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Neurodegenerative Disease: From Molecular Basis to Therapy, 3rd Edition
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Neurodegenerative Disease: From Molecular Basis to Therapy, 3rd 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: 20 August 2025 | Viewed by 8176

Special Issue Editor

Dr. Claudia Ricci

E-Mail Website
Guest Editor
Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
Interests: molecular biology; neurogenetics; motor neuron diseases; amyotrophic lateral sclerosis; gene variants; gene regulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases are a heterogeneous group of disorders, largely age-dependent, affecting the central nervous system and eventually leading to neurodegeneration. The prevalence of these diseases is increasing, partly due to the aging population, with a consequent growing economic burden on healthcare systems. The current treatments are mostly symptomatic, without affecting the underlying cause of disease, and have no or only slight effects on disease progression.

Recent advancements in neurobiology and neurogenetics have provided valuable insights into the pathogenesis of neurodegenerative diseases. This has paved the way for the development of molecularly targeted therapies, which are able to pause or slow the fundamental pathological processes that cause neuronal damage and consequent cognitive and motor dysfunctions. In some cases, neurodegenerative diseases are caused by genetic variants and/or cellular pathway dysregulation. Some mechanisms common to several neurodegenerative conditions have been identified, such as the presence of misfolded protein aggregates, the abnormal accumulation of proteins, RNA toxicity, or translational products from the expansion of repeats within genes. As advances are made in understanding critical aspects of the underlying molecular pathophysiology, therapeutic strategies continue to evolve. Among these, gene therapy is attracting great interest due to the possibility to deliver functional genetic material to cells to correct a defective gene.

This Special Issue aims to provide an updated overview of the advancements in the research on neurodegenerative diseases, from the understanding of the molecular bases to the development of new therapies. Contributions related but not limited to Alzheimer's disease and other types of dementia, Parkinson's disease and motor neuron diseases are welcome, including original research articles and full and short reviews.

Dr. Claudia Ricci
Guest Editor

Manuscript Submission Information

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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

  • neurodegenerative diseases
  • molecular biology
  • neurogenetics
  • pathogenesis
  • therapy
  • personalized medicine

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Related Special Issues

Published Papers (6 papers)

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Research

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15 pages, 5180 KiB  
Article
A Novel Small Molecule Enhances Stable Dopamine Delivery to the Brain in Models of Parkinson’s Disease
by Xiaoguang Liu, Michaeline L. Hebron, Max Stevenson and Charbel Moussa
Int. J. Mol. Sci. 2025, 26(9), 4251; https://doi.org/10.3390/ijms26094251 (registering DOI) - 30 Apr 2025
Abstract
Levodopa is the gold standard symptomatic treatment for Parkinson’s disease. Disease progression due to alpha-synuclein accumulation, brain inflammation, and the loss of dopamine neurons, as well as motor fluctuations, due to variations in levodopa plasma levels, remain a significant problem for Parkinson’s patients. [...] Read more.
Levodopa is the gold standard symptomatic treatment for Parkinson’s disease. Disease progression due to alpha-synuclein accumulation, brain inflammation, and the loss of dopamine neurons, as well as motor fluctuations, due to variations in levodopa plasma levels, remain a significant problem for Parkinson’s patients. Developing a therapeutic option that can simultaneously reduce the neuropathology associated with alpha-synuclein aggregation, attenuate oxidative stress and inflammation, and overcome variations in levodopa plasma levels is an unmet need to treat Parkinson’s disease. We determined the pharmacokinetics and pharmacodynamics of a small molecule, dubbed Pegasus, that conjugates dopamine with a nonantibiotic doxycycline derivative via a molecular linker. Mice harboring the human A53T mutation of alpha-synuclein or treated with MPTP were injected once daily with 50 mg/kg Pegasus for 2 weeks and assessed for motor, behavioral, and cognitive effects, followed by biochemical and histochemical analysis. Pegasus is a poor brain penetrant but it was metabolized to stable dopamine and tetracycline derivatives, and abundant plasma and brain levels of these metabolites were detected. Pegasus reduced soluble and insoluble alpha-synuclein levels, protected dopamine-producing neurons, and reduced astrocytic activation in A53T mice. Mice treated with Pegasus exhibited motor improvement (6.5 h) and reduction in anxiety-like behavior. Rotarod and grip strength improved in MPTP-treated mice when mice were treated with Pegasus or levodopa. Pegasus may be a multi-modal therapeutic option that can deliver stable dopamine into the CNS and reduce misfolded alpha-synuclein, activate dopamine receptors, and attenuate variations in dopamine levels. Full article
(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 3rd Edition)
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13 pages, 2506 KiB  
Article
Evidence of Oxytosis/Ferroptosis in Niemann–Pick Disease Type C
by Kayla L. Sanchez, Jeanyoung Kim, Jacob B. White, Andrew Tolan, Naren P. Rajagopal, Douglas W. Anderson, Alexandra N. Shin, Samuel D. Shin, Antonio Currais, David Soriano-Castell, Pamela Maher and Salvador Soriano
Int. J. Mol. Sci. 2025, 26(7), 2915; https://doi.org/10.3390/ijms26072915 - 23 Mar 2025
Viewed by 430
Abstract
Niemann–Pick Disease Type C (NPC) is a hereditary neurodegenerative disease characterized by selective cell vulnerability, particularly affecting cerebellar anterior Purkinje neurons. These neurons exhibit a distinctive pattern of degeneration due to the loss of NPC1 and/or NPC2 protein function, progressively extending towards posterior [...] Read more.
Niemann–Pick Disease Type C (NPC) is a hereditary neurodegenerative disease characterized by selective cell vulnerability, particularly affecting cerebellar anterior Purkinje neurons. These neurons exhibit a distinctive pattern of degeneration due to the loss of NPC1 and/or NPC2 protein function, progressively extending towards posterior cerebellar regions. Our study aimed to explore the early factors influencing this selective vulnerability of anterior Purkinje neurons in NPC. Oxytosis/ferroptosis, a novel form of regulated cell death, has been implicated in neurodegenerative diseases, with its inhibition showing promising therapeutic potential. Our laboratory has previously identified parallels between NPC cellular pathology and ferroptotic markers, including elevated levels of lipid peroxidation and iron, mitochondrial dysfunction, and Ca2+ dyshomeostasis. However, whether oxytosis/ferroptosis underlies NPC cellular pathology remains unexplored. We hypothesize that loss of NPC1 function increases vulnerability to ferroptosis and that anti-ferroptotic compounds will reverse NPC cellular pathology. Through bioinformatic analyses of pre-symptomatic Npc1−/− Purkinje neurons and in vitro studies using primary dermal fibroblasts derived from NPC patients, we provide evidence suggesting that oxytosis/ferroptosis may play a pathogenic role in NPC. These findings highlight the potential of anti-ferroptotic compounds as a promising therapeutic strategy to mitigate neurodegeneration in NPC and potentially other related disorders. Full article
(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 3rd Edition)
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21 pages, 2532 KiB  
Article
α-Synuclein Degradation in Brain Pericytes Is Mediated via Akt, ERK, and p38 MAPK Signaling Pathways
by Miki Yokoya, Fuyuko Takata, Takuro Iwao, Junichi Matsumoto, Yasuyoshi Tanaka, Hisataka Aridome, Miho Yasunaga, Junko Mizoguchi, Kazunori Sano and Shinya Dohgu
Int. J. Mol. Sci. 2025, 26(4), 1615; https://doi.org/10.3390/ijms26041615 - 14 Feb 2025
Viewed by 828
Abstract
Parkinson’s disease (PD) is characterized by widespread distribution of Lewy bodies, which are composed of phosphorylated and aggregated forms of α-Synuclein (α-Syn), in the brain. Although the accumulation and propagation of α-Syn contribute to the development of PD, the involvement of the blood–brain [...] Read more.
Parkinson’s disease (PD) is characterized by widespread distribution of Lewy bodies, which are composed of phosphorylated and aggregated forms of α-Synuclein (α-Syn), in the brain. Although the accumulation and propagation of α-Syn contribute to the development of PD, the involvement of the blood–brain barrier (BBB) in these processes remains unknown. Pericytes, one of the cell types that constitute the BBB, degrade various forms of α-Syn. However, the detailed mechanisms involved in α-Syn degradation by pericytes remain poorly understood. Therefore, in this study, we aimed to determine the ability of the BBB-constituting cells, particularly primary cultures of rat pericytes, brain endothelial cells, and astrocytes, to degrade α-Syn. After α-Syn uptake by the cells, intracellular α-Syn decreased only in pericytes. This pericyte-specific α-Syn decrease was inhibited by an autophagy inhibitor, bafilomycin A1, and a proteasome inhibitor, MG132. siRNA-mediated knockdown of degradation enzymes or familial PD-associated genes, including cathepsin D, DJ-1, and LRRK2, did not affect α-Syn clearance in pericytes. However, pharmacological inhibitors of Akt, ERK, and p38 MAPK inhibited α-Syn degradation by pericytes. In conclusion, our results suggest that α-Syn degradation by pericytes is mediated by an autophagy–lysosome system and a ubiquitin–proteasome system via α-Syn-activated Akt, ERK, and p38 MAPK signaling pathways. Full article
(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 3rd Edition)
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23 pages, 3265 KiB  
Article
A Map of Transcriptomic Signatures of Different Brain Areas in Alzheimer’s Disease
by Riccardo Rocco Ferrari, Valentina Fantini, Maria Garofalo, Rosalinda Di Gerlando, Francesca Dragoni, Bartolo Rizzo, Erica Spina, Michele Rossi, Chiara Calatozzolo, Xhulja Profka, Mauro Ceroni, Antonio Guaita, Annalisa Davin, Stella Gagliardi and Tino Emanuele Poloni
Int. J. Mol. Sci. 2024, 25(20), 11117; https://doi.org/10.3390/ijms252011117 - 16 Oct 2024
Cited by 1 | Viewed by 1631
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder that progressively involves brain regions with an often-predictable pattern. Damage to the brain appears to spread and worsen with time, but the molecular mechanisms underlying the region-specific distribution of AD pathology at different stages of the [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder that progressively involves brain regions with an often-predictable pattern. Damage to the brain appears to spread and worsen with time, but the molecular mechanisms underlying the region-specific distribution of AD pathology at different stages of the disease are still under-investigated. In this study, a whole-transcriptome analysis was carried out on brain samples from the hippocampus (HI), temporal and parietal cortices (TC and PC, respectively), cingulate cortex (CG), and substantia nigra (SN) of six subjects with a definite AD diagnosis and three healthy age-matched controls in duplicate. The transcriptomic results showed a greater number of differentially expressed genes (DEGs) in the TC (1571) and CG (1210) and a smaller number of DEGs in the HI (206), PC (109), and SN (60). Furthermore, the GSEA showed a difference between the group of brain areas affected early (HI and TC) and the group of areas that were subsequently involved (PC, CG, and SN). Notably, in the HI and TC, there was a significant downregulation of shared DEGs primarily involved in synaptic transmission, while in the PC, CG, and SN, there was a significant downregulation of genes primarily involved in protein folding and trafficking. The course of AD could follow a definite time- and severity-related pattern that arises from protein misfolding, as observed in the PC, CG, and SN, and leads to synaptic impairment, as observed in the HI and TC. Therefore, a map of the molecular and biological processes involved in AD pathogenesis may be traced. This could aid in the discovery of novel biological targets in order to develop effective and well-timed therapeutic approaches. Full article
(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 3rd Edition)
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Review

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15 pages, 969 KiB  
Review
SLC1A4 and Serine Homeostasis: Implications for Neurodevelopmental and Neurodegenerative Disorders
by Dana Elazar, Natalie Alvarez, Sabrina Drobeck and Teresa M. Gunn
Int. J. Mol. Sci. 2025, 26(5), 2104; https://doi.org/10.3390/ijms26052104 - 27 Feb 2025
Viewed by 952
Abstract
The solute carrier family 1 member 4 (SLC1A4) gene encodes a neutral amino acid transporter, also referred to as alanine-serine-cysteine transporter 1, ASCT1, that helps maintain amino acid balance in the brain and periphery. In the brain, SLC1A4 plays an important [...] Read more.
The solute carrier family 1 member 4 (SLC1A4) gene encodes a neutral amino acid transporter, also referred to as alanine-serine-cysteine transporter 1, ASCT1, that helps maintain amino acid balance in the brain and periphery. In the brain, SLC1A4 plays an important role in transporting levo (L) and dopa (D) isomers of serine. L-serine is required for many cellular processes, including protein and sphingolipid synthesis, while D-serine is a co-agonist required for normal neurotransmission through N-methyl-D-aspartate receptors. Through its roles transporting L-serine across the blood–brain barrier and regulating synaptic D-serine levels, SLC1A4 helps establish and maintain brain health across the lifespan. This review examines the role of SLC1A4 in neurodevelopment and neurodegeneration and assesses the therapeutic potential of serine supplementation to treat neurodevelopmental symptoms associated with mutations in SLC1A4, as well as schizophrenia, depression, traumatic brain injury, and Alzheimer’s and Parkinson’s diseases. Full article
(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 3rd Edition)
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63 pages, 1471 KiB  
Review
Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer’s, Parkinson’s, and ALS
by Corneliu Toader, Calin Petru Tataru, Octavian Munteanu, Matei Serban, Razvan-Adrian Covache-Busuioc, Alexandru Vlad Ciurea and Mihaly Enyedi
Int. J. Mol. Sci. 2024, 25(23), 12613; https://doi.org/10.3390/ijms252312613 - 24 Nov 2024
Cited by 4 | Viewed by 3321
Abstract
Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, ALS, and Huntington’s, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances—misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations—that slowly dismantle neuronal integrity. [...] Read more.
Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, ALS, and Huntington’s, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances—misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations—that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions. This review synthesizes the latest insights into the underlying molecular dynamics of neurodegeneration, revealing how intertwined pathways drive the course of these diseases. With an eye on the most promising advances, we explore innovative therapies emerging from cutting-edge research: nanotechnology-based drug delivery systems capable of navigating the blood–brain barrier, gene-editing tools like CRISPR designed to correct harmful genetic variants, and stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored therapies that align with individual genetic profiles, while molecular diagnostics and biomarkers are ushering in an era of early, precise disease detection. Furthermore, novel perspectives on the gut–brain axis are sparking interest as mounting evidence suggests that microbiome modulation may play a role in reducing neuroinflammatory responses linked to neurodegenerative progression. Taken together, these advances signal a shift toward a comprehensive, personalized approach that could transform neurodegenerative care. By integrating molecular insights and innovative therapeutic techniques, this review offers a forward-looking perspective on a future where treatments aim not just to manage symptoms but to fundamentally alter disease progression, presenting renewed hope for improved patient outcomes. Full article
(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 3rd Edition)
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