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Pathogenesis of Diseases of the Central Nervous System
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Pathogenesis of Diseases of the Central Nervous System

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 (15 March 2023) | Viewed by 16549

Special Issue Editor

Dr. Juan José Ramos-Rodríguez

E-Mail Website
Guest Editor
Department of Physiology, Faculty of Health Sciences (Ceuta), University of Granada, 51001 Ceuta, Spain
Interests: molecular neurobiology; brain pathology; diabetic; Alzheimer’s disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Physiology disbalance and pathogenesis of the central nervous system play an important role in the quality of people’s life and aging. In this sense, determining the pathways followed by the different pathologies of central nervous system diseases is crucial to prevent and treat them. This Special Issue is focused on the pathogenesis of diseases of the central nervous system, and it would include original works on aspects related with molecular mechanisms of physical and chemical insults, neuronal excitotoxicity, neuronal dysfunction, Alzheimer´s disease, dementia, Parkinson's disease, amyotrophic lateral sclerosis, ischemia, nephropathy, brain atrophies, acute injuries, neurogenesis, and central nervous system treatments, among others. This Special Issue will publish original research articles as well as mini and full reviews, including perspectives in the field on the current understanding of molecular mechanisms involved in the pathogenesis of diseases of the central nervous system. Manuscripts on molecular mechanisms, the introduction of ideas for new therapies or new techniques for diagnosis, and on treatment of diseases of the central nervous system are welcome.

Dr. Juan José Ramos-Rodríguez
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

  • neuronal death
  • neuronal excitotoxicity
  • neuronal dysfunction
  • neurogenesis
  • dementia
  • Alzheimer’s diseases
  • Parkinson’s disease
  • amyotrophic lateral sclerosis
  • nephropathy
  • brain atrophy

Related Special Issue

Published Papers (7 papers)

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Research

Jump to: Review

19 pages, 4062 KiB  
Article
Downregulation of Sirtuin 1 Does Not Account for the Impaired Long-Term Potentiation in the Prefrontal Cortex of Female APPswe/PS1dE9 Mice Modelling Alzheimer’s Disease
by Cátia R. Lopes, Joana S. Silva, Joana Santos, Matilde S. Rodrigues, Daniela Madeira, Andreia Oliveira, Ana Moreira-de-Sá, Vanessa S. Lourenço, Francisco Q. Gonçalves, Henrique B. Silva, Ana Patrícia Simões, Anabela P. Rolo, Paula M. Canas, Ângelo R. Tomé, Carlos M. Palmeira, João Pedro Lopes, Rodrigo A. Cunha, Paula Agostinho and Samira G. Ferreira
Int. J. Mol. Sci. 2023, 24(8), 6968; https://doi.org/10.3390/ijms24086968 - 9 Apr 2023
Cited by 2 | Viewed by 2042
Abstract
Alzheimer’s disease (AD), which predominantly affects women, involves at its onset a metabolic deregulation associated with a synaptic failure. Here, we performed a behavioral, neurophysiological and neurochemical characterization of 9-month-old female APPswe/PS1dE9 (APP/PS1) mice as a model of early AD. These animals showed [...] Read more.
Alzheimer’s disease (AD), which predominantly affects women, involves at its onset a metabolic deregulation associated with a synaptic failure. Here, we performed a behavioral, neurophysiological and neurochemical characterization of 9-month-old female APPswe/PS1dE9 (APP/PS1) mice as a model of early AD. These animals showed learning and memory deficits in the Morris water maze, increased thigmotaxis and anxiety-like behavior and showed signs of fear generalization. Long-term potentiation (LTP) was decreased in the prefrontal cortex (PFC), but not in the CA1 hippocampus or amygdala. This was associated with a decreased density of sirtuin-1 in cerebrocortical synaptosomes and a decreased density of sirtuin-1 and sestrin-2 in total cerebrocortical extracts, without alterations of sirtuin-3 levels or of synaptic markers (syntaxin, synaptophysin, SNAP25, PSD95). However, activation of sirtuin-1 did not affect or recover PFC-LTP deficit in APP/PS1 female mice; instead, inhibition of sirtuin-1 increased PFC-LTP magnitude. It is concluded that mood and memory dysfunction in 9-month-old female APP/PS1 mice is associated with a parallel decrease in synaptic plasticity and in synaptic sirtuin-1 levels in the prefrontal cortex, although sirtiun1 activation failed to restore abnormal cortical plasticity. Full article
(This article belongs to the Special Issue Pathogenesis of Diseases of the Central Nervous System)
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11 pages, 300 KiB  
Communication
LAG3/CD4 Genes Variants and the Risk for Restless Legs Syndrome
by Félix Javier Jiménez-Jiménez, Javier Gómez-Tabales, Hortensia Alonso-Navarro, Christopher Rodríguez, Laura Turpín-Fenoll, Jorge Millán-Pascual, Ignacio Álvarez, Pau Pastor, Marisol Calleja, Rafael García-Ruiz, Santiago Navarro-Muñoz, Marta Recio-Bermejo, José Francisco Plaza-Nieto, Esteban García-Albea, Elena García-Martín and José A. G. Agúndez
Int. J. Mol. Sci. 2022, 23(23), 14795; https://doi.org/10.3390/ijms232314795 - 26 Nov 2022
Cited by 1 | Viewed by 1343
Abstract
According to several studies, inflammatory factors could be related to the pathogenesis of idiopathic restless legs syndrome (RLS). In addition, RLS and Parkinson’s disease (PD) have shown a possible relationship, and recent studies have shown an association between CD4 rs1922452 and CD4 rs951818 [...] Read more.
According to several studies, inflammatory factors could be related to the pathogenesis of idiopathic restless legs syndrome (RLS). In addition, RLS and Parkinson’s disease (PD) have shown a possible relationship, and recent studies have shown an association between CD4 rs1922452 and CD4 rs951818 single nucleotide variants (SNVs) and the risk for PD. For these reasons, we investigated the possible association between common variants in the LAG3/CD4 genes (which encoded proteins involved in inflammatory and autoimmune responses) and the risk for RLS in a Caucasian Spanish population. We assessed the frequencies of CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants in 285 patients with idiopathic RLS and 350 healthy controls using a specific TaqMan-based qPCR assay. We also analyzed the possible influence of the genotypes’ frequencies on several variables, including age at onset of RLS, gender, family history of RLS, and response to drugs commonly used in the treatment of RLS. We found a lack of association between the frequencies of genotypes and allelic variants of the 3 SNVs studied and the risk of RLS, and a weak though significant association between the CD4 rs1922452 GG genotype and an older age at onset of RLS. With the exception of this association, our findings suggest that common SNVs in the CD4/LAG3 genes are not associated with the risk of developing idiopathic RLS in Caucasian Spanish people. Full article
(This article belongs to the Special Issue Pathogenesis of Diseases of the Central Nervous System)
13 pages, 1139 KiB  
Article
Saposin C, Key Regulator in the Alpha-Synuclein Degradation Mediated by Lysosome
by Clara Ruz, Francisco J. Barrero, Javier Pelegrina, Sara Bandrés-Ciga, Francisco Vives and Raquel Duran
Int. J. Mol. Sci. 2022, 23(19), 12004; https://doi.org/10.3390/ijms231912004 - 9 Oct 2022
Cited by 1 | Viewed by 1849
Abstract
Lysosomal dysfunction has been proposed as one of the most important pathogenic molecular mechanisms in Parkinson disease (PD). The most significant evidence lies in the GBA gene, which encodes for the lysosomal enzyme β-glucocerebrosidase (β-GCase), considered the main genetic risk factor for sporadic [...] Read more.
Lysosomal dysfunction has been proposed as one of the most important pathogenic molecular mechanisms in Parkinson disease (PD). The most significant evidence lies in the GBA gene, which encodes for the lysosomal enzyme β-glucocerebrosidase (β-GCase), considered the main genetic risk factor for sporadic PD. The loss of β-GCase activity results in the formation of α-synuclein deposits. The present study was aimed to determine the activity of the main lysosomal enzymes and the cofactors Prosaposin (PSAP) and Saposin C in PD and healthy controls, and their contribution to α-synuclein (α-Syn) aggregation. 42 PD patients and 37 age-matched healthy controls were included in the study. We first analyzed the β-GCase, β-galactosidase (β-gal), β-hexosaminidase (Hex B) and Cathepsin D (CatD) activities in white blood cells. We also measured the GBA, β-GAL, β-HEX, CTSD, PSAP, Saposin C and α-Syn protein levels by Western-blot. We found a 20% reduced β-GCase and β-gal activities in PD patients compared to controls. PSAP and Saposin C protein levels were significantly lower in PD patients and correlated with increased levels of α-synuclein. CatD, in contrast, showed significantly increased activity and protein levels in PD patients compared to controls. Increased CTSD protein levels in PD patients correlated, intriguingly, with a higher concentration of α-Syn. Our findings suggest that lysosomal dysfunction in sporadic PD is due, at least in part, to an alteration in Saposin C derived from reduced PSAP levels. That would lead to a significant decrease in the β-GCase activity, resulting in the accumulation of α-syn. The accumulation of monohexosylceramides might act in favor of CTSD activation and, therefore, increase its enzymatic activity. The evaluation of lysosomal activity in the peripheral blood of patients is expected to be a promising approach to investigate pathological mechanisms and novel therapies aimed to restore the lysosomal function in sporadic PD. Full article
(This article belongs to the Special Issue Pathogenesis of Diseases of the Central Nervous System)
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18 pages, 2668 KiB  
Article
Alpha-Synuclein: The Spark That Flames Dopaminergic Neurons, In Vitro and In Vivo Evidence
by Alexandre Henriques, Laura Rouvière, Elodie Giorla, Clémence Farrugia, Bilal El Waly, Philippe Poindron and Noëlle Callizot
Int. J. Mol. Sci. 2022, 23(17), 9864; https://doi.org/10.3390/ijms23179864 - 30 Aug 2022
Cited by 8 | Viewed by 2473
Abstract
Mitochondria, α-syn fibrils and the endo-lysosomal system are key players in the pathophysiology of Parkinson’s disease. The toxicity of α-syn is amplified by cell-to-cell transmission and aggregation of endogenous species in newly invaded neurons. Toxicity of α-syn PFF was investigated using primary cultures [...] Read more.
Mitochondria, α-syn fibrils and the endo-lysosomal system are key players in the pathophysiology of Parkinson’s disease. The toxicity of α-syn is amplified by cell-to-cell transmission and aggregation of endogenous species in newly invaded neurons. Toxicity of α-syn PFF was investigated using primary cultures of dopaminergic neurons or on aged mice after infusion in the SNpc and combined with mild inhibition of GBA. In primary dopaminergic neurons, application of α-syn PFF induced a progressive cytotoxicity associated with mitochondrial dysfunction, oxidative stress, and accumulation of lysosomes suggesting that exogenous α-syn reached the lysosome (from the endosome). Counteracting the α-syn endocytosis with a clathrin inhibitor, dopaminergic neuron degeneration was prevented. In vivo, α-syn PFF induced progressive neurodegeneration of dopaminergic neurons associated with motor deficits. Histology revealed progressive aggregation of α-syn and microglial activation and accounted for the seeding role of α-syn, injection of which acted as a spark suggesting a triggering of cell-to-cell toxicity. We showed for the first time that a localized SNpc α-syn administration combined with a slight lysosomal deficiency and aging triggered a progressive lesion. The cellular and animal models described could help in the understanding of the human disease and might contribute to the development of new therapies. Full article
(This article belongs to the Special Issue Pathogenesis of Diseases of the Central Nervous System)
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Review

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17 pages, 2157 KiB  
Review
Amyotrophic Lateral Sclerosis and Serum Lipid Level Association: A Systematic Review and Meta-Analytic Study
by Teresa Pardo-Moreno, Himan Mohamed-Mohamed, Sami Suleiman-Martos, Juan José Ramos-Rodriguez, Antonio Rivas-Dominguez, Lucía Melguizo-Rodríguez, José L. Gómez-Urquiza, Beatriz Bermudez-Pulgarin and Victoria Garcia-Morales
Int. J. Mol. Sci. 2023, 24(10), 8675; https://doi.org/10.3390/ijms24108675 - 12 May 2023
Cited by 1 | Viewed by 1673
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown etiology. Many metabolic alterations occur during ALS progress and can be used as a method of pre-diagnostic and early diagnosis. Dyslipidemia is one of the physiological changes observed in numerous ALS patients. [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown etiology. Many metabolic alterations occur during ALS progress and can be used as a method of pre-diagnostic and early diagnosis. Dyslipidemia is one of the physiological changes observed in numerous ALS patients. The aim of this study is to analyze the possible relationship between the rate of disease progression (functional rating scale (ALS-FRS)) and the plasma lipid levels at the early stage of ALS. A systematic review was carried out in July 2022. The search equation was “Triglycerides AND amyotrophic lateral sclerosis” and its variants. Four meta-analyses were performed. Four studies were included in the meta-analysis. No significant differences were observed between the lipid levels (total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol) and the ALS-FRS score at the onset of the disease. Although the number of studies included in this research was low, the results of this meta-analytic study suggest that there is no clear relationship between the symptoms observed in ALS patients and the plasma lipid levels. An increase in research, as well as an expansion of the geographical area, would be of interest. Full article
(This article belongs to the Special Issue Pathogenesis of Diseases of the Central Nervous System)
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18 pages, 806 KiB  
Review
Vascular Dysfunction in Alzheimer’s Disease: Alterations in the Plasma Contact and Fibrinolytic Systems
by Ana Badimon, Daniel Torrente and Erin H. Norris
Int. J. Mol. Sci. 2023, 24(8), 7046; https://doi.org/10.3390/ijms24087046 - 11 Apr 2023
Cited by 5 | Viewed by 1715
Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease, affecting millions of people worldwide. The classical hallmarks of AD include extracellular beta-amyloid (Aβ) plaques and neurofibrillary tau tangles, although they are often accompanied by various vascular defects. These changes include damage to the [...] Read more.
Alzheimer’s disease (AD) is the most common neurodegenerative disease, affecting millions of people worldwide. The classical hallmarks of AD include extracellular beta-amyloid (Aβ) plaques and neurofibrillary tau tangles, although they are often accompanied by various vascular defects. These changes include damage to the vasculature, a decrease in cerebral blood flow, and accumulation of Aβ along vessels, among others. Vascular dysfunction begins early in disease pathogenesis and may contribute to disease progression and cognitive dysfunction. In addition, patients with AD exhibit alterations in the plasma contact system and the fibrinolytic system, two pathways in the blood that regulate clotting and inflammation. Here, we explain the clinical manifestations of vascular deficits in AD. Further, we describe how changes in plasma contact activation and the fibrinolytic system may contribute to vascular dysfunction, inflammation, coagulation, and cognitive impairment in AD. Given this evidence, we propose novel therapies that may, alone or in combination, ameliorate AD progression in patients. Full article
(This article belongs to the Special Issue Pathogenesis of Diseases of the Central Nervous System)
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15 pages, 1633 KiB  
Review
Neural Tube Defects and Folate Deficiency: Is DNA Repair Defective?
by Xiuwei Wang, Jialu Yu and Jianhua Wang
Int. J. Mol. Sci. 2023, 24(3), 2220; https://doi.org/10.3390/ijms24032220 - 22 Jan 2023
Cited by 4 | Viewed by 4246
Abstract
Neural tube defects (NTDs) are complex congenital malformations resulting from failure of neural tube closure during embryogenesis, which is affected by the interaction of genetic and environmental factors. It is well known that folate deficiency increases the incidence of NTDs; however, the underlying [...] Read more.
Neural tube defects (NTDs) are complex congenital malformations resulting from failure of neural tube closure during embryogenesis, which is affected by the interaction of genetic and environmental factors. It is well known that folate deficiency increases the incidence of NTDs; however, the underlying mechanism remains unclear. Folate deficiency not only causes DNA hypomethylation, but also blocks the synthesis of 2′-deoxythymidine-5′–monophosphate (dTMP) and increases uracil misincorporation, resulting in genomic instabilities such as base mismatch, DNA breakage, and even chromosome aberration. DNA repair pathways are essential for ensuring normal DNA synthesis, genomic stability and integrity during embryonic neural development. Genomic instability or lack of DNA repair has been implicated in risk of development of NTDs. Here, we reviewed the relationship between folate deficiency, DNA repair pathways and NTDs so as to reveal the role and significance of DNA repair system in the pathogenesis of NTDs and better understand the pathogenesis of NTDs. Full article
(This article belongs to the Special Issue Pathogenesis of Diseases of the Central Nervous System)
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