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Molecular Research on Neurodegenerative Diseases 4.0

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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 (20 November 2024) | Viewed by 12973

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Prof. Dr. Cesar Borlongan

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Department of Neurosurgery, MDC 78, University of South Florida College Medicine, Tampa, FL 33612, USA
Interests: stem cell therapy; stroke; neonatal hypoxic-ischemic injury; Parkinson's disease; traumatic brain injury; translational research
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issues "Molecular Research on Neurodegenerative Diseases", "Molecular Research on Neurodegenerative Diseases 2.0" and "Molecular Research on Neurodegenerative Diseases 3.0".

Many neurological disorders are characterized by neurodegenerative processes, with key molecular signaling pathways participating in cascades of cell death events. Even brain diseases traditionally considered as acute central nervous system injuries, such as stroke and traumatic brain injury, have now been recognized as presenting major pathological components, known as hallmarks of chronic neurodegeneration. Among the many molecular signatures of neurodegeneration, specific molecules associated with inflammation and mitochondrial dysfunction have been implicated as pivotal checkpoints in the propagation of cell death mechanisms, yet have also been shown to be equally involved as robust targets for anchoring cell survival therapeutics. This Special Issue is dedicated to the recent research progress made in deciphering the molecular pathways mediating cell death and cell survival in neurodegeneration and its treatment. Our goal is to provide an in-depth understanding of the underlying central role of neurodegeneration in brain diseases and to exploit such knowledge for the development of novel molecule-based therapies against neurodegenerative disorders.

Prof. Dr. Cesar Borlongan
Guest Editor

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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.

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Keywords

neurological disorders
stroke
traumatic brain injury
neurodegeneration
Parkinson's disease
molecular pathways

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Related Special Issue

Molecular Research on Neurodegenerative Diseases 3.0 in International Journal of Molecular Sciences (22 articles)

Published Papers (10 papers)

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Research

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12 pages, 3421 KiB

Open AccessArticle

The Role of ETNPPL in Dopaminergic Neuron Stability: Insights from Neuromelanin-Associated Protein Expression in Parkinson’s Disease

by Francesca A. Schillaci, Giuseppe Lanza, Maria Grazia Salluzzo, Francesca L’Episcopo, Raffaele Ferri and Michele Salemi

Int. J. Mol. Sci. 2024, 25(23), 13107; https://doi.org/10.3390/ijms252313107 - 6 Dec 2024

Viewed by 771

Abstract

More than six million people worldwide are affected by Parkinson’s disease (PD), a multifactorial disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Several immunohistochemical studies suggest that neuromelanin (NM), found in these neurons, plays a key role in their degeneration. In this study, twelve formalin-fixed, paraffin-embedded (FFPE) brain sections were analyzed, comprising six samples from PD patients and six from healthy controls. Immunohistochemistry (IHC) was conducted to assess the expression of the ETNPPL protein in these samples. ETNPPL was detected in both PD and control samples. Additionally, we examined the expression of ETNPPL mRNA using Quantitative Real-Time PCR (qRT-PCR) in the same sample set. Notably, in control samples, ETNPPL protein was closely associated with the dark NM pigment in the cytoplasm of SNc dopaminergic neurons. In contrast, PD samples showed weak cytoplasmic expression of ETNPPL, with no association with the NM pigment. No nuclear ETNPPL signal was detected in dopaminergic neurons from either PD patients or controls. qRT-PCR results revealed lower ETNPPL mRNA expression in individual PD patients compared to controls. Importantly, we observed a higher concentration of ETNPPL protein at the NM level in the SNc neurons of controls, consistent with mRNA expression patterns. These findings suggest a potential role for ETNPPL in the normal function of dopaminergic neurons and underscore its altered expression in Parkinson’s disease. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 4.0)

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14 pages, 2185 KiB

Open AccessArticle

Establishment and Use of Primary Cultured Astrocytes from Alexander Disease Model Mice

by Yuto Kubota, Eiji Shigetomi, Kozo Saito, Youichi Shinozaki, Kenji Kobayashi, Masayoshi Tanaka, Bijay Parajuli, Kenji F. Tanaka and Schuichi Koizumi

Int. J. Mol. Sci. 2024, 25(22), 12100; https://doi.org/10.3390/ijms252212100 - 11 Nov 2024

Viewed by 1157

Abstract

Alexander disease (AxD) is an intractable neurodegenerative disease caused by mutations in glial fibrillary acidic protein (GFAP), which is predominantly expressed in astrocytes. Thus, AxD is a primary astrocyte disease. However, it remains unclear how GFAP mutations affect astrocytes and cause AxD pathology. Three features are characteristic of AxD astrocytes in vivo: (1) Rosenthal fibers (RFs), the hallmark of AxD; (2) aberrant Ca²⁺ signals (AxCa); and (3) upregulation of disease-associated genes (AxGen). We established a primary culture system for astrocytes from an AxD transgenic mouse model, and used it to analyze the above features of AxD pathogenesis in astrocytes in vitro. We observed the formation of RFs in AxD primary cultures. The abundance of RFs was greater in AxD-transgene-homozygous compared with -hemizygous astrocytes, indicating a gene dosage effect, and this abundance increased with time in culture, indicating a developmental process effect. However, cultured AxD astrocytes did not exhibit changes in either AxCa or AxGen. We therefore conclude that RFs in astrocytes form via a cell-autonomous mechanism, whereas AxCa and AxGen are likely to occur via a non-cell-autonomous mechanism through interactions with other cells, such as neurons, microglia, and vascular cells. Although primary cultured AxD astrocytes are suitable for elucidating the mechanisms of RFs formation and for intervention studies, it should be noted that they cannot reflect the pathophysiology of non-cell-autonomous events in astrocytes. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 4.0)

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23 pages, 3253 KiB

Open AccessArticle

Amino Acid Compound 2 (AAC2) Treatment Counteracts Insulin-Induced Synaptic Gene Expression and Seizure-Related Mortality in a Mouse Model of Alzheimer’s Disease

by Zhijie Deng, Aejin Lee, Tao Lin, Sagarika Taneja, Devan Kowdley, Jacob H. Leung, Marykate Hill, Tianyi Tao, Julie Fitzgerald, Lianbo Yu, Joshua J. Blakeslee, Kristy Townsend, Zachary M. Weil, Jon R. Parquette and Ouliana Ziouzenkova

Int. J. Mol. Sci. 2024, 25(21), 11689; https://doi.org/10.3390/ijms252111689 - 30 Oct 2024

Viewed by 1109

Abstract

Diabetes is a major risk factor for Alzheimer’s disease (AD). Amino acid compound 2 (AAC2) improves glycemic and cognitive functions in diabetic mouse models through mechanisms distinct from insulin. Our goal was to compare the effects of AAC2, insulin, and their nanofiber-forming combination on early asymptomatic AD pathogenesis in APP/PS1 mice. Insulin, but not AAC2 or the combination treatment (administered intraperitoneally every 48 h for 120 days), increased seizure-related mortality, altered the brain fat-to-lean mass ratio, and improved specific cognitive functions in APP/PS1 mice. NanoString and pathway analysis of cerebral gene expression revealed dysregulated synaptic mechanisms, with upregulation of Bdnf and downregulation of Slc1a6 in insulin-treated mice, correlating with insulin-induced seizures. In contrast, AAC2 promoted the expression of Syn2 and Syp synaptic genes, preserved brain composition, and improved survival. The combination of AAC2 and insulin counteracted free insulin’s effects. None of the treatments influenced canonical amyloidogenic pathways. This study highlights AAC2’s potential in regulating synaptic gene expression in AD and insulin-induced contexts related to seizure activity. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 4.0)

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20 pages, 4741 KiB

Open AccessArticle

Assessing the Potential of 1,2,3-Triazole-Dihydropyrimidinone Hybrids Against Cholinesterases: In Silico, In Vitro, and In Vivo Studies

by Carlos M. Gastalho, Ana M. Sena, Óscar López, José G. Fernández-Bolaños, Alfonso T. García-Sosa, Florbela Pereira, Célia M. Antunes, Ana R. Costa, Anthony J. Burke and Elisabete P. Carreiro

Int. J. Mol. Sci. 2024, 25(20), 11153; https://doi.org/10.3390/ijms252011153 - 17 Oct 2024

Cited by 1 | Viewed by 983

Abstract

Combining the pharmacological properties of the 1,2,3-triazole and dihydropyrimidinone classes of compounds, two small families of mono- and di(1,2,3-triazole)-dihydropyrimidinone hybrids, A and B, were previously synthesized. The main objective of this work was to investigate the potential anti-Alzheimer effects of these hybrids. The inhibitory activities of cholinesterases (AChE and BuChE), antioxidant activity, and the inhibitory mechanism through in silico (molecular docking) and in solution (STD-NMR) experiments were evaluated. The 1,2,3-triazole-dihydropyrimidinone hybrids (A and B) showed moderate in vitro inhibitory activity on eqBuChE (IC₅₀ values between 1 and 58.4 μM). The best inhibitor was the hybrid B4, featuring two 1,2,3-triazole cores, which exhibited stronger inhibition than galantamine, with an IC₅₀ of 1 ± 0.1 μM for eqBuChE, through a mixed inhibition mechanism. Among the hybrids A, the most promising inhibitor was A1, exhibiting an IC₅₀ of 12 ± 2 µM, similar to that of galantamine. Molecular docking and STD-NMR experiments revealed the key binding interactions of these promising inhibitors with BuChE. Hybrids A and B did not display Artemia salina toxicity below 100 μM. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 4.0)

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25 pages, 19318 KiB

Open AccessArticle

Spatiotemporal Dysregulation of Neuron–Glia Related Genes and Pro-/Anti-Inflammatory miRNAs in the 5xFAD Mouse Model of Alzheimer’s Disease

by Marta Ianni, Miriam Corraliza-Gomez, Tiago Costa-Coelho, Mafalda Ferreira-Manso, Sara Inteiro-Oliveira, Nuno Alemãn-Serrano, Ana M. Sebastião, Gonçalo Garcia, Maria José Diógenes and Dora Brites

Int. J. Mol. Sci. 2024, 25(17), 9475; https://doi.org/10.3390/ijms25179475 - 31 Aug 2024

Cited by 3 | Viewed by 2392

Abstract

Alzheimer’s disease (AD), the leading cause of dementia, is a multifactorial disease influenced by aging, genetics, and environmental factors. miRNAs are crucial regulators of gene expression and play significant roles in AD onset and progression. This exploratory study analyzed the expression levels of 28 genes and 5 miRNAs (miR-124-3p, miR-125b-5p, miR-21-5p, miR-146a-5p, and miR-155-5p) related to AD pathology and neuroimmune responses using RT-qPCR. Analyses were conducted in the prefrontal cortex (PFC) and the hippocampus (HPC) of the 5xFAD mouse AD model at 6 and 9 months old. Data highlighted upregulated genes encoding for glial fibrillary acidic protein (Gfap), triggering receptor expressed on myeloid cells (Trem2) and cystatin F (Cst7), in the 5xFAD mice at both regions and ages highlighting their roles as critical disease players and potential biomarkers. Overexpression of genes encoding for CCAAT enhancer-binding protein alpha (Cebpa) and myelin proteolipid protein (Plp) in the PFC, as well as for BCL2 apoptosis regulator (Bcl2) and purinergic receptor P2Y12 (P2yr12) in the HPC, together with upregulated microRNA(miR)-146a-5p in the PFC, prevailed in 9-month-old animals. miR-155 positively correlated with miR-146a and miR-21 in the PFC, and miR-125b positively correlated with miR-155, miR-21, while miR-146a in the HPC. Correlations between genes and miRNAs were dynamic, varying by genotype, region, and age, suggesting an intricate, disease-modulated interaction between miRNAs and target pathways. These findings contribute to our understanding of miRNAs as therapeutic targets for AD, given their multifaceted effects on neurons and glial cells. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 4.0)

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Review

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27 pages, 783 KiB

Open AccessReview

Current Development of iPSC-Based Modeling in Neurodegenerative Diseases

by Xiangge Guo, Xumeng Wang, Jiaxuan Wang, Min Ma and Qian Ren

Int. J. Mol. Sci. 2025, 26(8), 3774; https://doi.org/10.3390/ijms26083774 - 16 Apr 2025

Viewed by 400

Abstract

Over the past two decades, significant advancements have been made in the induced pluripotent stem cell (iPSC) technology. These developments have enabled the broader application of iPSCs in neuroscience, improved our understanding of disease pathogenesis, and advanced the investigation of therapeutic targets and methods. Specifically, optimizations in reprogramming protocols, coupled with improved neuronal differentiation and maturation techniques, have greatly facilitated the generation of iPSC-derived neural cells. The integration of the cerebral organoid technology and CRISPR/Cas9 genome editing has further propelled the application of iPSCs in neurodegenerative diseases to a new stage. Patient-derived or CRISPR-edited cerebral neurons and organoids now serve as ideal disease models, contributing to our understanding of disease pathophysiology and identifying novel therapeutic targets and candidates. In this review, we examine the development of iPSC-based models in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 4.0)

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15 pages, 1333 KiB

Open AccessReview

c-Myc and FOXO3a—The Everlasting Decision Between Neural Regeneration and Degeneration

by Andrey M. Khaitin, Valeria V. Guzenko, Stanislav S. Bachurin and Svetlana V. Demyanenko

Int. J. Mol. Sci. 2024, 25(23), 12621; https://doi.org/10.3390/ijms252312621 - 24 Nov 2024

Viewed by 978

Abstract

The transcription factors c-Myc and FoxO3a play significant roles in neurodegenerative processes, yet their interaction in neurological disorders remains largely unexplored. In contrast, much of the available information about their relationship comes from cancer research. While it is well-established that FoxO3a inhibits c-Myc activity, this interaction represents only a basic understanding of a far more complex dynamic, which includes exceptions under specific conditions and the involvement of additional regulatory factors. Given the critical need to address this gap for the treatment and prevention of neurodegenerative disorders, this review consolidates current knowledge on the joint roles of these two factors in neuropathology. It also highlights their conformational flexibility, post-translational modifications, and outlines potential directions for future research. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 4.0)

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12 pages, 1914 KiB

Open AccessReview

Olfactory Ecto-Mesenchymal Stem Cells in Modeling and Treating Alzheimer’s Disease

by Hongmin Wang and Abena Dwamena

Int. J. Mol. Sci. 2024, 25(15), 8492; https://doi.org/10.3390/ijms25158492 - 3 Aug 2024

Viewed by 2067

Abstract

Alzheimer’s disease (AD) is a condition in the brain that is marked by a gradual and ongoing reduction in memory, thought, and the ability to perform simple tasks. AD has a poor prognosis but no cure yet. Therefore, the need for novel models to study its pathogenesis and therapeutic strategies is evident, as the brain poorly recovers after injury and neurodegenerative diseases and can neither replace dead neurons nor reinnervate target structures. Recently, mesenchymal stem cells (MSCs), particularly those from the human olfactory mucous membrane referred to as the olfactory ecto-MSCs (OE-MSCs), have emerged as a potential avenue to explore in modeling AD and developing therapeutics for the disease due to their lifelong regeneration potency and facile accessibility. This review provides a comprehensive summary of the current literature on isolating OE-MSCs and delves into whether they could be reliable models for studying AD pathogenesis. It also explores whether healthy individual-derived OE-MSCs could be therapeutic agents for the disease. Despite being a promising tool in modeling and developing therapies for AD, some significant issues remain, which are also discussed in the review. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 4.0)

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Other

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9 pages, 636 KiB

Open AccessOpinion

PIEZO2 Proton Affinity and Availability May Also Regulate Mechanical Pain Sensitivity, Drive Central Sensitization and Neurodegeneration

by Balázs Sonkodi

Int. J. Mol. Sci. 2025, 26(3), 1246; https://doi.org/10.3390/ijms26031246 - 31 Jan 2025

Cited by 1 | Viewed by 977

Abstract

The current opinion manuscript posits that not only Piezo2 voltage block, but also proton affinity and availability in relation to Piezo2, a mechanically gated ion channel, may count in the mediation of pain and its sensitivity. Moreover, this paper argues that autonomously acquired Piezo2 channelopathy on somatosensory terminals is likely the initiating peripheral impaired input source that drives the central sensitization of spinal nociceptive neurons on the chronic path as being the autonomous pain generator. In parallel, impaired proprioception and the resultant progressive deficit in neuromuscular junctions of motoneurons might be initiated on the chronic path by the impairment of the proton-based ultrafast proprioceptive feedback to motoneurons due to disconnection through vesicular glutamate transporter 1. The irreversible form of this autonomously acquired Piezo2 ion channel microdamage, in association with genetic predisposition and/or environmental risk factors, is suggested to lead to progressive motoneuron death in addition to loss of pain sensation in amyotrophic lateral sclerosis. Furthermore, the impairment of the proton-based ultrafast long-range oscillatory synchronization to the hippocampus through vesicular glutamate transporter 2 may gain further importance in pain modulation and formation on the chronic path. Overall, this novel, unaccounted Piezo2-initiated protonic extrafast signaling, including both the protonic ultrafast proprioceptive and the rapid nociceptive ones, within the nervous system seems to be essential in order to maintain life. Hence, its microdamage promotes neurodegeneration and accelerates aging, while the complete loss of it is incompatible with life sustainment, as is proposed in amyotrophic lateral sclerosis. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 4.0)

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17 pages, 1353 KiB

Open AccessCase Report

Identification of SYNJ1 in a Complex Case of Juvenile Parkinsonism Using a Multiomics Approach

by Ester Leno-Durán, Luisa Arrabal, Susana Roldán, Inmaculada Medina, Clara Alcántara-Domínguez, Victor García-Cabrera, Jorge Saiz, Coral Barbas, Maria José Sánchez, Carmen Entrala-Bernal, Francisco Fernández-Rosado, Jose Antonio Lorente, Purificacion Gutierrez-Ríos and Luis Javier Martínez-Gonzalez

Int. J. Mol. Sci. 2024, 25(17), 9754; https://doi.org/10.3390/ijms25179754 - 9 Sep 2024

Viewed by 1761

Abstract

This study aimed to elucidate the genetic causes underlying the juvenile parkinsonism (JP) diagnosed in a girl with several family members diagnosed with spinocerebellar ataxia type 2 (SCA2). To achieve this, whole-exome sequencing, analysis of CAG repeats, RNA sequencing analysis on fibroblasts, and metabolite identification were performed. As a result, a homozygous missense mutation SNP T>C (rs2254562) in synaptojamin 1 (SYNJ1), which has been implicated in the regulation of membrane trafficking in the synaptic vesicles, was identified. Additionally, we observed overexpression of L1 cell adhesion molecule (L1CAM), Cdc37, GPX1, and GPX4 and lower expression of ceruloplasmin in the patient compared to the control. We also found changes in sphingolipid, inositol, and inositol phosphate metabolism. These findings help to clarify the mechanisms of JP and suggest that the etiology of JP in the patient may be multifactorial. This is the first report of the rs2254562 mutation in the SYNJ gene identified in a JP patient with seizures and cognitive impairment. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 4.0)

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