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The Brain as a Manager of the Body—Molecular Aspects of Development and Functioning in Health and Disease

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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 January 2023) | Viewed by 27942

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Prof. Dr. Michael Ugrumov

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1. Faculty of Psychology, National Research University “Higher School of Economy”, Moscow, Russia
2. Institute of Developmental Biology of the Russian Academy of Sciences, Moscow, Russia
Interests: developmental neurobiology; neuroendocrinology; neurodegenerative diseases; Parkinson’s disease; preclinical diagnosis; preventive neuroprotective therapy
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Dear Colleagues,

The brain can be considered with certainty the conductor or manager of the development and functioning of the body. Indeed, it provides nervous and neuroendocrine regulations of the most important functions of the body, such as adaptation to the environment and maintenance of homeostasis, reproduction, various types of behavior, including motor behavior, and cognitive and other functions. Both types of regulation are provided by neuronal ensembles that exchange information using a wide range of intercellular signals—classical, neurotransmitters, neuropeptides, amino acids. With both types of regulation, the chemical signals are involved in synaptic or volume neurotransmission in the brain, while at the last stage of neuroendocrine regulation, the same physiologically active substances are released into the bloodstream, exerting a direct or indirect (through the pituitary gland) hormonal effect on peripheral target organs. The action of intercellular signaling in the brain during ontogenesis is fundamentally different from that in adulthood. Thus, in the perinatal period, they exert an irreversible effect on differentiating target neurons and the brain as a whole. In addition, in the absence of the blood–brain barrier during this period of ontogenesis, brain-derived chemical signals are delivered to the general circulation, affecting peripheral target organs and the brain itself (autoregulation). Impairment of the brain operation in adulthood leads to the development of numerous neurological, mental, and neuroendocrine diseases, which are more or less treatable. Disruption of the functioning of the developing brain during the critical period of morphogenesis (the perinatal period) leads to the development of congenital diseases that are practically not treatable during subsequent life.

Thus, this Special Issue of IJMS on “The Brain as a Manager of the Body—Molecular Aspects of Development and Functioning in Health and Disease” is open to a wide range of studies on the molecular mechanisms of brain functioning in adulthood and in ontogenesis in health and in brain diseases. Studies on cells, animals, and humans are welcome.

Prof. Dr. Michael Ugrumov
Guest Editor

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Keywords

brain
animals
humans
neural regulation
neuroendocrine regulation
synaptic neurotransmission
volume neurotransmission
ontogenesis
body fluids
blood
blood–brain barrier
brain diseases
congenital diseases

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The Brain as a Manager of Central and Peripheral Functions—Molecular Aspects in Health and Disease in International Journal of Molecular Sciences (2 articles)

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Research

Jump to: Review

18 pages, 1824 KiB

Open AccessArticle

Exploring the Genetic Predisposition to Epigenetic Changes in Alzheimer’s Disease

by Leonid O. Bryzgalov, Elena E. Korbolina and Tatiana I. Merkulova

Int. J. Mol. Sci. 2023, 24(9), 7955; https://doi.org/10.3390/ijms24097955 - 27 Apr 2023

Cited by 3 | Viewed by 2352

Abstract

Alzheimer’s disease (AD) is a prevalent type of dementia in elderly populations with a significant genetic component. The accumulating evidence suggests that AD involves a reconfiguration of the epigenetic landscape, including DNA methylation, post-translational modification of histone proteins, and chromatin remodeling. Along with environmental factors, individual specific genetic features play a considerable role in the formation of epigenetic architecture. In this study, we attempt to identify the non-coding regulatory SNPs (rSNPs) able to affect the epigenetic mechanisms in AD. To this end, the multi-omics approach is used. The GEO (Gene Expression Omnibus) available data (GSE153875) for AD patients and controls are integrated to reveal the rSNPs that display allele-specific features in both ChIP-seq profiles of four histone modifications and RNA-seq. Furthermore, we analyze the presence of rSNPs in the promoters of genes reported to be differentially expressed between AD and the normal brain (AD-related genes) and involved in epigenetic regulation according to the EpiFactors database. We also searched for the rSNPs in the promoters of the genes coding for transcription regulators of the identified AD-related genes. These regulators were selected based on the corresponding ChIP-seq peaks (ENCODE) in the promoter regions of these genes. Finally, we formed a panel of rSNPs localized to the promoters of genes that contribute to the epigenetic landscape in AD and, thus, to the genetic predisposition for this disease. Full article

(This article belongs to the Special Issue The Brain as a Manager of the Body—Molecular Aspects of Development and Functioning in Health and Disease)

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18 pages, 6059 KiB

Open AccessArticle

Inter-Regional Proteomic Profiling of the Human Brain Using an Optimized Protein Extraction Method from Formalin-Fixed Tissue to Identify Signaling Pathways

by Jennilee M. Davidson, Stephanie L. Rayner, Sidong Liu, Flora Cheng, Antonio Di Ieva, Roger S. Chung and Albert Lee

Int. J. Mol. Sci. 2023, 24(5), 4283; https://doi.org/10.3390/ijms24054283 - 21 Feb 2023

Cited by 2 | Viewed by 3070

Abstract

Proteomics offers vast potential for studying the molecular regulation of the human brain. Formalin fixation is a common method for preserving human tissue; however, it presents challenges for proteomic analysis. In this study, we compared the efficiency of two different protein-extraction buffers on three post-mortem, formalin-fixed human brains. Equal amounts of extracted proteins were subjected to in-gel tryptic digestion and LC-MS/MS. Protein, peptide sequence, and peptide group identifications; protein abundance; and gene ontology pathways were analyzed. Protein extraction was superior using lysis buffer containing tris(hydroxymethyl)aminomethane hydrochloride, sodium dodecyl sulfate, sodium deoxycholate, and Triton X-100 (TrisHCl, SDS, SDC, Triton X-100), which was then used for inter-regional analysis. Pre-frontal, motor, temporal, and occipital cortex tissues were analyzed by label free quantification (LFQ) proteomics, Ingenuity Pathway Analysis and PANTHERdb. Inter-regional analysis revealed differential enrichment of proteins. We found similarly activated cellular signaling pathways in different brain regions, suggesting commonalities in the molecular regulation of neuroanatomically-linked brain functions. Overall, we developed an optimized, robust, and efficient method for protein extraction from formalin-fixed human brain tissue for in-depth LFQ proteomics. We also demonstrate herein that this method is suitable for rapid and routine analysis to uncover molecular signaling pathways in the human brain. Full article

(This article belongs to the Special Issue The Brain as a Manager of the Body—Molecular Aspects of Development and Functioning in Health and Disease)

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17 pages, 1308 KiB

Open AccessArticle

The Gene Expression of Proteins Involved in Intercellular Signaling and Neurodegeneration in the Substantia Nigra in a Mouse Subchronic Model of Parkinson’s Disease

by Anna Kolacheva, Ekaterina Pavlova, Alyona Bannikova, Vsevolod Bogdanov, Dmitry Troshev and Michael Ugrumov

Int. J. Mol. Sci. 2023, 24(3), 3027; https://doi.org/10.3390/ijms24033027 - 3 Feb 2023

Cited by 1 | Viewed by 2386

Abstract

Given the limited access to clinical material for studying the pathogenesis of Parkinson’s disease (PD), these studies should be carried out on experimental models. We have recently developed a subchronic model of the progressive development of PD with a gradual transition from the preclinical (asymptomatic) stage to the clinical (symptomatic) one. The aim of this study was to evaluate changes in the expression of a wide range of genes in the substantia nigra (SN), the central link in the regulation of motor function, in mice in our subchronic model of PD. We have found changes in the expression of a number of genes encoding enzymes involved in the synthesis and degradation of dopamine as well as proteins involved in the vesicular cycle, axonal transport, protein degradation in the proteasome system, neuroinflammation, and cell death in the SN of our mouse model of the clinical stage of PD. Similar changes in gene expression were previously demonstrated in patients (postmortem), indicating good reproducibility of PD in our model. Further analysis of the gene expression in the SN of mice has shown that the expression of some genes also changes in the model of the preclinical stage, when dopaminergic neurons have not yet died. Thus, this study opens up broad prospects for further evaluation of the molecular mechanisms of PD pathogenesis and the development of a test system for drug screening. Full article

(This article belongs to the Special Issue The Brain as a Manager of the Body—Molecular Aspects of Development and Functioning in Health and Disease)

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29 pages, 5472 KiB

Open AccessArticle

Searching for Biomarkers in the Blood of Patients at Risk of Developing Parkinson’s Disease at the Prodromal Stage

by Elena A. Katunina, Victor Blokhin, Marina R. Nodel, Ekaterina N. Pavlova, Alexander L. Kalinkin, Valerian G. Kucheryanu, Leyla Alekperova, Marianna V. Selikhova, Mikhail Yu. Martynov and Michael V. Ugrumov

Int. J. Mol. Sci. 2023, 24(3), 1842; https://doi.org/10.3390/ijms24031842 - 17 Jan 2023

Cited by 9 | Viewed by 3015

Abstract

Parkinson’s disease (PD) is diagnosed many years after its onset, under a significant degradation of the nigrostriatal dopaminergic system, responsible for the regulation of motor function. This explains the low effectiveness of the treatment of patients. Therefore, one of the highest priorities in neurology is the development of the early (preclinical) diagnosis of PD. The aim of this study was to search for changes in the blood of patients at risk of developing PD, which are considered potential diagnostic biomarkers. Out of 1835 patients, 26 patients were included in the risk group and 20 patients in the control group. The primary criteria for inclusion in a risk group were the impairment of sleep behavior disorder and sense of smell, and the secondary criteria were neurological and mental disorders. In patients at risk and in controls, the composition of plasma and the expression of genes of interest in lymphocytes were assessed by 27 indicators. The main changes that we found in plasma include a decrease in the concentrations of l-3,4-dihydroxyphenylalanine (L-DOPA) and urates, as well as the expressions of some types of microRNA, and an increase in the total oxidative status. In turn, in the lymphocytes of patients at risk, an increase in the expression of the DA D3 receptor gene and the lymphocyte activation gene 3 (LAG3), as well as a decrease in the expression of the Protein deglycase DJ-1 gene (PARK7), were observed. The blood changes we found in patients at risk are considered candidates for diagnostic biomarkers at the prodromal stage of PD. Full article

(This article belongs to the Special Issue The Brain as a Manager of the Body—Molecular Aspects of Development and Functioning in Health and Disease)

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17 pages, 2041 KiB

Open AccessArticle

Modeling of the Progressive Degradation of the Nigrostriatal Dopaminergic System in Mice to Study the Mechanisms of Neurodegeneration and Neuroplasticity in Parkinson’s Disease

by Anna Kolacheva, Alyona Bannikova, Ekaterina Pavlova, Vsevolod Bogdanov and Michael Ugrumov

Int. J. Mol. Sci. 2023, 24(1), 683; https://doi.org/10.3390/ijms24010683 - 30 Dec 2022

Cited by 7 | Viewed by 2791

Abstract

The fight against neurodegenerative diseases, including Parkinson’s disease (PD), is among the global challenges of the 21st century. The low efficiency of therapy is due to the late diagnosis and treatment of PD, which take place when there is already significant degradation of the nigrostriatal dopaminergic system, a key link in the regulation of motor function. We have developed a subchronic mouse model of PD by repeatedly administering 1–methyl–4–phenyl–1,2,3,6–tetrahydropyridine (MPTP) at gradually increasing doses with a 24 h interval between injections, a period comparable to the time of MPTP metabolism and elimination from the body. This model reproduces the main hallmarks of PD: progressive degeneration of dopaminergic neurons; the appearance of motor disorders with a 70–80% decrease in the level of dopamine in the striatum; an increase in dopamine turnover in the striatum to compensate for dopamine deficiency. When comparing the degradation of the nigrostriatal dopaminergic system and motor disorders in mice in the acute and subchronic models of PD, it has turned out that the resistance of dopaminergic neurons to MPTP increases with its repeated administration. Our subchronic model of PD opens up broad prospects for studying the molecular mechanisms of PD pathogenesis and developing technologies for early diagnosis and preventive treatment. Full article

(This article belongs to the Special Issue The Brain as a Manager of the Body—Molecular Aspects of Development and Functioning in Health and Disease)

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16 pages, 2336 KiB

Open AccessArticle

Role of Adenylyl Cyclase Type 7 in Functions of BV-2 Microglia

by Yawen Hu, Rebecca A. Hill and Masami Yoshimura

Int. J. Mol. Sci. 2023, 24(1), 347; https://doi.org/10.3390/ijms24010347 - 25 Dec 2022

Viewed by 1822

Abstract

To assess the role of adenylyl cyclase type 7 (AC7) in microglia’s immune function, we generated AC7 gene knockout (AC7 KO) clones from a mouse microglial cell line, BV-2, using the CRISPR-Cas9 gene editing system. The ability of BV-2 cells to generate cAMP and their innate immune functions were examined in the presence or absence of ethanol. The parental BV-2 cells showed robust cAMP production when stimulated with prostaglandin-E₁ (PGE₁) and ethanol increased cAMP production in a dose-dependent manner. AC7 KO clones of BV-2 cells showed diminished and ethanol-insensitive cAMP production. The phagocytic activity of the parental BV-2 cells was inhibited in the presence of PGE₁; AC7 KO BV-2 cells showed lower and PGE₁-insensitive phagocytic activity. Innate immune activities of the parental BV-2 cells, including bacterial killing, nitric oxide synthesis, and expression of arginase 1 and interleukin 10 were activated as expected with small effects of ethanol. However, the innate immune activities of AC7 KO cells were either drastically diminished or not detected. The data presented suggest that AC7 has an important role in the innate immune functions of microglial cells. AC7’s involvement in ethanol’s effects on immune functions remains unclear. Further studies are needed. Full article

(This article belongs to the Special Issue The Brain as a Manager of the Body—Molecular Aspects of Development and Functioning in Health and Disease)

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24 pages, 3804 KiB

Open AccessArticle

Anti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neurons

by Meenakshi Sundaram Kumar, Megan E. Fowler-Magaw, Daniel Kulick, Sivakumar Boopathy, Del Hayden Gadd, Melissa Rotunno, Catherine Douthwright, Diane Golebiowski, Issa Yusuf, Zuoshang Xu, Robert H. Brown, Jr., Miguel Sena-Esteves, Alison L. O'Neil and Daryl A. Bosco

Int. J. Mol. Sci. 2022, 23(24), 16013; https://doi.org/10.3390/ijms232416013 - 16 Dec 2022

Cited by 3 | Viewed by 3218

Abstract

ALS-linked mutations induce aberrant conformations within the SOD1 protein that are thought to underlie the pathogenic mechanism of SOD1-mediated ALS. Although clinical trials are underway for gene silencing of SOD1, these approaches reduce both wild-type and mutated forms of SOD1. Here, we sought to develop anti-SOD1 nanobodies with selectivity for mutant and misfolded forms of human SOD1 over wild-type SOD1. Characterization of two anti-SOD1 nanobodies revealed that these biologics stabilize mutant SOD1 in vitro. Further, SOD1 expression levels were enhanced and the physiological subcellular localization of mutant SOD1 was restored upon co-expression of anti-SOD1 nanobodies in immortalized cells. In human motor neurons harboring the SOD1 A4V mutation, anti-SOD1 nanobody expression promoted neurite outgrowth, demonstrating a protective effect of anti-SOD1 nanobodies in otherwise unhealthy cells. In vitro assays revealed that an anti-SOD1 nanobody exhibited selectivity for human mutant SOD1 over endogenous murine SOD1, thus supporting the preclinical utility of anti-SOD1 nanobodies for testing in animal models of ALS. In sum, the anti-SOD1 nanobodies developed and presented herein represent viable biologics for further preclinical testing in human and mouse models of ALS. Full article

(This article belongs to the Special Issue The Brain as a Manager of the Body—Molecular Aspects of Development and Functioning in Health and Disease)

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26 pages, 2108 KiB

Open AccessArticle

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

by Lorenza Vantaggiato, Enxhi Shaba, Alfonso Carleo, Daiana Bezzini, Giovanna Pannuzzo, Alice Luddi, Paola Piomboni, Luca Bini and Laura Bianchi

Int. J. Mol. Sci. 2022, 23(21), 13537; https://doi.org/10.3390/ijms232113537 - 4 Nov 2022

Cited by 8 | Viewed by 3652

Abstract

Krabbe disease (KD) is a rare autosomal recessive disorder caused by mutations in the galactocerebrosidase gene (GALC). Defective GALC causes aberrant metabolism of galactolipids present almost exclusively in myelin, with consequent demyelinization and neurodegeneration of the central and peripheral nervous system (NS). KD shares some similar features with other neuropathies and heterozygous carriers of GALC mutations are emerging with an increased risk in developing NS disorders. In this work, we set out to identify possible variations in the proteomic profile of KD-carrier brain to identify altered pathways that may imbalance its homeostasis and that may be associated with neurological disorders. The differential analysis performed on whole brains from 33-day-old twitcher (galc ^−/−), heterozygous (galc ^+/−), and wild-type mice highlighted the dysregulation of several multifunctional factors in both heterozygous and twitcher mice. Notably, the KD-carrier mouse, despite its normal phenotype, presents the deregulation of vimentin, receptor of activated protein C kinase 1 (RACK1), myelin basic protein (MBP), 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP), transitional endoplasmic reticulum ATPase (VCP), and N-myc downstream regulated gene 1 protein (NDRG1) as well as changes in the ubiquitinated-protein pattern. Our findings suggest the carrier may be affected by dysfunctions classically associated with neurodegeneration: (i) alteration of (mechano) signaling and intracellular trafficking, (ii) a generalized affection of proteostasis and lipid metabolism, with possible defects in myelin composition and turnover, and (iii) mitochondrion and energy supply dysfunctions. Full article

(This article belongs to the Special Issue The Brain as a Manager of the Body—Molecular Aspects of Development and Functioning in Health and Disease)

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24 pages, 5089 KiB

Open AccessArticle

Striatal Neurons Partially Expressing a Dopaminergic Phenotype: Functional Significance and Regulation

by Dmitry Troshev, Alyona Bannikova, Victor Blokhin, Anna Kolacheva, Tatiana Pronina and Michael Ugrumov

Int. J. Mol. Sci. 2022, 23(19), 11054; https://doi.org/10.3390/ijms231911054 - 21 Sep 2022

Cited by 6 | Viewed by 2630

Abstract

Since the discovery of striatal neurons expressing dopamine-synthesizing enzymes, researchers have attempted to identify their phenotype and functional significance. In this study, it was shown that in transgenic mice expressing green fluorescent protein (GFP) under the tyrosine hydroxylase (TH) gene promoter, (i) there are striatal neurons expressing only TH, only aromatic L-amino acid decarboxylase (AADC), or both enzymes of dopamine synthesis; (ii) striatal neurons expressing dopamine-synthesizing enzymes are not dopaminergic since they lack a dopamine transporter; (iii) monoenzymatic neurons expressing individual complementary dopamine-synthesizing enzymes produce this neurotransmitter in cooperation; (iv) striatal nerve fibers containing only TH, only AADC, or both enzymes project into the lateral ventricles, providing delivery pathways for L-3,4-dihydroxyphenylalanine and dopamine to the cerebrospinal fluid; and (v) striatal GFP neurons express receptor genes for various signaling molecules, i.e., classical neurotransmitters, neuropeptides, and steroids, indicating fine regulation of these neurons. Based on our data, it is assumed that the synthesis of dopamine by striatal neurons is a compensatory response to the death of nigral dopaminergic neurons in Parkinson’s disease, which opens broad prospects for the development of a fundamentally novel antiparkinsonian therapy. Full article

(This article belongs to the Special Issue The Brain as a Manager of the Body—Molecular Aspects of Development and Functioning in Health and Disease)

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Review

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24 pages, 2257 KiB

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An Overview of the Molecular Cues and Their Intracellular Signaling Shared by Cancer and the Nervous System: From Neurotransmitters to Synaptic Proteins, Anatomy of an All-Inclusive Cooperation

by Marco Arese, Federico Bussolino, Margherita Pergolizzi and Laura Bizzozero

Int. J. Mol. Sci. 2022, 23(23), 14695; https://doi.org/10.3390/ijms232314695 - 24 Nov 2022

Cited by 2 | Viewed by 2237

Abstract

We propose an overview of the molecular cues and their intracellular signaling involved in the crosstalk between cancer and the nervous system. While “cancer neuroscience” as a field is still in its infancy, the relation between cancer and the nervous system has been known for a long time, and a huge body of experimental data provides evidence that tumor–nervous system connections are widespread. They encompass different mechanisms at different tumor progression steps, are multifaceted, and display some intriguing analogies with the nervous system’s physiological processes. Overall, we can say that many of the paradigmatic “hallmarks of cancer” depicted by Weinberg and Hanahan are affected by the nervous system in a variety of manners. Full article

(This article belongs to the Special Issue The Brain as a Manager of the Body—Molecular Aspects of Development and Functioning in Health and Disease)

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