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Neurodegenerative Diseases: From Molecular Mechanisms to Pathophysiology

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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 December 2024) | Viewed by 12073

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Dr. Anne Vejux

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Equipe 5, Neurobiologie des Comportements Alimentaires/Neurobiology of Feeding Behaviours 9E, Boulevard Jeanne d'Arc, 21000 Dijon, France
Interests: oxysterols; very-long-chain fatty acids; lipid metabolism; diet; peroxisomes; biotherapies; inflammation; cancer; cell cycle and apoptosis; autophagy; biological membranes; oxidative damage; biomarkers; neurodegenerative diseases
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Dear Colleagues,

Neurodegenerative diseases are defined as the progressive degeneration or death of neurons in the central or peripheral nervous system. Genetic, environmental, and lifestyle factors all contribute to the development of neurodegenerative diseases. Most neurodegenerative diseases remain incurable despite treatment and slowing of progression.

Common processes contributing to neuronal degeneration exist, but the molecular mechanisms of neurodegenerative diseases remain complex and varied. Neurodegenerative processes and neuronal disorders can also occur peripherally, outside the brain, for example, in the spinal cord, retina, and enteric nervous system. These phenomes can either reflect and/or affect what is happening in the brain. The consequences of these conditions are often characterized by progressive decline and abnormalities in perceptual, cognitive, motor, behavioral, and social abilities.

Neurodegenerative diseases are a major threat to public health. These diseases generally occur in the elderly. However, longer life expectancy and lower fertility rates are leading to an increase in the prevalence of these disorders in middle age and a worsening health and economic burden for society.

We, therefore, need to know as much as possible about the molecular mechanisms involved in these diseases, both common and specific to each pathology. A better understanding of the functioning of the blood–brain barrier and its specific features is also important in the search for new drugs. In short, we need to know more about the pathophysiology of these neurodegenerative diseases.

Dr. Anne Vejux
Guest Editor

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Keywords

neurodegenerative diseases
molecular mechanisms
physiology
cell death
autophagy
oxidative stress
inflammation
genetic factors
diet
cognitive functions
exosomes
blood–brain barrier
immunity

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Related Special Issue

Neurodegenerative Diseases: From Molecular Mechanisms to Pathophysiology (Second Edition) in International Journal of Molecular Sciences

Published Papers (8 papers)

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Research

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16 pages, 2890 KiB

Open AccessArticle

Sex Differences in a Novel Mouse Model of Spinocerebellar Ataxia Type 1 (SCA1)

by Adem Selimovic, Kaelin Sbrocco, Gourango Talukdar, Adri McCall, Stephen Gilliat, Ying Zhang and Marija Cvetanovic

Int. J. Mol. Sci. 2025, 26(6), 2623; https://doi.org/10.3390/ijms26062623 - 14 Mar 2025

Viewed by 679

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant inherited neurodegenerative disease caused by the expansion of glutamine (Q)-encoding CAG repeats in the gene ATAXIN1 (ATXN1). Patients with SCA1 suffer from movement and cognitive deficits and severe cerebellar pathology. Previous studies identified sex differences in disease progression in SCA1 patients, but whether these differences are present in mouse models is unclear. Using a battery of behavioral tests, immunohistochemistry of brain slices, and RNA sequencing, we examined sex differences in motor and cognitive performance, cerebellar pathology, and cerebellar gene expression changes in a recently created conditional knock-in mouse model f-ATXN1^146Q expressing human coding regions of ATXN1 with 146 CAG repeats. We found worse motor performance and weight loss accompanied by increased microglial activation and an increase in immune viral response pathways in male f-ATXN1^146Q mice. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Mechanisms to Pathophysiology)

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22 pages, 4439 KiB

Open AccessArticle

Artificial Intelligence-Assisted Comparative Analysis of the Overlapping Molecular Pathophysiology of Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia

by Zihan Wei, Meghna R. Iyer, Benjamin Zhao, Jennifer Deng and Cassie S. Mitchell

Int. J. Mol. Sci. 2024, 25(24), 13450; https://doi.org/10.3390/ijms252413450 - 15 Dec 2024

Viewed by 1537

Abstract

The overlapping molecular pathophysiology of Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD) was analyzed using relationships from a knowledge graph of 33+ million biomedical journal articles. The unsupervised learning rank aggregation algorithm from SemNet 2.0 compared the most important amino acid, peptide, and protein (AAPP) nodes connected to AD, ALS, or FTD. FTD shared 99.9% of its nodes with ALS and AD; AD shared 64.2% of its nodes with FTD and ALS; and ALS shared 68.3% of its nodes with AD and FTD. The results were validated and mapped to functional biological processes using supervised human supervision and an external large language model. The overall percentages of mapped intersecting biological processes were as follows: inflammation and immune response, 19%; synapse and neurotransmission, 19%; cell cycle, 15%; protein aggregation, 12%; membrane regulation, 11%; stress response and regulation, 9%; and gene regulation, 4%. Once normalized for node count, biological mappings for cell cycle regulation and stress response were more prominent in the intersection of AD and FTD. Protein aggregation, gene regulation, and energetics were more prominent in the intersection of ALS and FTD. Synapse and neurotransmission, membrane regulation, and inflammation and immune response were greater at the intersection of AD and ALS. Given the extensive molecular pathophysiology overlap, small differences in regulation, genetic, or environmental factors likely shape the underlying expressed disease phenotype. The results help prioritize testable hypotheses for future clinical or experimental research. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Mechanisms to Pathophysiology)

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18 pages, 2815 KiB

Open AccessArticle

Melatonin Attenuates Ferritinophagy/Ferroptosis by Acting on Autophagy in the Liver of an Autistic Mouse Model BTBR T⁺Itpr3^tf/J

by Giorgia Cominelli, Claudio Lonati, Daniela Pinto, Fabio Rinaldi, Caterina Franco, Gaia Favero and Rita Rezzani

Int. J. Mol. Sci. 2024, 25(23), 12598; https://doi.org/10.3390/ijms252312598 - 23 Nov 2024

Viewed by 1141

Abstract

Autism spectrum disorders (ASDs) are a pool of neurodevelopment disorders in which social impairment is the main symptom. Presently, there are no definitive medications to cure the symptoms but the therapeutic strategies that are taken ameliorate them. The purpose of this study was to investigate the effects of melatonin (MLT) in treating ASDs using an autistic mouse model BTBR T⁺Itpr3^tf/J (BTBR). We evaluated the hepatic cytoarchitecture and some markers of autophagy, ferritinophagy/ferroptosis, in BTBR mice treated and not-treated with MLT. The hepatic morphology and the autophagy and ferritinophagy/ferroptosis pathways were analyzed by histological, immunohistochemical, and Western blotting techniques. We studied p62 and microtubule-associated protein 1 light chain 3 B (LC3B) for evaluating the autophagy; nuclear receptor co-activator 4 (NCOA4) and long-chain-coenzyme synthase (ACSL4) for monitoring ferritinophagy/ferroptosis. The liver of BTBR mice revealed that the hepatocytes showed many cytoplasmic inclusions recognized as Mallory–Denk bodies (MDBs); the expression and levels of p62 and LC3B were downregulated, whereas ACSL4 and NCOA4 were upregulated, as compared to control animals. MLT administration to BTBR mice ameliorated liver damage and reduced the impairment of autophagy and ferritinophagy/ferroptosis. In conclusion, we observed that MLT alleviates liver damage in BTBR mice by improving the degradation of intracellular MDBs, promoting autophagy, and suppressing ferritinophagy/ferroptosis. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Mechanisms to Pathophysiology)

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11 pages, 3493 KiB

Open AccessArticle

Biophysical Studies of Amyloid-Binding Fluorophores to Tau AD Core Fibrils Formed without Cofactors

by Daniela P. Freitas, Joana Saavedra, Isabel Cardoso and Cláudio M. Gomes

Int. J. Mol. Sci. 2024, 25(18), 9946; https://doi.org/10.3390/ijms25189946 - 15 Sep 2024

Viewed by 1532

Abstract

Tau is an intrinsically disordered protein involved in several neurodegenerative diseases where a common hallmark is the appearance of tau aggregates in the brain. One common approach to elucidate the mechanisms behind the aggregation of tau has been to recapitulate in vitro the self-assembly process in a fast and reproducible manner. While the seeding of tau aggregation is prompted by negatively charged cofactors, the obtained fibrils are morphologically distinct from those found in vivo. The Tau AD core fragment (TADC, tau 306–378) has emerged as a new model and potential solution for the cofactor-free in vitro aggregation of tau. Here, we use TADC to further study this process combining multiple amyloid-detecting fluorophores and fibril bioimaging. We confirmed by transmission electron microscopy that this fragment forms fibrils after quiescent incubation at 37 °C. We then employed a panel of eight amyloid-binding fluorophores to query the formed species by acquiring their emission spectra. The results obtained showed that nearly all dyes detect TADC self-assembled species. However, the successful monitoring of TADC aggregation kinetics was limited to three fluorophores (X-34, Bis-ANS, and pFTAA) which yielded sigmoidal curves but different aggregation half-times, hinting to different species being detected. Altogether, this study highlights the potential of using multiple extrinsic fluorescent probes, alone or in combination, as tools to further clarify mechanisms behind the aggregation of amyloidogenic proteins. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Mechanisms to Pathophysiology)

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Review

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15 pages, 1268 KiB

Open AccessReview

The Role and Mechanisms of the Hypocretin System in Zebrafish (Danio rerio)

by Vyacheslav Dyachuk

Int. J. Mol. Sci. 2025, 26(1), 256; https://doi.org/10.3390/ijms26010256 - 30 Dec 2024

Cited by 1 | Viewed by 1126

Abstract

Sleep is the most important physiological function of all animals studied to date. Sleep disorders include narcolepsy, which is characterized by excessive daytime sleepiness, disruption of night sleep, and muscle weakness—cataplexy. Narcolepsy is known to be caused by the degeneration of orexin-synthesizing neurons (hypocretin (HCRT) neurons or orexin neurons) in the hypothalamus. In mammals, HCRT neurons primarily regulate the sleep/wake cycle, nutrition, reward seeking, and addiction development. The hypocretin system of the brain is involved in a number of neurological disorders. The distinctive pathologies associated with the disruption of HCRT neurons are narcolepsy and cataplexy, which are caused by the loss of hypocretin neurons that produce HCRT. In Danio, the hypocretin system is also involved in the regulation of sleep and wakefulness. It is represented by a single hcrt gene that encodes the peptides HCRT1 and HCRT2, as well as one HCRT receptor (HCRTR), which is structurally closest to the mammalian HCRTR2. The overexpression of the hcrt gene in Danio rerio larvae causes wakefulness, whereas the physical destruction of HCRT cells or a pharmacological blockade of the type 2 hypocretin receptor leads to fragmentation of sleep in fish larvae, which is also observed in patients with narcolepsy. These data confirm the evolutionary conservatism of the hypocretin system. Thus, Danio rerio is an ideal model for studying the functions of HCRT neural networks and their functions. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Mechanisms to Pathophysiology)

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14 pages, 710 KiB

Open AccessReview

A Role of Inflammation in Charcot–Marie–Tooth Disorders—In a Perspective of Treatment?

by Joanna Kamińska and Andrzej Kochański

Int. J. Mol. Sci. 2025, 26(1), 15; https://doi.org/10.3390/ijms26010015 - 24 Dec 2024

Cited by 1 | Viewed by 960

Abstract

Despite the fact that there are published case reports and model work providing evidence of inflammation in Charcot–Marie–Tooth disorders (CMTs), in clinical practice, CMT and inflammatory neuropathies are always classified as two separate groups of disorders. This sharp separation of chronic neuropathies into two groups has serious clinical implications. As a consequence, the patients harboring CMT mutations are practically excluded from pharmacological anti-inflammatory treatments. In this review, we present that neuropathological studies of peripheral nerves taken from some patients representing familial aggregation of CMTs revealed the presence of inflammation within the nerves. This shows that neurodegeneration resulting from germline mutations and the inflammatory process are not mutually exclusive. We also point to reports demonstrating that, at the clinical level, a positive response to anti-inflammatory therapy was observed in some patients diagnosed with CMTs, confirming the role of the inflammatory component in CMT. We narrowed a group of more than 100 genes whose mutations were found in CMT-affected patients to the seven most common (MPZ, PMP22, GJB1, SEPT9, LITAF, FIG4, and GDAP1) as being linked to the coexistence of hereditary and inflammatory neuropathy. We listed studies of mouse models supporting the idea of the presence of an inflammatory process in some CMTs and studies demonstrating at the cellular level the presence of an inflammatory response. In the following, we discuss the possible molecular basis of some neuropathies involving neurodegenerative and inflammatory processes at both the clinical and morphological levels. Finally, we discuss the prospect of a therapeutic approach using immunomodulation in some patients affected by CMTs. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Mechanisms to Pathophysiology)

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20 pages, 1496 KiB

Open AccessReview

Gene Therapy for Parkinson’s Disease Using Midbrain Developmental Genes to Regulate Dopaminergic Neuronal Maintenance

by Jintae Kim and Mi-Yoon Chang

Int. J. Mol. Sci. 2024, 25(22), 12369; https://doi.org/10.3390/ijms252212369 - 18 Nov 2024

Cited by 2 | Viewed by 2703

Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. It is characterized by the progressive loss of dopaminergic (DAnergic) neurons in the substantia nigra and decreased dopamine (DA) levels, which lead to both motor and non-motor symptoms. Conventional PD treatments aim to alleviate symptoms, but do not delay disease progression. PD gene therapy offers a promising approach to improving current treatments, with the potential to alleviate significant PD symptoms and cause fewer adverse effects than conventional therapies. DA replacement approaches and DA enzyme expression do not slow disease progression. However, DA replacement gene therapies, such as adeno-associated virus (AAV)–glutamic acid decarboxylase (GAD) and L-amino acid decarboxylase (AADC) gene therapies, which increase DA transmitter levels, have been demonstrated to be safe and efficient in early-phase clinical trials. Disease-modifying strategies, which aim to slow disease progression, appear to be potent. These include therapies targeting downstream pathways, neurotrophic factors, and midbrain DAnergic neuronal factors, all of which have shown potential in preclinical and clinical trials. These approaches focus on maintaining the integrity of DAnergic neurons, not just targeting the DA transmitter level itself. In particular, critical midbrain developmental and maintenance factors, such as Nurr1 and Foxa2, can interact synergistically with neighboring glia, in a paracrine mode of action, to protect DAnergic neurons against various toxic factors. Similar outcomes could be achieved by targeting both DAnergic neurons and glial cells with other candidate gene therapies, but in-depth research is needed. Neurotrophic factors, such as neurturin, the glial-cell-line-derived neurotrophic factor (GDNF), the brain-derived neurotrophic factor (BDNF), and the vascular endothelial growth factor (VEGF), are also being investigated for their potential to support DAnergic neuron survival. Additionally, gene therapies targeting key downstream pathways, such as the autophagy–lysosome pathway, mitochondrial function, and endoplasmic reticulum (ER) stress, offer promising avenues. Gene editing and delivery techniques continue to evolve, presenting new opportunities to develop effective gene therapies for PD. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Mechanisms to Pathophysiology)

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16 pages, 331 KiB

Open AccessReview

In Search of Spinal Muscular Atrophy Disease Modifiers

by Daria Chudakova, Ludmila Kuzenkova, Andrey Fisenko and Kirill Savostyanov

Int. J. Mol. Sci. 2024, 25(20), 11210; https://doi.org/10.3390/ijms252011210 - 18 Oct 2024

Viewed by 1704

Abstract

The 5q Spinal Muscular Atrophy (SMA) is a hereditary autosomal recessive disease caused by defects in the survival motor neuron (SMN1) gene encoding survival motor neuron (SMN) protein. Currently, it is the leading cause of infantile mortality worldwide. SMA is a progressive neurodegenerative disease with “continuum of clinical severity”, which can be modulated by genetic and epigenetic factors known as disease modifiers (DMs). Individuals (even siblings) with the same defects in SMN1 gene might have strikingly different types of SMA, supposedly due to the impact of DMs. There are several therapeutic options for SMA, all of them focusing on the restoration of the SMN protein levels to normal. Determining DMs and the pathways in which they are involved might aid in enhancing existing curative approaches. Furthermore, DMs might become novel therapeutic targets or prognostic biomarkers of the disease. This narrative review provides a brief overview of the genetics and pathobiology of SMA, and its bona fide modifiers. We describe novel, emerging DMs, approaches and tools used to identify them, as well as their potential mechanisms of action and impact on disease severity. We also propose several disease-modifying molecular mechanisms which could provide a partial explanation of the staggering variability of SMA phenotypes. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Mechanisms to Pathophysiology)

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