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The Molecular and Cellular Mechanisms of Neurodegenerative Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 27312

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Special Issue Editor

Dr. Hongjun (Harry) Fu

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Guest Editor

Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Interests: Alzheimer’s disease; frontotemporal lobar degeneration; traumatic brain injury
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases are a group of age-related complex diseases in the central nervous system including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and prion diseases. They are characterized by protein aggregates in particular cell types and brain regions, selective neuronal loss, neuroinflammation, progressive degeneration of the nervous system, and neurobehavior changes. Over the last decade, our understanding of neurodegenerative dieases has witnessed significant advances, especially at the molecular and cellular levels, although there are no effective therapeutics to prevent or halt these devastating diseases to date.

The goal of this Special Issue is to gain a better understanding of the cellular and molecular mechanisms in the pathogenesis of different neurodegenerative disorders, with a focus on protein homeostasis, unfolded protein response, synpatic dysfunction, neuroinflammation, alterations in brain metabolism, mitochondrial dysfunction, and oxidative stress mechanisms at the molecular and cellular levels.

We would like to invite you to submit original research articles and reviews that focus on, but are not limited to, innovative and important findings that provide a comprehensive view of the molecular mechanisms underlying the pathogenesis of neurodegenerative diseases. Studies involving transcriptomic, proteomic, and metabolomic approaches are encouraged.

Dr. Hongjun (Harry) Fu
Guest Editor

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 100 words) can be sent to the Editorial Office for announcement on this website.

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
Alzheimer’s disease (AD)
Parkinson’s disease (PD)
frontotemporal lobar degeneration (FTLD)
amyotrophic lateral sclerosis (ALS)
Huntington’s disease (HD)
prion diseases
cellular and molecular mechanisms
omics

Published Papers (10 papers)

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Research

Jump to: Review

9 pages, 2908 KiB

Open AccessCommunication

Increase in hnRNPA1 Expression Suffices to Kill Motor Neurons in Transgenic Rats

by Bo Huang, Xionghao Liu, Tingting Zhang, Qinxue Wu, Cao Huang, Xu-Gang Xia and Hongxia Zhou

Int. J. Mol. Sci. 2023, 24(22), 16214; https://doi.org/10.3390/ijms242216214 - 11 Nov 2023

Viewed by 720

Abstract

A dominant mutation in hnRNPA1 causes amyotrophic lateral sclerosis (ALS), but it is not known whether this mutation leads to motor neuron death through increased or decreased function. To elucidate the relationship between pathogenic hnRNPA1 mutation and its native function, we created novel transgenic rats that overexpressed wildtype rat hnRNPA1 exclusively in motor neurons. This targeted expression of wildtype hnRNPA1 caused severe motor neuron loss and subsequent denervation muscle atrophy in transgenic rats that recapitulated the characteristics of ALS. These findings demonstrate that the augmentation of hnRNPA1 expression suffices to trigger motor neuron degeneration and the manifestation of ALS-like phenotypes. It is reasonable to infer that an amplification of an as-yet undetermined hnRNPA1 function plays a pivotal role in the pathogenesis of familial ALS caused by pathogenic hnRNPA1 mutation. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Neurodegenerative Diseases)

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14 pages, 1518 KiB

Open AccessArticle

The Association of Selected GWAS Reported AD Risk Loci with CSF Biomarker Levels and Cognitive Decline in Slovenian Patients

by David Vogrinc, Milica Gregorič Kramberger, Andreja Emeršič, Saša Čučnik, Katja Goričar and Vita Dolžan

Int. J. Mol. Sci. 2023, 24(16), 12966; https://doi.org/10.3390/ijms241612966 - 19 Aug 2023

Viewed by 1033

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease, with a complex genetic background. Apart from rare, familial cases, a combination of multiple risk loci contributes to the susceptibility of the disease. Genome-wide association studies (GWAS) have identified numerous AD risk loci. Changes in cerebrospinal fluid (CSF) biomarkers and imaging techniques can detect AD-related brain changes before the onset of clinical symptoms, even in the presence of preclinical mild cognitive impairment. In this study, we aimed to assess the associations between SNPs in well-established GWAS AD risk loci and CSF biomarker levels or cognitive test results in Slovenian patients with cognitive decline. The study included 82 AD patients, 28 MCI patients with pathological CSF biomarker levels and 35 MCI patients with normal CSF biomarker levels. Carriers of at least one polymorphic TOMM40 rs157581 C allele had lower Aβ₄₂ (p = 0.033) and higher total tau (p = 0.032) and p-tau₁₈₁ levels (p = 0.034). Carriers of at least one polymorphic T allele in SORCS1 rs1358030 had lower total tau (p = 0.019), while polymorphic SORCS1 rs1416406 allele was associated with lower total tau (p = 0.013) and p-tau₁₈₁ (p = 0.036). In addition, carriers of at least one polymorphic T allele in BCHE rs1803274 had lower cognitive test scores (p = 0.029). The study findings may contribute to the identification of genetic markers associated with AD and MCI and provide insights into early disease diagnostics. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Neurodegenerative Diseases)

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16 pages, 3110 KiB

Open AccessArticle

MiR-146a in ALS: Contribution to Early Peripheral Nerve Degeneration and Relevance as Disease Biomarker

by Eleonora Giagnorio, Claudia Malacarne, Paola Cavalcante, Letizia Scandiffio, Marco Cattaneo, Viviana Pensato, Cinzia Gellera, Nilo Riva, Angelo Quattrini, Eleonora Dalla Bella, Giuseppe Lauria, Renato Mantegazza, Silvia Bonanno and Stefania Marcuzzo

Int. J. Mol. Sci. 2023, 24(5), 4610; https://doi.org/10.3390/ijms24054610 - 27 Feb 2023

Viewed by 1695

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive, irreversible loss of upper and lower motor neurons (UMNs, LMNs). MN axonal dysfunctions are emerging as relevant pathogenic events since the early ALS stages. However, the exact molecular mechanisms leading to MN axon degeneration in ALS still need to be clarified. MicroRNA (miRNA) dysregulation plays a critical role in the pathogenesis of neuromuscular diseases. These molecules represent promising biomarkers for these conditions since their expression in body fluids consistently reflects distinct pathophysiological states. Mir-146a has been reported to modulate the expression of the NFL gene, encoding the light chain of the neurofilament (NFL) protein, a recognized biomarker for ALS. Here, we analyzed miR-146a and Nfl expression in the sciatic nerve of G93A-SOD1 ALS mice during disease progression. The miRNA was also analyzed in the serum of affected mice and human patients, the last stratified relying on the predominant UMN or LMN clinical signs. We revealed a significant miR-146a increase and Nfl expression decrease in G93A-SOD1 peripheral nerve. In the serum of both ALS mice and human patients, the miRNA levels were reduced, discriminating UMN-predominant patients from the LMN ones. Our findings suggest a miR-146a contribution to peripheral axon impairment and its potential role as a diagnostic and prognostic biomarker for ALS. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Neurodegenerative Diseases)

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18 pages, 598 KiB

Open AccessArticle

Proteomic Signature and mRNA Expression in Hippocampus of SAMP8 and SAMR1 Mice during Aging

by Marcella Reale, Erica Costantini, Lisa Aielli, Fabrizio Di Giuseppe, Stefania Angelucci, Mohammad A. Kamal and Nigel H. Greig

Int. J. Mol. Sci. 2022, 23(23), 15097; https://doi.org/10.3390/ijms232315097 - 1 Dec 2022

Cited by 5 | Viewed by 1894

Abstract

Aging is a complex process often accompanied by cognitive decline that represents a risk factor for many neurodegenerative disorders including Alzheimer’s and Parkinson’s disease. The molecular mechanisms involved in age-related cognitive decline are not yet fully understood, although increased neuroinflammation is considered to play a significant role. In this study, we characterized a proteomic view of the hippocampus of the senescence-accelerated mouse prone-8 (SAMP8), a model of enhanced senescence, in comparison with the senescence-accelerated-resistant mouse (SAMR1), a model of normal aging. We additionally investigated inflammatory cytokines and cholinergic components gene expression during aging in the mouse brain tissues. Proteomic data defined the expression of key proteins involved in metabolic and cellular processes in neuronal and glial cells of the hippocampus. Gene Ontology revealed that most of the differentially expressed proteins are involved in the cytoskeleton and cell motility regulation. Molecular analysis results showed that both inflammatory cytokines and cholinergic components are differentially expressed during aging, with a downward trend of cholinergic receptors and esterase enzymes expression, in contrast to an upward trend of inflammatory cytokines in the hippocampus of SAMP8. Together, our results support the important role of the cholinergic and cytokine systems in the aging of the murine brain. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Neurodegenerative Diseases)

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15 pages, 7629 KiB

Open AccessArticle

Neuropathology of the Basal Ganglia in SNCA Transgenic Rat Model of Parkinson’s Disease: Involvement of Parvalbuminergic Interneurons and Glial-Derived Neurotropic Factor

by Emanuela Paldino, Vincenza D’angelo, Mariangela Massaro Cenere, Ezia Guatteo, Simone Barattucci, Giorgia Migliorato, Nicola Berretta, Olaf Riess, Giuseppe Sancesario, Nicola Biagio Mercuri and Francesca Romana Fusco

Int. J. Mol. Sci. 2022, 23(17), 10126; https://doi.org/10.3390/ijms231710126 - 4 Sep 2022

Cited by 5 | Viewed by 2146

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein, encoded by the SNCA gene. The main neuropathological hallmark of PD is the degeneration of dopaminergic neurons leading to striatal dopamine depletion. Trophic support by a neurotrophin called glial-derived neurotrophic factor (GDNF) is also lacking in PD. We performed immunohistochemical studies to investigate neuropathological changes in the basal ganglia of a rat transgenic model of PD overexpressing alfa-synuclein. We observed that neuronal loss also occurs in the dorsolateral part of the striatum in the advanced stages of the disease. Moreover, along with the degeneration of the medium spiny projection neurons, we found a dramatic loss of parvalbumin interneurons. A marked decrease in GDNF, which is produced by parvalbumin interneurons, was observed in the striatum and in the substantia nigra of these animals. This confirmed the involvement of the striatum in the pathophysiology of PD and the importance of GDNF in maintaining the health of the substantia nigra. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Neurodegenerative Diseases)

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Review

Jump to: Research

36 pages, 1713 KiB

Open AccessReview

Decoding Neurodegeneration: A Comprehensive Review of Molecular Mechanisms, Genetic Influences, and Therapeutic Innovations

by Victor Voicu, Calin Petre Tataru, Corneliu Toader, Razvan-Adrian Covache-Busuioc, Luca Andrei Glavan, Bogdan-Gabriel Bratu, Horia Petre Costin, Antonio Daniel Corlatescu and Alexandru Vlad Ciurea

Int. J. Mol. Sci. 2023, 24(16), 13006; https://doi.org/10.3390/ijms241613006 - 21 Aug 2023

Cited by 1 | Viewed by 2149

Abstract

Neurodegenerative disorders often acquire due to genetic predispositions and genomic alterations after exposure to multiple risk factors. The most commonly found pathologies are variations of dementia, such as frontotemporal dementia and Lewy body dementia, as well as rare subtypes of cerebral and cerebellar atrophy-based syndromes. In an emerging era of biomedical advances, molecular–cellular studies offer an essential avenue for a thorough recognition of the underlying mechanisms and their possible implications in the patient’s symptomatology. This comprehensive review is focused on deciphering molecular mechanisms and the implications regarding those pathologies’ clinical advancement and provides an analytical overview of genetic mutations in the case of neurodegenerative disorders. With the help of well-developed modern genetic investigations, these clinically complex disturbances are highly understood nowadays, being an important step in establishing molecularly targeted therapies and implementing those approaches in the physician’s practice. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Neurodegenerative Diseases)

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16 pages, 698 KiB

Open AccessReview

Iron and Ferroptosis More than a Suspect: Beyond the Most Common Mechanisms of Neurodegeneration for New Therapeutic Approaches to Cognitive Decline and Dementia

by Michele Cerasuolo, Irene Di Meo, Maria Chiara Auriemma, Francesca Trojsi, Maria Ida Maiorino, Mario Cirillo, Fabrizio Esposito, Rita Polito, Anna Maria Colangelo, Giuseppe Paolisso, Michele Papa and Maria Rosaria Rizzo

Int. J. Mol. Sci. 2023, 24(11), 9637; https://doi.org/10.3390/ijms24119637 - 1 Jun 2023

Cited by 7 | Viewed by 2961

Abstract

Neurodegeneration is a multifactorial process that involves multiple mechanisms. Examples of neurodegenerative diseases are Parkinson’s disease, multiple sclerosis, Alzheimer’s disease, prion diseases such as Creutzfeldt–Jakob’s disease, and amyotrophic lateral sclerosis. These are progressive and irreversible pathologies, characterized by neuron vulnerability, loss of structure or function of neurons, and even neuron demise in the brain, leading to clinical, functional, and cognitive dysfunction and movement disorders. However, iron overload can cause neurodegeneration. Dysregulation of iron metabolism associated with cellular damage and oxidative stress is reported as a common event in several neurodegenerative diseases. Uncontrolled oxidation of membrane fatty acids triggers a programmed cell death involving iron, ROS, and ferroptosis, promoting cell death. In Alzheimer’s disease, the iron content in the brain is significantly increased in vulnerable regions, resulting in a lack of antioxidant defenses and mitochondrial alterations. Iron interacts with glucose metabolism reciprocally. Overall, iron metabolism and accumulation and ferroptosis play a significant role, particularly in the context of diabetes-induced cognitive decline. Iron chelators improve cognitive performance, meaning that brain iron metabolism control reduces neuronal ferroptosis, promising a novel therapeutic approach to cognitive impairment. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Neurodegenerative Diseases)

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49 pages, 2361 KiB

Open AccessReview

Recent Development in the Understanding of Molecular and Cellular Mechanisms Underlying the Etiopathogenesis of Alzheimer’s Disease

by Atefeh Afsar, Maria del Carmen Chacon Castro, Adedamola Saidi Soladogun and Li Zhang

Int. J. Mol. Sci. 2023, 24(8), 7258; https://doi.org/10.3390/ijms24087258 - 14 Apr 2023

Cited by 8 | Viewed by 3460

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to dementia and patient death. AD is characterized by intracellular neurofibrillary tangles, extracellular amyloid beta (Aβ) plaque deposition, and neurodegeneration. Diverse alterations have been associated with AD progression, including genetic mutations, neuroinflammation, blood–brain barrier (BBB) impairment, mitochondrial dysfunction, oxidative stress, and metal ion imbalance.Additionally, recent studies have shown an association between altered heme metabolism and AD. Unfortunately, decades of research and drug development have not produced any effective treatments for AD. Therefore, understanding the cellular and molecular mechanisms underlying AD pathology and identifying potential therapeutic targets are crucial for AD drug development. This review discusses the most common alterations associated with AD and promising therapeutic targets for AD drug discovery. Furthermore, it highlights the role of heme in AD development and summarizes mathematical models of AD, including a stochastic mathematical model of AD and mathematical models of the effect of Aβ on AD. We also summarize the potential treatment strategies that these models can offer in clinical trials. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Neurodegenerative Diseases)

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12 pages, 2493 KiB

Open AccessReview

Understanding the Molecular Progression of Chronic Traumatic Encephalopathy in Traumatic Brain Injury, Aging and Neurodegenerative Disease

by FNU Ruchika, Siddharth Shah, Durga Neupane, Ruddra Vijay, Yusuf Mehkri and Brandon Lucke-Wold

Int. J. Mol. Sci. 2023, 24(3), 1847; https://doi.org/10.3390/ijms24031847 - 17 Jan 2023

Cited by 7 | Viewed by 4431

Abstract

Traumatic brain injury (TBI) is one of the leading causes of death and disability among children and adults in America. In addition, the acute morbidity caused by TBI is implicated in the development of devastating neuropsychiatric and neurodegenerative sequela. TBI is associated with the development of a neurodegenerative condition termed ‘Punch Drunk syndrome’ or ‘dementia pugilistica’, and the more recently renamed ‘chronic traumatic encephalopathy’. Chronic traumatic encephalopathy (CTE) is a slowly progressive neurodegenerative condition caused by a single or repetitive blow to the head. CTE was first described in boxers and was later found to be associated with other contact sports and military combat. It is defined by a constellation of symptoms consisting of mood disorders, cognitive impairment, and memory loss with or without sensorimotor changes. It is also a Tauopathy characterized by the deposition of hyperphosphorylated Tau protein in the form of neurofibrillary tangles, astrocytoma tangles, and abnormal neurites found in clusters around small vessels, typically at the sulcal depths. Oxidative stress, neuroinflammation, and glutaminergic toxicity caused due to the insult play a role in developing this pathology. Additionally, the changes in the brain due to aging also plays an important role in the development of this condition. In this review, we discuss the molecular mechanisms behind the development of CTE, as well as genetic and environmental influences on its pathophysiology. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Neurodegenerative Diseases)

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17 pages, 1445 KiB

Open AccessReview

Choroid Plexus Aquaporins in CSF Homeostasis and the Glymphatic System: Their Relevance for Alzheimer’s Disease

by Cristina Municio, Laura Carrero, Desireé Antequera and Eva Carro

Int. J. Mol. Sci. 2023, 24(1), 878; https://doi.org/10.3390/ijms24010878 - 3 Jan 2023

Cited by 14 | Viewed by 5231

Abstract

The glymphatic system, a fluid-clearance pathway involved in brain waste clearance, is known to be impaired in neurological disorders, including Alzheimer’s disease (AD). For this reason, it is important to understand the specific mechanisms and factors controlling glymphatic function. This pathway enables the flow of cerebrospinal fluid (CSF) into the brain and subsequently the brain interstitium, supported by aquaporins (AQPs). Continuous CSF transport through the brain parenchyma is critical for the effective transport and drainage of waste solutes, such as toxic proteins, through the glymphatic system. However, a balance between CSF production and secretion from the choroid plexus, through AQP regulation, is also needed. Thus, any condition that affects CSF homeostasis will also interfere with effective waste removal through the clearance glymphatic pathway and the subsequent processes of neurodegeneration. In this review, we highlight the role of AQPs in the choroid plexus in the modulation of CSF homeostasis and, consequently, the glymphatic clearance pathway, with a special focus on AD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Neurodegenerative Diseases)

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