M2 phenotype (alternatively activated) is critical in determining the fate of immune responses in neurodegenerative diseases (NDs). M1 macrophages contribute to neurotoxicity, neuronal and synaptic damage, and oxidative stress and are the first line of defense, and M2 macrophages elicit an anti-inflammatory response to regulate neuroinflammation, clear cell debris, and promote neuroregeneration. Various studies have focused on the ability of natural compounds to promote microglial polarization from the M1 phenotype to the M2 phenotype in several diseases, including NDs. However, studies on the roles of fatty acids in microglial polarization and their implications in NDs are a rare find. Most of the studies support the role of polyunsaturated fatty acids (PUFAs) in microglial polarization using cell and animal models. Thus, we aimed to collect data and provide a narrative account of microglial types, markers, and studies pertaining to fatty acids, particularly PUFAs, on microglial polarization and their neuroprotective effects. The involvement of only PUFAs in the chosen topic necessitates more in-depth research into the role of unexplored fatty acids in microglial polarization and their mechanistic implications. The review also highlights limitations and future challenges. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies in Neurological Diseases 2022)
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Other

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11 pages, 2799 KiB  
Case Report
A Variant in TBCD Associated with Motoneuronopathy and Corpus Callosum Hypoplasia: A Case Report
by Maria Caputo, Ilaria Martinelli, Nicola Fini, Giulia Gianferrari, Cecilia Simonini, Rosanna Trovato, Filippo Maria Santorelli, Alessandra Tessa, Jessica Mandrioli and Elisabetta Zucchi
Int. J. Mol. Sci. 2023, 24(15), 12386; https://doi.org/10.3390/ijms241512386 - 03 Aug 2023
Viewed by 832
Abstract
Mutations in the tubulin-specific chaperon D (TBCD) gene, involved in the assembly and disassembly of the α/β-tubulin heterodimers, have been reported in early-onset progressive neurodevelopment regression, with epilepsy and mental retardation. We describe a rare homozygous variant in TBCD, namely [...] Read more.
Mutations in the tubulin-specific chaperon D (TBCD) gene, involved in the assembly and disassembly of the α/β-tubulin heterodimers, have been reported in early-onset progressive neurodevelopment regression, with epilepsy and mental retardation. We describe a rare homozygous variant in TBCD, namely c.881G>A/p.Arg294Gln, in a young woman with a phenotype dominated by distal motorneuronopathy and mild mental retardation, with neuroimaging evidence of corpus callosum hypoplasia. The peculiar phenotype is discussed in light of the molecular interpretation, enriching the literature data on tubulinopathies generated from TBCD mutations. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies in Neurological Diseases 2022)
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