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: 10 November 2025 | Viewed by 1081

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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

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

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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 (1 paper)

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Research

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
Viewed by 750
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
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