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Recent Advances in the Molecular Mechanisms of Neurodegenerative Diseases: Current...
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Recent Advances in the Molecular Mechanisms of Neurodegenerative Diseases: Current Progress and Future Directions for Disease-Modifying Therapies

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (15 April 2026) | Viewed by 2564

Special Issue Editors

Dr. Rengasamy Balakrishnan

E-Mail Website
Guest Editor
Department of Biotechnology, College of Biomedical and Health Science, Research Institute of Inflammatory Disease (RID), Konkuk University, Chungju 27478, Republic of Korea
Interests: pharmacology; new drug discovery; myokines; physical exercise; neurodegenerative diseases; dementia
Dr. Balamuralikrishnan Balasubramanian

E-Mail Website
Guest Editor
Department of Food Science and Biotechnology College of Life Science, Sejong University, Seoul, Republic of Korea
Interests: pharmacology; natural products; gut microbiota; dietary supplements; nutrition
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As life expectancy increases due to advances in medical care, humanity faces a new crisis associated with the growing aging population. This results in a corresponding increase in the prevalence of incurable neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis. These diseases typically affect brain activity in the elderly by impairing their cognitive and behavioral functions. Notably, several pathogenic features—including specific neuronal loss, gliosis, oxidative stress, mitochondrial dysfunction, neuroinflammation, and gut dysfunction—tend to overlap in common neurodegenerative diseases. Despite advances in our understanding, the development of disease-modifying treatments that target the underlying molecular mechanisms of disease pathogenesis remains challenging; only a few symptomatic-modifying therapies are currently available for PD, but not disease-modifying therapies. Therefore, this Special Issue aims to explore the potential disease-modifying therapies related to the advancement of research on the neuropathogenesis of neurodegenerative diseases, with the goal of achieving significant breakthroughs in disease modeling and drug development. The original research articles and reviews focused on investigating the natural drug, neuroprotective signaling mechanisms, microglial-mediated neuroinflammation, and neuronal cell death, as well as the relationship between the gut–brain axis. We also invite you to submit research and review articles that focus on the relationship between physical exercise and neurodegenerative diseases. These articles should explore how different types of physical exercise regulate brain function and contribute to the prevention of neurodegenerative diseases, as well as how non-pharmacological therapeutic strategies can reduce disease progression through exercise interventions.

Dr. Rengasamy Balakrishnan
Dr. Balamuralikrishnan Balasubramanian
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 250 words) can be sent to the Editorial Office for assessment.

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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • neuroprotection
  • new drug development
  • natural products
  • blood–brain barrier
  • molecular mechanisms
  • neuronal signaling
  • neuroinflammation
  • microglial cells
  • neurotoxicity
  • neurodegenerative diseases

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Published Papers (2 papers)

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Research

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22 pages, 4448 KB  
Article
PLEKHM1 Overexpression Impairs Autophagy and Exacerbates Neurodegeneration in rAAV-α-Synuclein Mice
by Lennart Höfs, David Geißler-Lösch and Björn H. Falkenburger
Cells 2025, 14(17), 1340; https://doi.org/10.3390/cells14171340 - 29 Aug 2025
Cited by 1 | Viewed by 1574
Abstract
The aggregation of α-synuclein (αSyn) is a central feature of Parkinson’s disease (PD) and other synucleinopathies. The efficient clearance of αSyn depends largely on the autophagy–lysosomal pathway. Emerging genetic evidence highlights the role of pleckstrin homology and RUN domain-containing M1 protein (PLEKHM1), a [...] Read more.
The aggregation of α-synuclein (αSyn) is a central feature of Parkinson’s disease (PD) and other synucleinopathies. The efficient clearance of αSyn depends largely on the autophagy–lysosomal pathway. Emerging genetic evidence highlights the role of pleckstrin homology and RUN domain-containing M1 protein (PLEKHM1), a critical regulator of autophagosome–lysosome fusion, in the pathogenesis of multiple neurodegenerative diseases. This study investigates the possible effects of increased PLEKHM1 expression on αSyn pathology and neurodegeneration in mice. We utilized a mouse model of PD that is based on A53T-αSyn overexpression, achieved by the stereotactic injection of recombinant adeno-associated viral vectors (rAAV) into the substantia nigra. Additionally, this study explores the effect of PLEKHM1 overexpression on the autophagy–lysosomal pathway under physiological conditions, using transgenic autophagy reporter mice. PLEKHM1 overexpression facilitated the αSyn-induced degeneration of dopaminergic somata in the substantia nigra and degeneration of dopaminergic axon terminals in the striatum. In concert with αSyn expression, PLEKHM1 also potentiated microglial activation. The extent of αSyn pathology, as reported by staining for phosphorylated αSyn, was not affected by PLEKHM1. Using RFP-EGFP-LC3 autophagy reporter mice, rAAV-mediated PLEKHM1 overexpression reduced lysosomal and autolysosomal area, increased LAMP1-LC3 colocalization, and decreased the autolysosome-to-autophagosome ratio. Concurrently, PLEKHM1 overexpression in both genotypes caused p62 accumulation, accompanied by reduced overlap with lysosomal and autophagosomal markers but increased colocalization with autolysosomal markers, indicating impaired cargo degradation during late-stage autophagy. Taken together, elevated PLEKHM1 levels exacerbate neurodegeneration in αSyn-overexpressing mice, possibly by impairing autophagic flux. Now, with in vivo evidence complementing genetic data, alterations in PLEKHM1 expression appear to compromise autophagy, potentially enhancing neuronal vulnerability to secondary insults like αSyn pathology. Full article
(This article belongs to the Special Issue Recent Advances in the Molecular Mechanisms of Neurodegenerative Diseases: Current Progress and Future Directions for Disease-Modifying Therapies)
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Review

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33 pages, 1693 KB  
Review
GLP-1 and Parkinson’s Disease: A Comprehensive Review of Biology, Mechanisms and Efficacy
by Roxana Mezabrovschi, Matthew E. Gegg and Anthony H. V. Schapira
Cells 2026, 15(9), 804; https://doi.org/10.3390/cells15090804 - 29 Apr 2026
Viewed by 99
Abstract
Neurodegenerative disorders, including Parkinson’s disease (PD), are largely treated with symptomatic therapies, underscoring the need for strategies that target underlying disease mechanisms. Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R), a class B G protein-coupled receptor best known for metabolic regulation, have attracted interest [...] Read more.
Neurodegenerative disorders, including Parkinson’s disease (PD), are largely treated with symptomatic therapies, underscoring the need for strategies that target underlying disease mechanisms. Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R), a class B G protein-coupled receptor best known for metabolic regulation, have attracted interest due to the increasing evidence of central nervous system (CNS) actions. This review synthesises mechanistic, preclinical, and clinical evidence examining GLP-1R signalling in PD and related neurodegenerative contexts. We integrate findings from cellular and animal models with early-phase clinical studies of GLP-1 receptor agonists (GLP-1RAs). Across experimental systems, GLP-1R activation engages conserved intracellular pathways—cAMP/PKA, PI3K/Akt, and ERK—that regulate mitochondrial function, oxidative stress, autophagy-lysosomal dynamics, and inflammatory signalling. In PD-relevant models, these pathways intersect with key pathogenic features, including α-synuclein accumulation, dopaminergic neuron vulnerability, and glial reactivity. Clinical studies to date demonstrate acceptable safety and tolerability, alongside biomarker evidence of central pathway engagement and variable effects on motor and non-motor outcomes. However, uncertainties remain regarding CNS target engagement, peripheral versus CNS mechanisms, and disease-stage dependence. Overall, the current evidence positions GLP-1R signalling as a biologically plausible therapeutic pathway in PD that warrants further mechanistic clarification and rigorous evaluation in ongoing and future clinical trials. Full article
(This article belongs to the Special Issue Recent Advances in the Molecular Mechanisms of Neurodegenerative Diseases: Current Progress and Future Directions for Disease-Modifying Therapies)
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