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Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition
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Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition

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: 30 August 2024 | Viewed by 4258

Special Issue Editors

Dr. Zhidong Zhou

E-Mail Website
Guest Editor
Translational Therapeutics Laboratory, Duke-NUS Graduate Medical School, NBD, Level 6, 8 College Road, Singapore 169857, Singapore
Interests: neurodegenerative disease; neuroprotection; pathogenesis therapeutic targets
Special Issues, Collections and Topics in MDPI journals
Dr. Alexandre Hiroaki Kihara

E-Mail Website
Guest Editor
Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, São Bernardo do Campo, Brazil
Interests: stem cells; sci; genome; CRISPR associated endonuclease Cas9; gene editing; electrocorticography; high frequency oscillation; seizures
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases are a group of heterogeneous disorders characterized with progressive neuron vulnerability and even neuron demise in the brain or peripheral nervous system, which are listed within the leading causes for human death. Among various neurodegenerative conditions, Alzheimer's disease and Parkinson's disease (PD) are the most common neurodegenerative disorders. With the aging of our population, the prevalence of neurodegenerative diseases increases significantly, posing serious healthy and economic challenges all around the world. Although oxidative stress, protein aggregation, mitochondria impairment, and neuroinflammation are relevant to neurodegeneration, the disease pathogenesis are not fully understood and no therapy available for these degenerative disorders. Recently, cell therapies using human cell derived dopamine neurons to replace lost neurons in PD patient brains show promise and the first human clinical trial of transplantation of induced pluripotent stem cells derived human dopamine progenitors is under investigation in the Center for iPS Cell Research and Application (CiRA), Kyoto University, which brings hopes to patients with PD and other degenerative diseases.

The aim of this Special Issue is to discuss the disease pathogenesis and new therapeutic agents or therapeutic strategies to protect or alleviate neurodegeneration in human neurodegenerative disorders.

Dr. Zhidong Zhou
Dr. Alexandre Hiroaki Kihara
Guest Editors

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

  • neurodegeneration
  • neurodegenerative diseases
  • protein aggregation
  • pathogenesis
  • mitochondria
  • neuroinflammation
  • oxidative stress
  • cell therapy
  • clinical trial

Published Papers (4 papers)

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Research

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15 pages, 4368 KiB  
Article
Proteomic Analysis of a Rat Streptozotocin Model Shows Dysregulated Biological Pathways Implicated in Alzheimer’s Disease
by Esdras Matheus Gomes da Silva, Juliana S. G. Fischer, Isadora de Lourdes Signorini Souza, Amanda Caroline Camillo Andrade, Leonardo de Castro e Souza, Marcos Kaoann de Andrade, Paulo C. Carvalho, Ricardo Lehtonen Rodrigues Souza, Maria Aparecida Barbato Frazao Vital and Fabio Passetti
Int. J. Mol. Sci. 2024, 25(5), 2772; https://doi.org/10.3390/ijms25052772 - 28 Feb 2024
Viewed by 710
Abstract
Alzheimer’s Disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive impairment, affecting 35 million individuals worldwide. Intracerebroventricular (ICV) injection of low to moderate doses of streptozotocin (STZ) in adult male Wistar rats can reproduce classical physiopathological hallmarks of [...] Read more.
Alzheimer’s Disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive impairment, affecting 35 million individuals worldwide. Intracerebroventricular (ICV) injection of low to moderate doses of streptozotocin (STZ) in adult male Wistar rats can reproduce classical physiopathological hallmarks of AD. This biological model is known as ICV-STZ. Most studies are focused on the description of behavioral and morphological aspects of the ICV-STZ model. However, knowledge regarding the molecular aspects of the ICV-STZ model is still incipient. Therefore, this work is a first attempt to provide a wide proteome description of the ICV-STZ model based on mass spectrometry (MS). To achieve that, samples from the pre-frontal cortex (PFC) and hippocampus (HPC) of the ICV-STZ model and control (wild-type) were used. Differential protein abundance, pathway, and network analysis were performed based on the protein identification and quantification of the samples. Our analysis revealed dysregulated biological pathways implicated in the early stages of late-onset Alzheimer’s disease (LOAD), based on differentially abundant proteins (DAPs). Some of these DAPs had their mRNA expression further investigated through qRT-PCR. Our results shed light on the AD onset and demonstrate the ICV-STZ as a valid model for LOAD proteome description. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)
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15 pages, 2347 KiB  
Article
Beyond Amyloid: A Machine Learning-Driven Approach Reveals Properties of Potent GSK-3β Inhibitors Targeting Neurofibrillary Tangles
by Martin Nwadiugwu, Ikenna Onwuekwe, Echezona Ezeanolue and Hongwen Deng
Int. J. Mol. Sci. 2024, 25(5), 2646; https://doi.org/10.3390/ijms25052646 - 24 Feb 2024
Viewed by 1122
Abstract
Current treatments for Alzheimer’s disease (AD) focus on slowing memory and cognitive decline, but none offer curative outcomes. This study aims to explore and curate the common properties of active, drug-like molecules that modulate glycogen synthase kinase 3β (GSK-3β), a well-documented kinase with [...] Read more.
Current treatments for Alzheimer’s disease (AD) focus on slowing memory and cognitive decline, but none offer curative outcomes. This study aims to explore and curate the common properties of active, drug-like molecules that modulate glycogen synthase kinase 3β (GSK-3β), a well-documented kinase with increased activity in tau hyperphosphorylation and neurofibrillary tangles—hallmarks of AD pathology. Leveraging quantitative structure–activity relationship (QSAR) data from the PubChem and ChEMBL databases, we employed seven machine learning models: logistic regression (LogR), k-nearest neighbors (KNN), random forest (RF), support vector machine (SVM), extreme gradient boosting (XGB), neural networks (NNs), and ensemble majority voting. Our goal was to correctly predict active and inactive compounds that inhibit GSK-3β activity and identify their key properties. Among the six individual models, the NN demonstrated the highest performance with a 79% AUC-ROC on unbalanced external validation data, while the SVM model was superior in accurately classifying the compounds. The SVM and RF models surpassed NN in terms of Kappa values, and the ensemble majority voting model demonstrated slightly better accuracy to the NN on the external validation data. Feature importance analysis revealed that hydrogen bonds, phenol groups, and specific electronic characteristics are important features of molecular descriptors that positively correlate with active GSK-3β inhibition. Conversely, structural features like imidazole rings, sulfides, and methoxy groups showed a negative correlation. Our study highlights the significance of structural, electronic, and physicochemical descriptors in screening active candidates against GSK-3β. These predictive features could prove useful in therapeutic strategies to understand the important properties of GSK-3β candidate inhibitors that may potentially benefit non-amyloid-based AD treatments targeting neurofibrillary tangles. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)
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15 pages, 2088 KiB  
Article
New Insights into Endogenous Retrovirus-K Transcripts in Amyotrophic Lateral Sclerosis
by Laura Moreno-Martinez, Sofía Macías-Redondo, Mark Strunk, María Isabel Guillén-Antonini, Christian Lunetta, Claudia Tarlarini, Silvana Penco, Ana Cristina Calvo, Rosario Osta and Jon Schoorlemmer
Int. J. Mol. Sci. 2024, 25(3), 1549; https://doi.org/10.3390/ijms25031549 - 26 Jan 2024
Viewed by 758
Abstract
Retroviral reverse transcriptase activity and the increased expression of human endogenous retroviruses (HERVs) are associated with amyotrophic lateral sclerosis (ALS). We were interested in confirming HERVK overexpression in the ALS brain, its use as an accessory diagnostic marker for ALS, and its potential [...] Read more.
Retroviral reverse transcriptase activity and the increased expression of human endogenous retroviruses (HERVs) are associated with amyotrophic lateral sclerosis (ALS). We were interested in confirming HERVK overexpression in the ALS brain, its use as an accessory diagnostic marker for ALS, and its potential interplay with neuroinflammation. Using qPCR to analyze HERVK expression in peripheral blood mononuclear cells (PBMCs) and in postmortem brain samples from ALS patients, no significant differences were observed between patients and control subjects. By contrast, we report alterations in the expression patterns of specific HERVK copies, especially in the brainstem. Out of 27 HERVK copies sampled, the relative expression of 17 loci was >1.2-fold changed in samples from ALS patients. In particular, the relative expression of two HERVK copies (Chr3-3 and Chr3-5) was significantly different in brainstem samples from ALS patients compared with controls. Further qPCR analysis of inflammation markers in brain samples revealed a significant increase in NLRP3 levels, while TNFA, IL6, and GZMB showed slight decreases. We cannot confirm global HERVK overexpression in ALS, but we can report the ALS-specific overexpression of selected HERVK copies in the ALS brain. Our data are compatible with the requirement for better patient stratification and support the potential importance of particular HERVK copies in ALS. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)
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Review

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12 pages, 871 KiB  
Review
History of Parkinson’s Disease-Associated Gene, Parkin: Research over a Quarter Century in Quest of Finding the Physiological Substrate
by Tohru Kitada, Mustafa T. Ardah and M. Emdadul Haque
Int. J. Mol. Sci. 2023, 24(23), 16734; https://doi.org/10.3390/ijms242316734 - 24 Nov 2023
Cited by 1 | Viewed by 1195
Abstract
Parkin, the gene responsible for hereditary Parkinson’s disease (PD) called “Autosomal Recessive Juvenile Parkinsonism (AR-JP)” was discovered a quarter of a century ago. Owing to its huge gene structure and unique protein functions, parkin has become a subject of interest to those [...] Read more.
Parkin, the gene responsible for hereditary Parkinson’s disease (PD) called “Autosomal Recessive Juvenile Parkinsonism (AR-JP)” was discovered a quarter of a century ago. Owing to its huge gene structure and unique protein functions, parkin has become a subject of interest to those involved in PD research and researchers and clinicians in various fields and is being vigorously studied worldwide in relation to its nature and disease. The gene structure was registered under the gene name “parkin” in the GenBank in 1997. In 1998, deletion and point mutations in the parkin gene were reported, thereby demonstrating parkin is the causative gene for hereditary PD. Although 25 years have passed since the gene’s discovery and many researchers have worked tirelessly to elucidate the function of the Parkin protein and the mechanism of its role against neuronal cell death and pathogenesis remain unknown, which raises a major question concerning the current leading hypothesis. In this review, we present the results of related research on the parkin gene in chronological order and discuss unresolved problems concerning its function and pathology as well as new trends in the research conducted to solve them. The relationship between parkin and tumorigenesis has also been addressed from the perspective of Parkin’s redox molecule. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies, 2nd Edition)
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