18 research outputs found

    Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

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    Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer's disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed

    Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia

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    Age-associated memory decline is due to variable combinations of genetic and environmental risk factors. How these risk factors interact to drive disease onset is currently unknown. Here we begin to elucidate the mechanisms by which post-traumatic stress disorder (PTSD) at a young age contributes to an increased risk to develop dementia at old age. We show that the actin nucleator Formin 2 (Fmn2) is deregulated in PTSD and in Alzheimer's disease (AD) patients. Young mice lacking the Fmn2 gene exhibit PTSD-like phenotypes and corresponding impairments of synaptic plasticity, while the consolidation of new memories is unaffected. However, Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. In conclusion, our data present a new approach to explore the connection between AD risk factors across life span and provide mechanistic insight to the processes by which neuropsychiatric diseases at a young age affect the risk for developing dementia

    MyBrain-Seq: A Pipeline for MiRNA-Seq Data Analysis in Neuropsychiatric Disorders

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    High-throughput sequencing of small RNA molecules such as microRNAs (miRNAs) has become a widely used approach for studying gene expression and regulation. However, analyzing miRNA-Seq data can be challenging because it requires multiple steps, from quality control and preprocessing to differential expression and pathway-enrichment analyses, with many tools and databases available for each step. Furthermore, reproducibility of the analysis pipeline is crucial to ensure that the results are accurate and reliable. Here, we present myBrain-Seq, a comprehensive and reproducible pipeline for analyzing miRNA-Seq data that incorporates miRNA-specific solutions at each step of the analysis. The pipeline was designed to be flexible and user-friendly, allowing researchers with different levels of expertise to perform the analysis in a standardized and reproducible manner, using the most common and widely used tools for each step. In this work, we describe the implementation of myBrain-Seq and demonstrate its capacity to consistently and reproducibly identify differentially expressed miRNAs and enriched pathways by applying it to a real case study in which we compared schizophrenia patients who responded to medication with treatment-resistant schizophrenia patients to obtain a 16-miRNA treatment-resistant schizophrenia profile

    Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

    No full text
    Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer's disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed

    Proteómica shotgun aplicada al estudio de nuevos biomarcadores en esquizofrenia

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    Poster.-- VIII Edición Foro Internacional en Esquizofrenia CIBERSAM, 21-22 November 2019, MadridLa Esquizofrenia es un trastorno psiquiátrico altamente complejo y heterogéneo desde un punto de vista clínico y molecular, producto de la combinación de factores genéticos y ambientales que influyen en el correcto desarrollo de las funciones cerebrales. Pese a afectar a un 1% de la población mundial, su etiología representa una incógnita y su diagnóstico se basa en entrevistas clínicas y evaluaciones mentales debido a que no existen pruebas biológicas que corroboren el juicio del psiquiatra. Por ello, es extremadamente necesario el hallazgo de biomarcadores que permitan la obtención de un diagnóstico, pronóstico y teranóstico correcto de esta enfermedadEste trabajo fue financiado los prpyectos Ramón & Cajal (RYC-2014-15246) y por la Agencia Gallega de innovación-GAIN grant (IN607D-2016/003; IN607D-2017/01)Peer reviewe

    Data-Driven Phenotyping of Alzheimer’s Disease under Epigenetic Conditions Using Partial Volume Correction of PET Studies and Manifold Learning

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    Alzheimer’s disease (AD) is the most common form of dementia. An increasing number of studies have confirmed epigenetic changes in AD. Consequently, a robust phenotyping mechanism must take into consideration the environmental effects on the patient in the generation of phenotypes. Positron Emission Tomography (PET) is employed for the quantification of pathological amyloid deposition in brain tissues. The objective is to develop a new methodology for the hyperparametric analysis of changes in cognitive scores and PET features to test for there being multiple AD phenotypes. We used a computational method to identify phenotypes in a retrospective cohort study (532 subjects), using PET and Magnetic Resonance Imaging (MRI) images and neuropsychological assessments, to develop a novel computational phenotyping method that uses Partial Volume Correction (PVC) and subsets of neuropsychological assessments in a non-biased fashion. Our pipeline is based on a Regional Spread Function (RSF) method for PVC and a t-distributed Stochastic Neighbor Embedding (t-SNE) manifold. The results presented demonstrate that (1) the approach to data-driven phenotyping is valid, (2) the different techniques involved in the pipelines produce different results, and (3) they permit us to identify the best phenotyping pipeline. The method identifies three phenotypes and permits us to analyze them under epigenetic conditions

    Genomic Factors and Therapeutic Approaches in HIV-Associated Neurocognitive Disorders: A Comprehensive Review

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    HIV-associated neurocognitive disorders (HANDs) still persist despite improved life expectancy, reduced viral loads, and decreased infection severity. The number of patients affected by HANDs ranges from (30 to 50) % of HIV-infected individuals. The pathological mechanisms contributing to HANDs and the most serious manifestation of the disease, HIV-associated dementia (HAD), are not yet well understood. Evidence suggests that these mechanisms are likely multifactorial, producing neurocognitive complications involving disorders such as neurogenesis, autophagy, neuroinflammation, and mitochondrial dysfunction. Over the years, multiple pharmacological approaches with specific mechanisms of action acting upon distinct targets have been approved. Although these therapies are effective in reducing viral loading to undetectable levels, they also present some disadvantages such as common side effects, the need for administration with a very high frequency, and the possibility of drug resistance. Genetic studies on HANDs provide insights into the biological pathways and mechanisms that contribute to cognitive impairment in people living with HIV-1. Furthermore, they also help identify genetic variants that increase susceptibility to HANDs and can be used to tailor treatment approaches for HIV-1 patients. Identification of the genetic markers associated with disease progression can help clinicians predict which individuals require more aggressive management and by understanding the genetic basis of the disorder, it will be possible to develop targeted therapies to mitigate cognitive impairment. The main goal of this review is to provide details on the epidemiological data currently available and to summarise the genetic (specifically, the genetic makeup of the immune system), transcriptomic, and epigenetic studies available on HANDs to date. In addition, we address the potential pharmacological therapeutic strategies currently being investigated. This will provide valuable information that can guide clinical care, drug development, and our overall understanding of these diseases

    Data-Driven Phenotyping of Alzheimer’s Disease under Epigenetic Conditions Using Partial Volume Correction of PET Studies and Manifold Learning

    No full text
    Alzheimer’s disease (AD) is the most common form of dementia. An increasing number of studies have confirmed epigenetic changes in AD. Consequently, a robust phenotyping mechanism must take into consideration the environmental effects on the patient in the generation of phenotypes. Positron Emission Tomography (PET) is employed for the quantification of pathological amyloid deposition in brain tissues. The objective is to develop a new methodology for the hyperparametric analysis of changes in cognitive scores and PET features to test for there being multiple AD phenotypes. We used a computational method to identify phenotypes in a retrospective cohort study (532 subjects), using PET and Magnetic Resonance Imaging (MRI) images and neuropsychological assessments, to develop a novel computational phenotyping method that uses Partial Volume Correction (PVC) and subsets of neuropsychological assessments in a non-biased fashion. Our pipeline is based on a Regional Spread Function (RSF) method for PVC and a t-distributed Stochastic Neighbor Embedding (t-SNE) manifold. The results presented demonstrate that (1) the approach to data-driven phenotyping is valid, (2) the different techniques involved in the pipelines produce different results, and (3) they permit us to identify the best phenotyping pipeline. The method identifies three phenotypes and permits us to analyze them under epigenetic conditions

    Insulin-like Growth Factor 2 (IGF-2) and Insulin-like Growth Factor Binding Protein 7 (IGFBP-7) Are Upregulated after Atypical Antipsychotics in Spanish Schizophrenia Patients

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    Insulin-like growth factor 2 (IGF-2) and IGF binding protein 7 (IGFBP-7) have been related to schizophrenia (SZ) due to their implication in neurodevelopment. The purpose of this study was to assess whether the alterations in IGF-2 and IGFBP-7 in SZ patients are intrinsically related to the psychiatric disorder itself or are a secondary phenomenon due to antipsychotic treatment. In order to test this hypothesis, we measured plasma IGF-2 and IGFBP-7 in drug-naïve first episode (FE) and multiple episodes or chronic (ME) SZ Caucasian patients who have been following treatment for years. A total of 55 SZ patients (FE = 15, ME = 40) and 45 healthy controls were recruited. The Positive and Negative Syndrome Scale (PANSS) and the Self-Assessment Anhedonia Scale (SAAS) were employed to check schizophrenic symptomatology and anhedonia, respectively. Plasma IGF-2 and IGFBP-7 levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA). The FE SZ patients had much lower IGF-2, but not IGFBP-7, than controls. Moreover, both IGF-2 and IGFBP-7 significantly increased after atypical antipsychotic treatment (aripiprazole, olanzapine, or risperidone) in these patients. On the other hand, chronic patients showed higher levels of both proteins when compared to controls. Our study suggests that circulatory IGF-2 and IGFBP-7 increase after antipsychotic treatment, regardless of long-term conditions and being lower in drug-naïve FE patients

    Association between Peer Victimization (PV) in Childhood/Adolescence and Personality Disorders among Adult Patients

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    Peer Victimization (PV) or being bullied in childhood/adolescence has been associated with several negative outcomes in mental health conditions beyond the time of its occurrence. However, its possible association with personality disorders has been slightly explored. In the present study we have compared the frequency of DSM IV personality disorders among adult patients with (N = 28) or without (N = 418) a reported history of PV. For this purpose, axis II was evaluated with the Self-Report Checklist for Preliminary Items for Major Categories, whereas self-esteem and self-assessment of functioning were evaluated with single questions. Patients with PV history have met the diagnostic criteria of the avoidant (60.7% vs. 12.2%), depressive (28.5% vs. 5.2%) and paranoid (17.9% vs. 5%) personality disorders more frequently than patients without history of PV. Moreover, these patients with antecedents of being bullied have also reported lower self-esteem (2 vs. 3) and in the assessment of social functioning (4 vs. 5). Our study indicated that there is a clear association between PV and avoidant, depressive and paranoid personality patterns. These results suggest that the stress related with the experience of PV threatens a basic psychobiological need such as social acceptance with implications for the beginning of long-term dysfunctional personality trajectories
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