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Genomics of Brain Disorders 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 45694

Special Issue Editor

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our 2018 Special Issue, "Genomics of Brain Disorders" (https://www.mdpi.com/journal/ijms/special_issues/genomics_brain).
Brain disorders represent the third major problem of health and disability in developed countries after cardiovascular disorders and cancer. From a global health perspective, important issues to be addressed with regard to neuropsychiatric disorders (NPDs) are: (i) disease burden (DALYs: disability-adjusted life years; YLDs: years lived with disability; YLLs: years of life lost); (ii) the costs (direct, indirect) of disease; (iii) disease pathogenesis; (iv) the identification of presymptomatic biomarkers; (v) novel targets for drug development; and (vi) personalized treatments with pharmacogenetic procedures for optimizing drug efficacy and safety. NPDs contribute approximately 10% of the global burden of disease. About 30% of all YLDs are assigned to NPDs, especially depression, alcohol use disorders, schizophrenia, bipolar disorder, and dementia. NPDs are the leading cause of disease burden, responsible for 7.4% of global DALYs and 22.9% of global YLDs. Within NPDs, mental disorders account for 56.7% DALYs, followed by neurological disorders (28.6%) and substance use disorder (14.7%).
The global cost of NPDs is projected to be about US$6 trillion by 2030. An estimated eight million deaths annually are attributed to mental disorders. Approximately 127 million Europeans suffer brain disorders. The total annual cost of brain disorders in Europe is about €386 billion, with €135 billion in direct medical expenditures, €179 billion in indirect costs, and €72 billion in direct non-medical costs. Mental disorders represent €240 billion (62% of the total cost, excluding dementia), followed by neurological diseases (€84 billion, 22%).
The primary cause of most brain disorders is poorly understood. In NPDs there is a convergence of multiple genomic defects distributed across the human genome with epigenetic phenomena and environmental risk factors leading to the phenotypic expression of the disease. In children, neurodevelopmental disorders are determinant for abnormal brain maturation and early mental derailment. In age-related neurodegenerative disorders, a common feature is the presence of intracellular and/or extracellular deposits of abnormally processed proteins that represent prototypical hallmarks probably contributing to premature neuronal death. A better characterization of the genomic background of mental and neurological disorders is necessary for elucidating disease-specific pathogenesis, as well as the identification of accurate biomarkers, and the implementation of novel treatments addressing pathogenic, mechanistic, metabolic, transporter and pleiotropic genes, and their products, associated with specific NPDs.

Prof. Dr. Ramón Cacabelos
Guest Editor

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Keywords

  • Alzheimer’s disease
  • Attention deficit/hyperactivity disorder
  • Autism spectrum disorders
  • Brain tumors
  • Demyelinating disorders
  • Drug addition
  • Epilepsy
  • Migraine
  • Mood disorders
  • Motor neuron disorders
  • Parkinson’s disease
  • Schizophrenia
  • Sleep disorders
  • Stroke
  • Vascular dementia

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Published Papers (9 papers)

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Research

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18 pages, 4840 KiB  
Article
Passive Transfer of Sera from ALS Patients with Identified Mutations Evokes an Increased Synaptic Vesicle Number and Elevation of Calcium Levels in Motor Axon Terminals, Similar to Sera from Sporadic Patients
by Valéria Meszlényi, Roland Patai, Tamás F. Polgár, Bernát Nógrádi, Laura Körmöczy, Rebeka Kristóf, Krisztina Spisák, Kornélia Tripolszki, Márta Széll, Izabella Obál, József I. Engelhardt and László Siklós
Int. J. Mol. Sci. 2020, 21(15), 5566; https://doi.org/10.3390/ijms21155566 - 3 Aug 2020
Cited by 4 | Viewed by 2669
Abstract
Previously, we demonstrated increased calcium levels and synaptic vesicle densities in the motor axon terminals (MATs) of sporadic amyotrophic lateral sclerosis (ALS) patients. Such alterations could be conferred to mice with an intraperitoneal injection of sera from these patients or with purified immunoglobulin [...] Read more.
Previously, we demonstrated increased calcium levels and synaptic vesicle densities in the motor axon terminals (MATs) of sporadic amyotrophic lateral sclerosis (ALS) patients. Such alterations could be conferred to mice with an intraperitoneal injection of sera from these patients or with purified immunoglobulin G. Later, we confirmed the presence of similar alterations in the superoxide dismutase 1 G93A transgenic mouse strain model of familial ALS. These consistent observations suggested that calcium plays a central role in the pathomechanism of ALS. This may be further reinforced by completing a similar analytical study of the MATs of ALS patients with identified mutations. However, due to the low yield of muscle biopsy samples containing MATs, and the low incidence of ALS patients with the identified mutations, these examinations are not technically feasible. Alternatively, a passive transfer of sera from ALS patients with known mutations was used, and the MATs of the inoculated mice were tested for alterations in their calcium homeostasis and synaptic activity. Patients with 11 different ALS-related mutations participated in the study. Intraperitoneal injection of sera from these patients on two consecutive days resulted in elevated intracellular calcium levels and increased vesicle densities in the MATs of mice, which is comparable to the effect of the passive transfer from sporadic patients. Our results support the idea that the pathomechanism underlying the identical manifestation of the disease with or without identified mutations is based on a common final pathway, in which increasing calcium levels play a central role. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 2.0)
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14 pages, 1005 KiB  
Article
The Sodium Channel B4-Subunits are Dysregulated in Temporal Lobe Epilepsy Drug-Resistant Patients
by Mariam A. Sheilabi, Louise Y. Takeshita, Edward J. Sims, Francesco Falciani and Alessandra P. Princivalle
Int. J. Mol. Sci. 2020, 21(8), 2955; https://doi.org/10.3390/ijms21082955 - 22 Apr 2020
Cited by 10 | Viewed by 3665
Abstract
Temporal lobe epilepsy (TLE) is the most common type of partial epilepsy referred for surgery due to antiepileptic drug (AED) resistance. A common molecular target for many of these drugs is the voltage-gated sodium channel (VGSC). The VGSC consists of four domains of [...] Read more.
Temporal lobe epilepsy (TLE) is the most common type of partial epilepsy referred for surgery due to antiepileptic drug (AED) resistance. A common molecular target for many of these drugs is the voltage-gated sodium channel (VGSC). The VGSC consists of four domains of pore-forming α-subunits and two auxiliary β-subunits, several of which have been well studied in epileptic conditions. However, despite the β4-subunits’ role having been reported in some neurological conditions, there is little research investigating its potential significance in epilepsy. Therefore, the purpose of this work was to assess the role of SCN4β in epilepsy by using a combination of molecular and bioinformatics approaches. We first demonstrated that there was a reduction in the relative expression of SCN4B in the drug-resistant TLE patients compared to non-epileptic control specimens, both at the mRNA and protein levels. By analyzing a co-expression network in the neighborhood of SCN4B we then discovered a linkage between the expression of this gene and K+ channels activated by Ca2+, or K+ two-pore domain channels. Our approach also inferred several potential effector functions linked to variation in the expression of SCN4B. These observations support the hypothesis that SCN4B is a key factor in AED-resistant TLE, which could help direct both the drug selection of TLE treatments and the development of future AEDs. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 2.0)
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16 pages, 2328 KiB  
Article
DNA Methylation in Neurodegenerative and Cerebrovascular Disorders
by Olaia Martínez-Iglesias, Iván Carrera, Juan Carlos Carril, Lucía Fernández-Novoa, Natalia Cacabelos and Ramón Cacabelos
Int. J. Mol. Sci. 2020, 21(6), 2220; https://doi.org/10.3390/ijms21062220 - 23 Mar 2020
Cited by 44 | Viewed by 4001
Abstract
DNA methylation is an epigenetic mechanism by which methyl groups are added to DNA, playing a crucial role in gene expression regulation. The aim of the present study is to compare methylation status of healthy subjects with that of patients with Alzheimer’s, Parkinson’s [...] Read more.
DNA methylation is an epigenetic mechanism by which methyl groups are added to DNA, playing a crucial role in gene expression regulation. The aim of the present study is to compare methylation status of healthy subjects with that of patients with Alzheimer’s, Parkinson’s or Cerebrovascular diseases. We also analyze methylation status of a transgenic Alzheimer’s disease mouse model (3xTg-AD). Our results show that both global methylation (n = 141) and hydroxymethylation (n = 131) levels are reduced in DNA samples from buffy coats of patients with neurodegenerative disorders and age-related cerebrovascular disease. The importance of methylation and hydroxymethylation reduction is stressed by the finding that DNMT3a mRNA levels are also downregulated in buffy coats of patients with Dementia (n = 25). Global methylation is also reduced in brain, liver and serum samples of 3xTg-AD vs. wild type mice, such as DNMT3a mRNA levels that are also decreased in the brain of 3xTg-AD (n = 10). These results suggest that the use of global methylation and hydroxymethylation levels, together with the study of DNMT3a expression, could be useful as a new diagnostic biomarker for these prevalent disorders. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 2.0)
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16 pages, 1526 KiB  
Article
Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Mitochondrial DNA Profiling of Parkinson’s Disease
by Annamaria Zaia, Pierluigi Maponi, Martina Zannotti and Tiziana Casoli
Int. J. Mol. Sci. 2020, 21(5), 1758; https://doi.org/10.3390/ijms21051758 - 4 Mar 2020
Cited by 8 | Viewed by 3769
Abstract
Increasing evidence implicates mitochondrial dysfunction in the etiology of Parkinson’s disease (PD). Mitochondrial DNA (mtDNA) mutations are considered a possible cause and this mechanism might be shared with the aging process and with other age-related neurodegenerative disorders such as Alzheimer’s disease (AD). We [...] Read more.
Increasing evidence implicates mitochondrial dysfunction in the etiology of Parkinson’s disease (PD). Mitochondrial DNA (mtDNA) mutations are considered a possible cause and this mechanism might be shared with the aging process and with other age-related neurodegenerative disorders such as Alzheimer’s disease (AD). We have recently proposed a computerized method for mutated mtDNA characterization able to discriminate between AD and aging. The present study deals with mtDNA mutation-based profiling of PD. Peripheral blood mtDNA sequences from late-onset PD patients and age-matched controls were analyzed and compared to the revised Cambridge Reference Sequence (rCRS). The chaos game representation (CGR) method, modified to visualize heteroplasmic mutations, was used to display fractal properties of mtDNA sequences and fractal lacunarity analysis was applied to quantitatively characterize PD based on mtDNA mutations. Parameter β, from the hyperbola model function of our lacunarity method, was statistically different between PD and control groups when comparing mtDNA sequence frames corresponding to GenBank np 5713-9713. Our original method, based on CGR and lacunarity analysis, represents a useful tool to analyze mtDNA mutations. Lacunarity parameter β is able to characterize individual mutation profile of mitochondrial genome and could represent a promising index to discriminate between PD and aging. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 2.0)
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13 pages, 762 KiB  
Article
Impaired Innate Immunity Mechanisms in the Brain of Alzheimer’s Disease
by Martina Romagnoli, Elisa Porcellini, Ilaria Carbone, Robert Veerhuis and Federico Licastro
Int. J. Mol. Sci. 2020, 21(3), 1126; https://doi.org/10.3390/ijms21031126 - 8 Feb 2020
Cited by 12 | Viewed by 3002
Abstract
Among environmental factors likely associated with Alzheimer’s disease (AD), persistent virus infections, and age-related progressive decline of immune competence might play a pivotal role. However, AD antimicrobial brain immune responses are poorly investigated. The present study focused on genes involved in antimicrobial defenses, [...] Read more.
Among environmental factors likely associated with Alzheimer’s disease (AD), persistent virus infections, and age-related progressive decline of immune competence might play a pivotal role. However, AD antimicrobial brain immune responses are poorly investigated. The present study focused on genes involved in antimicrobial defenses, especially against virus infections, in the AD brain. In particular, mRNA levels of IRF7, MED23, IL28B, and IFN-α genes were analyzed in hippocampus and temporal cortex brain samples from AD and non-demented controls. All subjects were also genotyped for APOE ε, IRF7, MED23, and IL28B gene polymorphisms. Most AD patients showed decreased mRNA levels of all investigated genes in the hippocampus and temporal cortex. However, a small group of AD patients showed increased hippocampal mRNA expression of MED23, IL28B, and IFN-α. mRNA levels of MED23, IL28B, IFN-α from the hippocampus and those of MED23 from the temporal cortex were further decreased in APOE ε4 allele AD carriers. Moreover, rs6598008 polymorphism of IRF7 was significantly associated with decreased hippocampal expression of IRF7, MED23, IL28B, and IFN-α. These findings suggest that AD brains show impaired innate antimicrobial gene expression profiles, and individual genetic makeup, such as positivity for the APOE ε4 and IRF7 A alleles, might affect brain immune efficiency. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 2.0)
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12 pages, 632 KiB  
Article
Tackling Missing Heritability by Use of an Optimum Curve: A Systematic Review and Meta-Analysis
by Anneke Wegener Sleeswijk, Reinout Heijungs and Sarah Durston
Int. J. Mol. Sci. 2019, 20(20), 5104; https://doi.org/10.3390/ijms20205104 - 15 Oct 2019
Cited by 3 | Viewed by 2701
Abstract
Missing heritability is a common problem in psychiatry that impedes precision medicine approaches to autism and other heritable complex disorders. This proof-of-concept study uses a systematic review and meta-analysis of the association between variants of the serotonin transporter promoter (5-HTTLPR) and autism to [...] Read more.
Missing heritability is a common problem in psychiatry that impedes precision medicine approaches to autism and other heritable complex disorders. This proof-of-concept study uses a systematic review and meta-analysis of the association between variants of the serotonin transporter promoter (5-HTTLPR) and autism to explore the hypothesis that some missing heritability can be explained using an optimum curve. A systematic literature search was performed to identify transmission disequilibrium tests on the short/long (S/L) 5-HTTLPR polymorphism in relation to autism. We analysed five American, seven European, four Asian and two American/European samples. We found no transmission preference in the joint samples and in Europe, preferential transmission of S in America and preferential transmission of L in Asia. Heritability will be underestimated or missed in genetic association studies if two alternative genetic variants are associated with the same disorder in different subsets of a sample. An optimum curve, relating a multifactorial biological variable that incorporates genes and environment to a score for a human trait, such as social competence, can explain this. We suggest that variants of functionally related genes will sometimes appear in fixed combinations at both sides of an optimum curve and propose that future association studies should account for such combinations. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 2.0)
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14 pages, 258 KiB  
Article
The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes
by Miriam Ciani, Cristian Bonvicini, Catia Scassellati, Matteo Carrara, Carlo Maj, Silvia Fostinelli, Giuliano Binetti, Roberta Ghidoni and Luisa Benussi
Int. J. Mol. Sci. 2019, 20(16), 3903; https://doi.org/10.3390/ijms20163903 - 10 Aug 2019
Cited by 17 | Viewed by 4021
Abstract
Frontotemporal dementia (FTD) is a common form of dementia among early-onset cases. Several genetic factors for FTD have been revealed, but a large proportion of FTD cases still have an unidentified genetic origin. Recent studies highlighted common pathobiological mechanisms among neurodegenerative diseases. In [...] Read more.
Frontotemporal dementia (FTD) is a common form of dementia among early-onset cases. Several genetic factors for FTD have been revealed, but a large proportion of FTD cases still have an unidentified genetic origin. Recent studies highlighted common pathobiological mechanisms among neurodegenerative diseases. In the present study, we investigated a panel of candidate genes, previously described to be associated with FTD and/or other neurodegenerative diseases by targeted next generation sequencing (NGS). We focused our study on sporadic FTD (sFTD), devoid of disease-causing mutations in GRN, MAPT and C9orf72. Since genetic factors have a substantially higher pathogenetic contribution in early onset patients than in late onset dementia, we selected patients with early onset (<65 years). Our study revealed that, in 50% of patients, rare missense potentially pathogenetic variants in genes previously associated with Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis and Lewy body dementia (GBA, ABCA7, PARK7, FUS, SORL1, LRRK2, ALS2), confirming genetic pleiotropy in neurodegeneration. In parallel, a synergic genetic effect on FTD is suggested by the presence of variants in five different genes in one single patient. Further studies employing genome-wide approaches might highlight pathogenic variants in novel genes that explain the still missing heritability of FTD. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 2.0)

Review

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21 pages, 2830 KiB  
Review
Genetic and Neuroimaging Approaches to Understanding Post-Traumatic Stress Disorder
by Sabah Nisar, Ajaz A. Bhat, Sheema Hashem, Najeeb Syed, Santosh K. Yadav, Shahab Uddin, Khalid Fakhro, Puneet Bagga, Paul Thompson, Ravinder Reddy, Michael P. Frenneaux and Mohammad Haris
Int. J. Mol. Sci. 2020, 21(12), 4503; https://doi.org/10.3390/ijms21124503 - 24 Jun 2020
Cited by 22 | Viewed by 10674
Abstract
Post-traumatic stress disorder (PTSD) is a highly disabling condition, increasingly recognized as both a disorder of mental health and social burden, but also as an anxiety disorder characterized by fear, stress, and negative alterations in mood. PTSD is associated with structural, metabolic, and [...] Read more.
Post-traumatic stress disorder (PTSD) is a highly disabling condition, increasingly recognized as both a disorder of mental health and social burden, but also as an anxiety disorder characterized by fear, stress, and negative alterations in mood. PTSD is associated with structural, metabolic, and molecular changes in several brain regions and the neural circuitry. Brain areas implicated in the traumatic stress response include the amygdala, hippocampus, and prefrontal cortex, which play an essential role in memory function. Abnormalities in these brain areas are hypothesized to underlie symptoms of PTSD and other stress-related psychiatric disorders. Conventional methods of studying PTSD have proven to be insufficient for diagnosis, measurement of treatment efficacy, and monitoring disease progression, and currently, there is no diagnostic biomarker available for PTSD. A deep understanding of cutting-edge neuroimaging genetic approaches is necessary for the development of novel therapeutics and biomarkers to better diagnose and treat the disorder. A current goal is to understand the gene pathways that are associated with PTSD, and how those genes act on the fear/stress circuitry to mediate risk vs. resilience for PTSD. This review article explains the rationale and practical utility of neuroimaging genetics in PTSD and how the resulting information can aid the diagnosis and clinical management of patients with PTSD. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 2.0)
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24 pages, 2799 KiB  
Review
Autophagy in Neurodegenerative Diseases: A Hunter for Aggregates
by Hyungsun Park, Ju-Hee Kang and Seongju Lee
Int. J. Mol. Sci. 2020, 21(9), 3369; https://doi.org/10.3390/ijms21093369 - 10 May 2020
Cited by 117 | Viewed by 10222
Abstract
Cells have developed elaborate quality-control mechanisms for proteins and organelles to maintain cellular homeostasis. Such quality-control mechanisms are maintained by conformational folding via molecular chaperones and by degradation through the ubiquitin-proteasome or autophagy-lysosome system. Accumulating evidence suggests that impaired autophagy contributes to the [...] Read more.
Cells have developed elaborate quality-control mechanisms for proteins and organelles to maintain cellular homeostasis. Such quality-control mechanisms are maintained by conformational folding via molecular chaperones and by degradation through the ubiquitin-proteasome or autophagy-lysosome system. Accumulating evidence suggests that impaired autophagy contributes to the accumulation of intracellular inclusion bodies consisting of misfolded proteins, which is a hallmark of most neurodegenerative diseases. In addition, genetic mutations in core autophagy-related genes have been reported to be linked to neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Conversely, the pathogenic proteins, such as amyloid β and α-synuclein, are detrimental to the autophagy pathway. Here, we review the recent advances in understanding the relationship between autophagic defects and the pathogenesis of neurodegenerative diseases and suggest autophagy induction as a promising strategy for the treatment of these conditions. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 2.0)
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