Molecular and Genetic Basis of Neurodegenerative Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Genetics".

Deadline for manuscript submissions: 31 October 2025 | Viewed by 3328

Special Issue Editors


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Guest Editor
McLaughlin Research Institute, Great Falls, MT, USA
Interests: molecular and genetic mechanisms of neurodegeneration; endo-lysosomal trafficking; ubiquitination; mitochondrial dysfunction; myelination; mouse models

E-Mail Website
Guest Editor
McLaughlin Research Institute, Great Falls, MT, USA
Interests: molecular influences in disease outcomes and transmissibility in neurodegenerative and zoonotic diseases; chronic wasting disease; prion diseases; Huntington’s disease

Special Issue Information

Dear Colleagues,

Neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, frontotemporal dementia, amyotrophic lateral sclerosis, prion diseases, and peripheral neuropathies are a significant public health concern due to their increasing prevalence worldwide, but accurate, early diagnostics and effective treatment options remain limited. Identifying underlying mechanisms is a critical area of study for the identification of early biomarkers of disease and the development of effective preventative and therapeutic strategies. Although diverse in their histopathology and clinical symptoms, shared molecular pathways have been identified across many neurodegenerative disorders, often through rare inherited forms of disease or human genome-wide association studies (GWASs). These pathways include those that regulate protein folding, trafficking, and degradation; mitochondrial and ion homeostasis; oxidative and other cellular stress pathways; neuroinflammation; and synaptic signaling. Despite exciting advances, much remains to be learned about the underlying mechanisms by which these pathways contribute to neurodegeneration and the downstream effects that modulate disease pathogenesis and progression.

We are pleased to invite you to submit your work to this Special Issue of Biomolecules, which will focus on molecular, genetic, and genomic studies that provide insight into pathogenic mechanisms of neurodegeneration, biomarker discovery, and the identification and/or characterization of novel potential therapeutic targets. Basic and pre-clinical studies, in vitro research, and in vivo investigations using animal models are welcome.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following topics:

  1. Novel insights into the genetic and molecular mechanisms of neurodegeneration;
  2. Development of biomarkers for improved disease diagnostics;  
  3. Investigations into disease-driving mechanisms or risk factors, such as inflammation, gene–environment interactions, and aging;
  4. Identifying new genetic variants associated with neurodegenerative diseases and dissecting how they influence disease presentation;
  5.  Novel treatment options based on molecular or biochemical targets;
  6. Transmissibility assessments between species in infectious neurodegenerative diseases in which molecular genetics may modify species barriers;
  7. Epigenetic modifications.

We look forward to receiving your contributions.

Dr. Teresa M. Gunn
Dr. Andrea Grindeland
Guest Editors

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Keywords

  • neurodegeneration
  • neurodegenerative diseases
  • protein misfolding
  • protein trafficking
  • mitochondrial dysfunction
  • oxidative stress
  • neuronal homeostasis
  • neuroinflammation

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Published Papers (5 papers)

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Research

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23 pages, 4085 KiB  
Article
Microbial Composition, Disease Trajectory and Genetic Background in a Slow Onset Model of Frontotemporal Lobar Degeneration
by Nathalie Daude, Ivana Machado, Luis Arce, Jing Yang and David Westaway
Biomolecules 2025, 15(5), 636; https://doi.org/10.3390/biom15050636 - 29 Apr 2025
Viewed by 199
Abstract
Slow-onset neurodegenerative disease in a low-expresser 2N4R P301L transgenic (Tg) mouse model is marked by neuroinflammation and by differing patterns of CNS deposition and accumulation of tau conformers, with such heterogeneities present even within inbred backgrounds. Gut microbial genotypes were notably divergent within [...] Read more.
Slow-onset neurodegenerative disease in a low-expresser 2N4R P301L transgenic (Tg) mouse model is marked by neuroinflammation and by differing patterns of CNS deposition and accumulation of tau conformers, with such heterogeneities present even within inbred backgrounds. Gut microbial genotypes were notably divergent within C57BL6/Tac or 129SvEv/Tac congenic (Cg) sublines of TgTauP301L mice, and these sublines differed when challenged with antibiotic treatment and fecal microbial transplantation. Whereas aged, transplanted Cg 129SvEv/Tac TgTauP301L mice had neuroanatomical deposition of tau resembling controls, transplanted Cg C57BL6/Tac TgTauP301L mice had different proportions of rostral versus caudal tau accumulation (p = 0.0001). These data indicate the potential for environmental influences on tau neuropathology in this model. Furthermore, Cg C57BL6/Tac TgTauP301L cohorts differed from 129SvEv/Tac counterparts by showing 28% versus 9% net intercurrent loss (p = 0.0027). While the origin of this phenomenon is not established, it offers a parallel to differing patterns of frailty observed in C57BL6 versus 129 SvEv Tg mice expressing the 695 amino acid isoform of human amyloid precursor protein. We infer that generalized responses to protein aggregation might account for similar reductions in viability even when expressing different human proteins in the same inbred strain background. Full article
(This article belongs to the Special Issue Molecular and Genetic Basis of Neurodegenerative Diseases)
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18 pages, 18769 KiB  
Article
Evaluation of the Effects of Thymoquinone on RAGE/NOX4 Expressions and Brain Tissue Morphometry in Experimental Alzheimer’s Disease Induced by Amyloid Beta 1–42 Peptide
by Şükrü Ateş, Harun Ülger, Sümeyye Uçar, Aslı Okan, Mert Ocak, Ecma Güvenilir, Zeynep Yılmaz Şükranlı, Emin Kaymak, Züleyha Doğanyiğit, Serpil Taheri and Seher Yilmaz
Biomolecules 2025, 15(4), 543; https://doi.org/10.3390/biom15040543 - 7 Apr 2025
Viewed by 422
Abstract
The onset of Alzheimer’s disease (AD) is attributed to widespread amyloid beta (Aβ) plaque accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation. However, the underlying mechanism of AD remains unclear, and no curative treatment currently exists. The aim was to investigate the effect of [...] Read more.
The onset of Alzheimer’s disease (AD) is attributed to widespread amyloid beta (Aβ) plaque accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation. However, the underlying mechanism of AD remains unclear, and no curative treatment currently exists. The aim was to investigate the effect of thymoquinone by suppressing the RAGE/NOX4 pathway in AD. Mice (n = 60) were divided into five groups, and an experimental AD model induced by an Aβ1–42 peptide was established in two groups. We also administered 5 mg/kg thymoquinone (TMQ) to the mice for its properties to slow or treat neurodegeneration in AD. Behavioral tests for memory and emotional states, micro-computed tomography (Micro CT) to assess brain volume, ELISA to measure malondialdehyde (MDA) levels, hematoxylin and eosin staining (H&E) to evaluate neuronal degeneration were used. Immunohistochemical (IHC), Western blot (WB), and real-time polymerase chain reaction (PCR) methods were used to evaluate the inhibitory effect of TMQ on a receptor for advanced glycation end products (RAGE)/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) signaling in AD. The results showed that TMQ may have ameliorative effects on memory, spatial learning, learning ability, and anxiety in AD. We showed that TMQ has an antioxidative effect by decreasing MDA levels by the ELSIA method (p < 0.05). There was a marked increase in neuronal degeneration in AD mice compared to other groups (p < 0.05). We concluded that TMQ could ameliorate neuronal degeneration in AD by H&E staining and suppress RAGE/NOX4 signaling by IHC and WB analysis. We concluded that TMQ could be therapeutic in AD by reducing AB expression level by IHC analysis (p < 0.05). Real-time PCR analysis showed that APP (p < 0.05), RAGE, and NOX4 (p < 0.05) gene expressions could be reduced by TMQ. In conclusion, TMQ has a high therapeutic potential in AD and an effective preventive and therapeutic strategy can be developed with more comprehensive studies on TMQ. Full article
(This article belongs to the Special Issue Molecular and Genetic Basis of Neurodegenerative Diseases)
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14 pages, 3899 KiB  
Article
The Inhibition of Bromodomain and Extraterminal Domain (BET) Proteins Protects Against Microglia-Mediated Neuronal Loss In Vitro
by Marta Matuszewska, Anna Wilkaniec, Magdalena Cieślik, Marcin Strawski and Grzegorz A. Czapski
Biomolecules 2025, 15(4), 528; https://doi.org/10.3390/biom15040528 - 4 Apr 2025
Viewed by 294
Abstract
Neuroinflammation is a key feature of all neurodegenerative disorders, including Alzheimer’s disease, and is tightly regulated by epigenetic mechanisms. Among them, bromodomain and extraterminal domain (BET) proteins play a crucial role by recognizing acetylated histones and acting as transcriptional co-regulators to modulate gene [...] Read more.
Neuroinflammation is a key feature of all neurodegenerative disorders, including Alzheimer’s disease, and is tightly regulated by epigenetic mechanisms. Among them, bromodomain and extraterminal domain (BET) proteins play a crucial role by recognizing acetylated histones and acting as transcriptional co-regulators to modulate gene expression. This study investigates the potential of inhibiting BET proteins in preventing microglia-mediated neuronal damage in vitro. Murine BV2 microglial cells were exposed to lipopolysaccharide (LPS) or amyloid-β (Aβ) to induce an inflammatory response, and the subsequent effects on murine HT22 neuronal cells were examined. Among the BET proteins tested, only Brd4 was significantly upregulated in BV2 cells upon pro-inflammatory stimulation. JQ1, a potent pan-inhibitor of BET proteins, suppressed LPS-induced upregulation of pro-inflammatory cytokine mRNA levels, including Il1b, Il6, and Tnf, in BV2 microglia. Pre-treatment with JQ1 attenuated the cytotoxicity of LPS-activated BV2 cells toward neurons. Additionally, conditioned media from Aβ fibril-stimulated BV2 cells induced neuronal cell death, which was partially prevented by pre-treatment with JQ1. Co-culture assays further demonstrated the beneficial effect of BET inhibition. Our findings suggest that targeting BET proteins may offer a neuroprotective strategy by modulating microglial activation, potentially providing therapeutic benefits in neurodegenerative diseases. Full article
(This article belongs to the Special Issue Molecular and Genetic Basis of Neurodegenerative Diseases)
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22 pages, 4605 KiB  
Article
Adverse Effects of Aβ1-42 Oligomers: Impaired Contextual Memory and Altered Intrinsic Properties of CA1 Pyramidal Neurons
by Min-Kaung-Wint-Mon, Hiroyuki Kida, Itsuki Kanehisa, Masahiko Kurose, Junko Ishikawa, Yuya Sakimoto, Paw-Min-Thein-Oo, Ryoichi Kimura and Dai Mitsushima
Biomolecules 2024, 14(11), 1425; https://doi.org/10.3390/biom14111425 - 8 Nov 2024
Viewed by 1354
Abstract
1-42 (amyloid beta) oligomers, the major neurotoxic culprits in Alzheimer’s disease, initiate early pathophysiological events, including neuronal hyperactivity, that underlie aberrant network activity and cognitive impairment. Although several synaptotoxic effects have been extensively studied, neuronal hyperexcitability, which may also contribute to cognitive [...] Read more.
1-42 (amyloid beta) oligomers, the major neurotoxic culprits in Alzheimer’s disease, initiate early pathophysiological events, including neuronal hyperactivity, that underlie aberrant network activity and cognitive impairment. Although several synaptotoxic effects have been extensively studied, neuronal hyperexcitability, which may also contribute to cognitive deficits, is not fully understood. Here, we found several adverse effects of in vivo injection of Aβ1-42 oligomers on contextual memory and intrinsic properties of CA1 pyramidal neurons. Male rats underwent behavioral and electrophysiological studies 1 week after microinjections into the dorsal CA1 region, followed by histological analysis. After 1 week, Aβ1-42 oligomers impaired contextual learning without affecting basic physiological functions and triggered training-induced neuronal excitability. Furthermore, riluzole, a persistent sodium current (INaP) blocker, dose-dependently reduced Aβ1-42 oligomer-induced hyperexcitability. Congo red staining, which detects insoluble amyloid deposits, further identified labeling of CA1 pyramidal neurons while immunohistochemistry with lecanemab, which detects soluble Aβ oligomers, revealed immunoreactivity of both pyramidal and non-pyramidal cells in the target area. Therefore, our study suggests that a single injection of Aβ1-42 oligomers resulted in contextual memory deficits along with concomitant neuronal hyperexcitability and amyloid deposition in the CA1 region after 1 week. Full article
(This article belongs to the Special Issue Molecular and Genetic Basis of Neurodegenerative Diseases)
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Review

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16 pages, 586 KiB  
Review
Iatrogenic Dementia: Providing Insight into Transmissible Subtype of Alzheimer’s Disease, Creutzfeldt–Jakob Disease and Cerebral Amyloid Angiopathy
by Stella Karatzetzou, Serafeim Ioannidis, Eleni Konstantinopoulou, Dimitrios Parisis, Theodora Afrantou and Panagiotis Ioannidis
Biomolecules 2025, 15(4), 522; https://doi.org/10.3390/biom15040522 - 3 Apr 2025
Viewed by 391
Abstract
Within the phenotypic spectrum of Alzheimer’s disease (AD), Creutzfeldt–Jakob disease (CJD) and cerebral amyloid angiopathy (CAA), dementia that is attributed to iatrogenic transmission has increasingly gained scientific attention recently. Newly recognized, this treatment-induced form of dementia may result from exposure to certain medical [...] Read more.
Within the phenotypic spectrum of Alzheimer’s disease (AD), Creutzfeldt–Jakob disease (CJD) and cerebral amyloid angiopathy (CAA), dementia that is attributed to iatrogenic transmission has increasingly gained scientific attention recently. Newly recognized, this treatment-induced form of dementia may result from exposure to certain medical or surgical procedures. The present review aims to explore the distinct features of acquired dementia encompassing a history of potential exposure and relatively early age of onset, highlighting transmission potential with a rather prion-like pattern. Having reviewed all available relevant literature, dementia of iatrogenic etiology represents a new disease entity that requires an individualized investigation process and poses a great clinical challenge as far as patients with AD, CJD and CAA are concerned. Understanding the underlying pathophysiology of these rare forms of dementia may significantly enhance awareness within clinical field of neurodegenerative diseases and facilitate their prompt management. Full article
(This article belongs to the Special Issue Molecular and Genetic Basis of Neurodegenerative Diseases)
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