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Molecular Advances in Nervous System Disorders

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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 (31 December 2023) | Viewed by 17491

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Dr. Nadezhda S. Dyrkheeva

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Guest Editor

Institute of Chemical Biology and Fundamental Medicine, SB RAS, Novosibirsk 630090, Russia
Interests: oncology; nervous system disorders
Special Issues, Collections and Topics in MDPI journals

Dr. Darya V. Bazovkina

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Guest Editor

Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 650065, Russia
Interests: molecular neuroscience; neuropharmacology

Special Issue Information

Dear Colleagues,

It is a great pleasure to invite you to contribute to this Special Issue, entitled “Molecular Advances in Nervous System Disorders”. In recent years, there has been great progress in the ability to deal with various diseases. Molecular biology has become a discipline that has had a profound impact on medicine. These scientific advances extremely affect the diagnosis and treatment of different types of diseases, including neurological diseases. It is very important to understand the molecular mechanisms of disease progression. Pathological processes, ultimately, lead to some kind of disease. The search and study of the mechanism of action of the molecular markers at present is the main task of molecular biology and molecular medicine. With the development of the disease, normal molecular processes undergo significant changes at the level of intermolecular interactions. Thus, the idea of controlling molecular interactions during pathological changes is key in the development of future medicine. This Special Issue welcomes studies and reviews on neurological diseases. We invite researchers from different fields to submit manuscripts on the prevention and treatment of diseases, and the genetic manipulation for desired phenotypic traits that are addressed by the methods of molecular biology.

Dr. Nadezhda S. Dyrkheeva
Dr. Darya V. Bazovkina
Guest Editors

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Published Papers (7 papers)

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Research

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17 pages, 3058 KiB

Open AccessArticle

Potential Binding Sites of Pharmacological Chaperone NCGC00241607 on Mutant β-Glucocerebrosidase and Its Efficacy on Patient-Derived Cell Cultures in Gaucher and Parkinson’s Disease

by Alena E. Kopytova, George N. Rychkov, Alexander A. Cheblokov, Elena V. Grigor’eva, Mikhail A. Nikolaev, Elena S. Yarkova, Diana A. Sorogina, Farid M. Ibatullin, Galina V. Baydakova, Artem D. Izyumchenko, Daria A. Bogdanova, Vitali M. Boitsov, Akim V. Rybakov, Irina V. Miliukhina, Vadim A. Bezrukikh, Galina N. Salogub, Ekaterina Y. Zakharova, Sofya N. Pchelina and Anton K. Emelyanov

Int. J. Mol. Sci. 2023, 24(10), 9105; https://doi.org/10.3390/ijms24109105 - 22 May 2023

Cited by 4 | Viewed by 2706

Abstract

Mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), cause Gaucher disease (GD) and are the most common genetic risk factor for Parkinson’s disease (PD). Pharmacological chaperones (PCs) are being developed as an alternative treatment approach for GD and PD. To date, NCGC00241607 (NCGC607) is one of the most promising PCs. Using molecular docking and molecular dynamics simulation we identified and characterized six allosteric binding sites on the GCase surface suitable for PCs. Two sites were energetically more preferable for NCGC607 and located nearby to the active site of the enzyme. We evaluated the effects of NCGC607 treatment on GCase activity and protein levels, glycolipids concentration in cultured macrophages from GD (n = 9) and GBA-PD (n = 5) patients as well as in induced human pluripotent stem cells (iPSC)—derived dopaminergic (DA) neurons from GBA-PD patient. The results showed that NCGC607 treatment increased GCase activity (by 1.3-fold) and protein levels (by 1.5-fold), decreased glycolipids concentration (by 4.0-fold) in cultured macrophages derived from GD patients and also enhanced GCase activity (by 1.5-fold) in cultured macrophages derived from GBA-PD patients with N370S mutation (p < 0.05). In iPSC-derived DA neurons from GBA-PD patients with N370S mutation NCGC607 treatment increased GCase activity and protein levels by 1.1-fold and 1.7-fold (p < 0.05). Thus, our results showed that NCGC607 could bind to allosteric sites on the GCase surface and confirmed its efficacy on cultured macrophages from GD and GBA-PD patients as well as on iPSC-derived DA neurons from GBA-PD patients. Full article

(This article belongs to the Special Issue Molecular Advances in Nervous System Disorders)

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13 pages, 3568 KiB

Open AccessArticle

β-Secretase-1: In Silico Drug Reposition for Alzheimer’s Disease

by Roberto A. Galeana-Ascencio, Liliana Mendieta, Daniel I. Limon, Dino Gnecco, Joel L. Terán, María L. Orea and Alan Carrasco-Carballo

Int. J. Mol. Sci. 2023, 24(9), 8164; https://doi.org/10.3390/ijms24098164 - 3 May 2023

Cited by 2 | Viewed by 2993

Abstract

The β-secretase-1 enzyme (BACE-1) performs a key role in the production of beta-Amyloid protein (Aβ), which is associated with the development of Alzheimer’s disease (AD). The inhibition of BACE-1 has been an important pharmacological strategy in the treatment of this neurodegenerative disease. This study aims to identify new potential candidates for the treatment of Alzheimer’s with the help of in silico studies, such as molecular docking and ADME prediction, from a broad list of candidates provided by the DrugBank database. From this analysis, 1145 drugs capable of interacting with the enzyme with a higher coupling energy than Verubecestat were obtained, subsequently only 83 presented higher coupling energy than EJ7. Applying the oral route of administration as inclusion criteria, only 41 candidates met this requirement; however, 6 of them are associated with diagnostic tests and not treatment, so 33 candidates were obtained. Finally, five candidates were identified as possible BACE-1 inhibitors drugs: Fluphenazine, Naratriptan, Bazedoxifene, Frovatriptan, and Raloxifene. These candidates exhibit pharmacophore-specific features, including the indole or thioindole group, and interactions with key amino acids in BACE-1. Overall, this study provides insights into the potential use of in silico methods for drug repurposing and identification of new candidates for the treatment of Alzheimer’s disease, especially those targeting BACE-1. Full article

(This article belongs to the Special Issue Molecular Advances in Nervous System Disorders)

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18 pages, 17187 KiB

Open AccessArticle

Biochemical Characteristics of iPSC-Derived Dopaminergic Neurons from N370S GBA Variant Carriers with and without Parkinson’s Disease

by Elena V. Grigor’eva, Alena E. Kopytova, Elena S. Yarkova, Sophia V. Pavlova, Diana A. Sorogina, Anastasia A. Malakhova, Tuyana B. Malankhanova, Galina V. Baydakova, Ekaterina Y. Zakharova, Sergey P. Medvedev, Sofia N. Pchelina and Suren M. Zakian

Int. J. Mol. Sci. 2023, 24(5), 4437; https://doi.org/10.3390/ijms24054437 - 23 Feb 2023

Cited by 10 | Viewed by 3035

Abstract

GBA variants increase the risk of Parkinson’s disease (PD) by 10 times. The GBA gene encodes the lysosomal enzyme glucocerebrosidase (GCase). The p.N370S substitution causes a violation of the enzyme conformation, which affects its stability in the cell. We studied the biochemical characteristics of dopaminergic (DA) neurons generated from induced pluripotent stem cells (iPSCs) from a PD patient with the GBA p.N370S mutation (GBA-PD), an asymptomatic GBA p.N370S carrier (GBA-carrier), and two healthy donors (control). Using liquid chromatography with tandem mass spectrometry (LC-MS/MS), we measured the activity of six lysosomal enzymes (GCase, galactocerebrosidase (GALC), alpha-glucosidase (GAA), alpha-galactosidase (GLA), sphingomyelinase (ASM), and alpha-iduronidase (IDUA)) in iPSC-derived DA neurons from the GBA-PD and GBA-carrier. DA neurons from the GBA mutation carrier demonstrated decreased GCase activity compared to the control. The decrease was not associated with any changes in GBA expression levels in DA neurons. GCase activity was more markedly decreased in the DA neurons of GBA-PD patient compared to the GBA-carrier. The amount of GCase protein was decreased only in GBA-PD neurons. Additionally, alterations in the activity of the other lysosomal enzymes (GLA and IDUA) were found in GBA-PD neurons compared to GBA-carrier and control neurons. Further study of the molecular differences between the GBA-PD and the GBA-carrier is essential to investigate whether genetic factors or external conditions are the causes of the penetrance of the p.N370S GBA variant. Full article

(This article belongs to the Special Issue Molecular Advances in Nervous System Disorders)

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17 pages, 4735 KiB

Open AccessArticle

On Associations between Fear-Induced Aggression, Bdnf Transcripts, and Serotonin Receptors in the Brains of Norway Rats: An Influence of Antiaggressive Drug TC-2153

by Vitalii S. Moskaliuk, Rimma V. Kozhemyakina, Tatyana M. Khomenko, Konstantin P. Volcho, Nariman F. Salakhutdinov, Alexander V. Kulikov, Vladimir S. Naumenko and Elizabeth A. Kulikova

Int. J. Mol. Sci. 2023, 24(2), 983; https://doi.org/10.3390/ijms24020983 - 4 Jan 2023

Cited by 4 | Viewed by 2203

Abstract

The Bdnf (brain-derived neurotrophic factor) gene contains eight regulatory exons (I–VIII) alternatively spliced to the protein-coding exon IX. Only exons I, II, IV, and VI are relatively well studied. The BDNF system and brain serotonergic system are tightly interconnected and associated with aggression. The benzopentathiepine TC-2153 affects both systems and exerts antiaggressive action. Our aim was to evaluate the effects of TC-2153 on the Bdnf exons I–IX’s expressions and serotonin receptors’ mRNA levels in the brain of rats featuring high aggression toward humans (aggressive) or its absence (tame). Aggressive and tame adult male rats were treated once with vehicle or 10 or 20 mg/kg of TC-2153. mRNA was quantified in the cortex, hippocampus, hypothalamus, and midbrain with real-time PCR. Selective breeding for high aggression or its absence affected the serotonin receptors’ and Bdnf exons’ transcripts differentially, depending on the genotype (strain) and brain region. TC-2153 had comprehensive effects on the Bdnf exons’ expressions. The main trend was downregulation in the hypothalamus and midbrain. TC-2153 increased 5-HT_1B receptor hypothalamusc mRNA expression. For the first time, an influence of TC-2153 on the expressions of Bdnf regulatory exons and the 5-HT_1B receptor was shown, as was an association between Bdnf regulatory exons and fear-induced aggression involving genetic predisposition. Full article

(This article belongs to the Special Issue Molecular Advances in Nervous System Disorders)

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Review

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28 pages, 4628 KiB

Open AccessReview

Mutant-Huntingtin Molecular Pathways Elucidate New Targets for Drug Repurposing

by Vladlena S. Makeeva, Nadezhda S. Dyrkheeva, Olga I. Lavrik, Suren M. Zakian and Anastasia A. Malakhova

Int. J. Mol. Sci. 2023, 24(23), 16798; https://doi.org/10.3390/ijms242316798 - 27 Nov 2023

Cited by 3 | Viewed by 2193

Abstract

The spectrum of neurodegenerative diseases known today is quite extensive. The complexities of their research and treatment lie not only in their diversity. Even many years of struggle and narrowly focused research on common pathologies such as Alzheimer’s, Parkinson’s, and other brain diseases have not brought cures for these illnesses. What can be said about orphan diseases? In particular, Huntington’s disease (HD), despite affecting a smaller part of the human population, still attracts many researchers. This disorder is known to result from a mutation in the HTT gene, but having this information still does not simplify the task of drug development and studying the mechanisms of disease progression. Nonetheless, the data accumulated over the years and their analysis provide a good basis for further research. Here, we review studies devoted to understanding the mechanisms of HD. We analyze genes and molecular pathways involved in HD pathogenesis to describe the action of repurposed drugs and try to find new therapeutic targets. Full article

(This article belongs to the Special Issue Molecular Advances in Nervous System Disorders)

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21 pages, 1573 KiB

Open AccessReview

The Promising Role of a Zebrafish Model Employed in Neural Regeneration Following a Spinal Cord Injury

by Chih-Wei Zeng and Huai-Jen Tsai

Int. J. Mol. Sci. 2023, 24(18), 13938; https://doi.org/10.3390/ijms241813938 - 11 Sep 2023

Cited by 5 | Viewed by 2286

Abstract

Spinal cord injury (SCI) is a devastating event that results in a wide range of physical impairments and disabilities. Despite the advances in our understanding of the biological response to injured tissue, no effective treatments are available for SCIs at present. Some studies have addressed this issue by exploring the potential of cell transplantation therapy. However, because of the abnormal microenvironment in injured tissue, the survival rate of transplanted cells is often low, thus limiting the efficacy of such treatments. Many studies have attempted to overcome these obstacles using a variety of cell types and animal models. Recent studies have shown the utility of zebrafish as a model of neural regeneration following SCIs, including the proliferation and migration of various cell types and the involvement of various progenitor cells. In this review, we discuss some of the current challenges in SCI research, including the accurate identification of cell types involved in neural regeneration, the adverse microenvironment created by SCIs, attenuated immune responses that inhibit nerve regeneration, and glial scar formation that prevents axonal regeneration. More in-depth studies are needed to fully understand the neural regeneration mechanisms, proteins, and signaling pathways involved in the complex interactions between the SCI microenvironment and transplanted cells in non-mammals, particularly in the zebrafish model, which could, in turn, lead to new therapeutic approaches to treat SCIs in humans and other mammals. Full article

(This article belongs to the Special Issue Molecular Advances in Nervous System Disorders)

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19 pages, 24100 KiB

Open AccessReview

Nerve Structure-Function: Unusual Structural Details and Unmasking of Sulfhydryl Groups by Electrical Stimulation or Asphyxia in Axon Membranes and Gap Junctions

by Camillo Peracchia

Int. J. Mol. Sci. 2023, 24(17), 13565; https://doi.org/10.3390/ijms241713565 - 1 Sep 2023

Viewed by 1219

Abstract

This review describes and discusses unusual axonal structural details and evidence for unmasking sulfhydryl groups (-SH) in axoplasmic membranes resulting from electrical stimulation or asphyxia. Crayfish axons contain fenestrated septa (FS) that, in phase contrast, micrographs appear as repeated striations. In the electron microscope, each septum is made of two cross-sectioned membranes containing ~55 nm pores, each occupied by a microtubule. Thin filaments, which we believe are made of kinesin, bridge the microtubule to the edge of the pore. FS are believed to play a role in axoplasmic flow. The axons also display areas in which axon and sheath glial cell plasma membranes are sharply curved and project into the axoplasm. In freeze-fractures, the protoplasmic leaflet (P-face) of the projections appears as elongated indentations containing parallel chains of particles. The sheath glial cell plasma membrane also contains particles, but they are irregularly aggregated. The axons also display areas where axonal and glial plasma membranes fuse, creating intercellular pores. In axons fixed during electrical stimulation, the plasma membrane, the outer membrane of mitochondria, membranes of other cytoplasmic organelles, and gap junctions increase in electron opacity and thickness, resulting from unmasking of sulfhydryl groups (-SH). Similar changes occur in asphyxiated nerve cords. Full article

(This article belongs to the Special Issue Molecular Advances in Nervous System Disorders)

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