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1.
Adv Clin Chem ; 90: 81-132, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31122612

RESUMO

Ever since their discovery, the telomeres and the telomerase have been topics of intensive research, first as a mechanism of cellular aging and later as an indicator of health and diseases in humans. By protecting the chromosome ends, the telomeres play a vital role in preserving the information in our genome. Telomeres shorten with age and the rate of telomere erosion provides insight into the proliferation history of cells. The pace of telomere attrition is known to increase at the onset of several pathological conditions. Telomere shortening has been emerging as a potential contributor in the pathogenesis of several neurological disorders including autism spectrum disorders (ASD), schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD) and depression. The rate of telomere attrition in the brain is slower than that of other tissues owing to the low rate of cell proliferation in brain. Telomere maintenance is crucial for the functioning of stem cells in brain. Taking together the studies on telomere attrition in various neurological disorders, an association between telomere shortening and disease status has been demonstrated in schizophrenia, AD and depression, in spite of a few negative reports. But, studies in ASD and PD have failed to produce conclusive results. The cause-effect relationship between TL and neurological disorders is yet to be elucidated. The factors responsible for telomere erosion, which have also been implicated in the pathogenesis of neurological disorders, need to be explored in detail. Telomerase activation is now being considered as a potential therapeutic strategy for neurological disorders.


Assuntos
Doenças do Sistema Nervoso/genética , Telômero/genética , Telômero/metabolismo , Animais , Southern Blotting , Humanos , Hibridização in Situ Fluorescente , Reação em Cadeia da Polimerase
4.
Genesis ; 57(5): e23292, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30884088

RESUMO

Medullary thyroid carcinoma (MTC) develops from hyperplasia of thyroid C cells and represents one of the major causes of thyroid cancer mortality. Mutations in the cysteine-rich domain (CRD) of the RET gene are the most prevalent genetic cause of MTC. The current consensus holds that such cysteine mutations cause ligand-independent dimerization and constitutive activation of RET. However, given the number of the CRD mutations left uncharacterized, our understanding of the pathogenetic mechanisms by which CRD mutations lead to MTC remains incomplete. We report here that RET(C618F), a mutation identified in MTC patients, displays moderately high basal activity and requires the ligand for its full activation. To assess the biological significance of RET(C618F) in organogenesis, we generated a knock-in mouse line conditionally expressing RET(C618F) cDNA by the Ret promoter. The RET(C618F) allele can be made to be Ret-null and express mCherry by Cre-loxP recombination, which allows the assessment of the biological influence of RET(C618F) in vivo. Mice expressing RET(C618F) display mild C cell hyperplasia and increased numbers of enteric neurons, indicating that RET(C618F) confers gain-of-function phenotypes. This mouse line serves as a novel biological platform for investigating pathogenetic mechanisms involved in MTC and enteric hyperganglionosis.


Assuntos
Carcinoma Neuroendócrino/genética , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Animais , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Sistema Nervoso Entérico/metabolismo , Sistema Nervoso Entérico/patologia , Técnicas de Introdução de Genes/métodos , Mutação em Linhagem Germinativa , Humanos , Hiperplasia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Proteínas Proto-Oncogênicas c-ret/biossíntese , Proteínas Proto-Oncogênicas c-ret/metabolismo , Hiperplasia do Timo/genética , Hiperplasia do Timo/metabolismo , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo
5.
Genome Res ; 29(4): 532-542, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30858344

RESUMO

Coding variants in epigenetic regulators are emerging as causes of neurological dysfunction and cancer. However, a comprehensive effort to identify disease candidates within the human epigenetic machinery (EM) has not been performed; it is unclear whether features exist that distinguish between variation-intolerant and variation-tolerant EM genes, and between EM genes associated with neurological dysfunction versus cancer. Here, we rigorously define 295 genes with a direct role in epigenetic regulation (writers, erasers, remodelers, readers). Systematic exploration of these genes reveals that although individual enzymatic functions are always mutually exclusive, readers often also exhibit enzymatic activity (dual-function EM genes). We find that the majority of EM genes are very intolerant to loss-of-function variation, even when compared to the dosage sensitive transcription factors, and we identify 102 novel EM disease candidates. We show that this variation intolerance is driven by the protein domains encoding the epigenetic function, suggesting that disease is caused by a perturbed chromatin state. We then describe a large subset of EM genes that are coexpressed within multiple tissues. This subset is almost exclusively populated by extremely variation-intolerant genes and shows enrichment for dual-function EM genes. It is also highly enriched for genes associated with neurological dysfunction, even when accounting for dosage sensitivity, but not for cancer-associated EM genes. Finally, we show that regulatory regions near epigenetic regulators are genetically important for common neurological traits. These findings prioritize novel disease candidate EM genes and suggest that this coexpression plays a functional role in normal neurological homeostasis.


Assuntos
Epigênese Genética , Doenças do Sistema Nervoso/genética , Polimorfismo Genético , Montagem e Desmontagem da Cromatina , Humanos , Mutação com Perda de Função , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
6.
Trends Pharmacol Sci ; 40(4): 278-293, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30871735

RESUMO

The family of adhesion G protein-coupled receptors (aGPCRs) consists of 33 members in humans. Although the majority are orphan receptors with unknown functions, many reports have demonstrated critical functions for some members of this family in organogenesis, neurodevelopment, myelination, angiogenesis, and cancer progression. Importantly, mutations in several aGPCRs have been linked to human diseases. The crystal structure of a shared protein domain, the GPCR Autoproteolysis INducing (GAIN) domain, has enabled the discovery of a common signaling mechanism - a tethered agonist - for this class of receptors. A series of recent reports has shed new light on their biological functions and disease relevance. This review focuses on these recent advances in our understanding of aGPCR biology in the nervous system and the untapped potential of aGPCRs as novel therapeutic targets for neurological disease.


Assuntos
Terapia de Alvo Molecular , Doenças do Sistema Nervoso/tratamento farmacológico , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Desenvolvimento de Medicamentos/métodos , Humanos , Mutação , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/fisiopatologia , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais
7.
Biomed Res Int ; 2019: 9450240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30854399

RESUMO

An increasing number of research studies over recent years have focused on the function of microRNA (miRNA) molecules which have unique characteristics in terms of structure and function. They represent a class of endogenous noncoding single-strand small molecules. An abundance of miRNA clusters has been found in the genomes of various organisms often located in a polycistron. The miR-17-92 family is among the most famous miRNAs and has been identified as an oncogene. The functions of this cluster, together with the seven individual molecules that it comprises, are most related to cancers, so it would not be surprising that they are considered to have involvement in the development of tumors. The miR-17-92 cluster is therefore expected not only to be a tumor marker, but also to perform an important role in the early diagnosis of those diseases and possibly also be a target for tumor biotherapy. The miR-17-92 cluster affects the development of disease by regulating many related cellular processes and multiple target genes. Interestingly, it also has important roles that cannot be ignored in disease of the nervous system and circulation and modulates the growth and development of bone. Therefore, it provides new opportunities for disease prevention, clinical diagnosis, prognosis, and targeted therapy. Here we review the role of the miR-17-92 cluster that has received little attention in relation to neurological diseases, cardiac diseases, and the development of bone and tumors.


Assuntos
Desenvolvimento Ósseo/genética , MicroRNAs/genética , Neoplasias/genética , Doenças do Sistema Nervoso/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Cardiopatias/genética , Cardiopatias/patologia , Humanos , Família Multigênica/genética , Neoplasias/patologia , Doenças do Sistema Nervoso/patologia , Prognóstico
8.
Hormones (Athens) ; 18(1): 109-112, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30612286

RESUMO

OBJECTIVE: Triple A syndrome is a rare autosomal recessive disorder caused by mutations in the AAAS gene on chromosome 12q13. Its main clinical features are alacrima, achalasia, and adrenal insufficiency, with most patients also having neurological symptoms and autonomic dysfunction. The neurologic manifestations are less well-understood, especially in children. Here, we examine two siblings who were found to have a novel mutation in the AAAS gene and who were found to have subtle, but important, neurologic findings. DESIGN: This is a case report of two siblings. RESULTS: We discuss two siblings exhibiting different signs of the disorder including neurologic dysfunction found at varying ages. Genetic analysis revealed that both patients have the same compound heterozygous mutations in the AAAS gene consisting of one novel mutation (c.500 C>A, A167E) and one previously described mutation (c.1331+1G> A/IVS14+1 G>A). A diagnosis of triple A syndrome was reached based on their clinical and genetic findings. CONCLUSIONS: The unique characteristic of these two cases is the novel mutation in the AAAS gene, which is likely pathogenic. In addition, they showcase the genotype-phenotype variability of the disease, as well as the importance of early identification of the neurologic abnormalities, which can result in early intervention and possibly improved outcomes.


Assuntos
Insuficiência Adrenal/genética , Acalasia Esofágica/genética , Proteínas do Tecido Nervoso/genética , Doenças do Sistema Nervoso/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Insuficiência Adrenal/complicações , Criança , Pré-Escolar , Acalasia Esofágica/complicações , Feminino , Humanos , Masculino , Doenças do Sistema Nervoso/etiologia , Irmãos
9.
Mol Cell Probes ; 44: 14-20, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30682426

RESUMO

The heterooctameric mitochondrial trifunctional protein (MTP), composed of four α- and ß-subunits harbours three enzymes that each perform a different function in mitochondrial fatty acid ß-oxidation. Pathogenic variants in the MTP genes (HADHA and HADHB) cause MTP deficiency, a rare autosomal recessive metabolic disorder characterized by phenotypic heterogeneity ranging from severe, early-onset, cardiac disease to milder, later-onset, myopathy and neuropathy. Since metabolic myopathies and neuropathies are a group of rare genetic disorders and their associated muscle symptoms may be subtle, the diagnosis is often delayed. Here we evaluated data of 161 patients with myopathy and 242 patients with neuropathy via next generation sequencing (NGS) and report the diagnostic yield in three patients of this cohort by the detection of disease-causing variants in the HADHA or HADHB gene. The mitigated phenotypes of this treatable disease were missed by the newborn screening, highlighting the importance of phenotype-based NGS analysis in patients with rare and clinically very variable disorders such as MTP deficiency.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Subunidade alfa da Proteína Mitocondrial Trifuncional/genética , Subunidade beta da Proteína Mitocondrial Trifuncional/genética , Mutação/genética , Adolescente , Cardiomiopatias/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Miopatias Mitocondriais/genética , Proteína Mitocondrial Trifuncional/deficiência , Proteína Mitocondrial Trifuncional/genética , Doenças do Sistema Nervoso/genética , Fenótipo , Rabdomiólise/genética , Síndrome
10.
Nervenarzt ; 90(2): 131-137, 2019 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-30645660

RESUMO

After an impressively successful application as a research instrument, whole-exome sequencing (WES) now enters the clinical practice due to its high diagnostic, time, and economic efficiency. WES is the diagnostic method of choice for symptoms that may be due to many different monogenic causes. Neurological indications include movement disorders, especially in cases of early symptom onset, familial clustering and complex manifestation. Starting from a blood sample, enrichment and sequencing of the exome enable the examination of all coding DNA regions for point mutations and small insertions/deletions. The identification of variants as the cause of a disease requires a professional evaluation pipeline, variant prioritization schemes and variant classification databases. Whereas many variants can be reliably classified as pathogenic or benign, variants of unclear significance (VUS) remain a challenge for the clinical evaluation and necessitate a periodic reanalysis of WES data. As a genetic examination WES requires adequate patient informed consent which in particular should address possible secondary findings as well as data security. A positive molecular result ends diagnostic odysseys, enables accurate genetic counseling and can point to targeted preventive measures and treatment. A WES significantly contributes to the understanding of the genetic architecture and pathophysiology of neurological diseases, enriching and enabling precision medicine.


Assuntos
Exoma , Testes Genéticos , Doenças do Sistema Nervoso , Neurologia , Exoma/genética , Humanos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Neurologia/tendências , Sequenciamento Completo do Exoma
11.
Methods Mol Biol ; 1912: 55-76, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30635890

RESUMO

Circular RNAs are an emerging class of transcript isoforms created by unique back splicing of exons to form a closed covalent circular structure. While initially considered as product of aberrant splicing, recent evidence suggests unique functions and conservation across evolution. While circular RNAs could be largely attributed to have little or no potential to encode for proteins, recent evidence points to at least a small subset of circular RNAs which encode for peptides. Circular RNAs are also increasingly shown to be biomarkers for a number of diseases including neurological disorders and cancer. The advent of deep sequencing has enabled large-scale identification of circular RNAs in human and other genomes. A number of computational approaches have come up in recent years to query circular RNAs on a genome-wide scale from RNA-seq data. In this chapter, we describe the application and methodology of identifying circular RNAs using three popular computational tools: FindCirc, Segemehl, and CIRI along with approaches for experimental validation of the unique splice junctions.


Assuntos
Biologia Computacional/métodos , Anotação de Sequência Molecular/métodos , Neoplasias/diagnóstico , Doenças do Sistema Nervoso/diagnóstico , RNA/isolamento & purificação , Biomarcadores , Biologia Computacional/instrumentação , Conjuntos de Dados como Assunto , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias/genética , Doenças do Sistema Nervoso/genética , RNA/genética , RNA/metabolismo , Processamento de RNA , Análise de Sequência de RNA/instrumentação , Análise de Sequência de RNA/métodos , Software
12.
Nat Commun ; 10(1): 409, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679421

RESUMO

Microglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. Here we report that the proportion of morphologically activated microglia (PAM) in postmortem cortical tissue is strongly associated with ß-amyloid, tau-related neuropathology, and the rate of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE ε4, the strongest genetic risk factor for Alzheimer's disease, and mediation models support an upstream role for microglial activation in Alzheimer's disease via accumulation of tau. Further, we identify a common variant (rs2997325) influencing PAM that also affects in vivo microglial activation measured by [11C]-PBR28 PET in an independent cohort. Thus, our analyses begin to uncover pathways regulating resident neuroinflammation and identify overlaps of PAM's genetic architecture with those of Alzheimer's disease and several other traits.


Assuntos
Microglia/metabolismo , Microglia/patologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Neuropatologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Inflamação/genética , Inflamação/patologia , Modelos Logísticos , Masculino , Fenótipo , Proteômica , Fatores de Risco
13.
Lipids Health Dis ; 18(1): 26, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683111

RESUMO

Brain is a vital organ of the human body which performs very important functions such as analysis, processing, coordination, and execution of electrical signals. For this purpose, it depends on a complex network of nerves which are ensheathed in lipids tailored myelin; an abundant source of lipids in the body. The nervous system is enriched with important classes of lipids; sphingolipids and cholesterol which compose the major portion of the brain particularly in the form of myelin. Both cholesterol and sphingolipids are embedded in the microdomains of membrane rafts and are functional units of the neuronal cell membrane. These molecules serve as the signaling molecules; hold important roles in the neuronal differentiation, synaptogenesis, and many others. Thus, their adequate provision and active metabolism are of crucial importance in the maintenance of physiological functions of brain and body of an individual. In the present review, we have highlighted the physiological roles of cholesterol and sphingolipids in the development of the nervous system as well as the association of their altered metabolism to neurological and neurodegenerative diseases.


Assuntos
Encéfalo/crescimento & desenvolvimento , Colesterol/metabolismo , Doenças do Sistema Nervoso/genética , Esfingolipídeos/metabolismo , Animais , Encéfalo/metabolismo , Membrana Celular/genética , Colesterol/genética , Humanos , Lipídeos/genética , Microdomínios da Membrana/genética , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/fisiopatologia , Neurônios/metabolismo , Neurônios/patologia , Esfingolipídeos/genética
14.
Invest Ophthalmol Vis Sci ; 60(1): 93-97, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30640974

RESUMO

Purpose: Germline and somatic mutations in CTNNB1 have been found in different types of human diseases. This follow-up study aimed to identify causative germline mutations in CTNNB1 and their associated ocular phenotypes through a comparative analysis of whole-exome sequencing data. Methods: Annotated sequence variations in CTNNB1 were selected from in-house data from whole-exome sequencing of genomic DNA prepared from leucocytes of 3280 unrelated probands with different forms of eye diseases. Potentially pathogenic variants in CTNNB1 were analyzed by multistep bioinformatics analyses. Clinical data from probands with pathogenic variants in CTNNB1 were collected, and potential genotype-phenotype correlations were analyzed. Results: Eleven rare variants that potentially affect the coding regions of CTNNB1 were detected in 11 of the 3280 samples, and four variants were considered to be potentially pathogenic. All four mutations, namely, c.999delC (p.Tyr333*), c.1104delT (p.His369Thrfs*2), c.1738_1742delinsACA (p.Leu580Thrfs*28), and c.1867C>T (p.Gln623*), were heterozygotes and considered to have a germline origin. Three of the four mutations are de novo mutations, and the status of the remaining mutation is unavailable. All four probands had the same class of closely related ocular diseases: one proband had FEVR, and three probands had Norrie-like retinopathy. The molecular results indicated that three probands showed systemic anomalies, as demonstrated by a follow-up survey, but relevant information for the remaining proband was unavailable. Conclusions: The data suggest that germline truncating mutations in CTNNB1 cause autosomal dominant syndromic FEVR or Norrie disease. Patients with mutations in CTNNB1, KIF11, or NDP may have similar or overlapping phenotypes, but this phenomenon needs to be studied further.


Assuntos
Cegueira/congênito , Oftalmopatias Hereditárias/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação em Linhagem Germinativa , Doenças do Sistema Nervoso/genética , Degeneração Retiniana/genética , Doenças Retinianas/genética , Espasmos Infantis/genética , beta Catenina/genética , Cegueira/diagnóstico , Cegueira/genética , Análise Mutacional de DNA , Oftalmopatias Hereditárias/diagnóstico , Feminino , Angiofluoresceinografia , Seguimentos , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Lactente , Masculino , Doenças do Sistema Nervoso/diagnóstico , Fenótipo , Degeneração Retiniana/diagnóstico , Doenças Retinianas/diagnóstico , Espasmos Infantis/diagnóstico , Sequenciamento Completo do Genoma
15.
Eur J Neurol ; 26(1): 66-e7, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30063100

RESUMO

BACKGROUND AND PURPOSE: CACNA1A encodes the α1 subunit of the neuronal calcium channel P/Q. CACNA1A mutations underlie three allelic disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). A clear-cut genotype-phenotype correlation is often lacking since clinical manifestations may overlap. Several case reports have described cognitive and behavioral features in CACNA1A disorders, but studies in larger case series are lacking. METHODS: Genetically confirmed CACNA1A cases were retrieved from the database of the ataxia outpatient clinic of the Department of Neurology at Innsbruck Medical University. Clinical charts and neuropsychological test results were retrospectively analyzed. In addition, a review of the literature including only genetically confirmed cases was performed. RESULTS: Forty-four CACNA1A cases were identified in our database. Delayed psychomotor milestones and poor school performance were described in seven (four FHM1, three EA2) and eight (three FHM1, five EA2) patients, respectively. Psychiatric comorbidities were diagnosed in eight patients (two FHM1, six EA2). Neuropsychological testing was available for 23 patients (11 FHM1, 10 EA2, two SCA6). Various cognitive deficits were documented in 21 cases (all patients except one SCA6). Impairments were predominantly seen in figural memory, visuoconstructive abilities and verbal fluency. In the literature, an early psychomotor delay is described in several children with EA2 and FHM1, whilst reports of cognitive and psychiatric findings from adult cases are scarce. CONCLUSIONS: Neuropsychiatric manifestations are common in episodic CACNA1A disorders. In the case of otherwise unexplained developmental delay and a positive family history, CACNA1A mutations should be considered in the differential diagnosis.


Assuntos
Canais de Cálcio/genética , Transtornos Mentais/genética , Doenças do Sistema Nervoso/genética , Adolescente , Adulto , Ataxia/genética , Ataxia Cerebelar/genética , Criança , Pré-Escolar , Comorbidade , Escolaridade , Feminino , Genótipo , Humanos , Masculino , Transtornos Mentais/psicologia , Transtornos de Enxaqueca/genética , Doenças do Sistema Nervoso/psicologia , Testes Neuropsicológicos , Fenótipo , Desempenho Psicomotor , Estudos Retrospectivos , Ataxias Espinocerebelares/genética , Adulto Jovem
16.
J Mol Neurosci ; 67(1): 150-164, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30554402

RESUMO

Alzheimer's disease, Parkinson's disease, prion diseases, schizophrenia, and multiple sclerosis are the most common nervous system diseases, affecting millions of people worldwide. The current scientific literature associates these pathological conditions to abnormal expression levels of certain proteins, which in turn improved the knowledge concerning normal and affected brains. However, there is no available cure or preventive therapy for any of these disorders. Proteogenomics is a recent approach defined as the data integration of both nucleotide high-throughput sequencing and protein mass spectrometry technologies. In the last years, proteogenomics studies in distinct diseases have emerged as a strategy for the identification of uncharacterized proteoforms, which are all the different protein forms derived from a single gene. For many of these diseases, at least one protein used as biomarker presents more than one proteoform, which fosters the analysis of publicly available data focusing proteoforms. Given this context, we describe the most important biomarkers for each neurodegenerative disease and how genomics, transcriptomics, and proteomics separately contributed to unveil them. Finally, we present a selection of proteogenomics studies in which the combination of nucleotide and proteome high-throughput data, from cell lines or brain tissue samples, is used to uncover proteoforms not previously described. We believe that this new approach may improve our knowledge about nervous system diseases and brain function and an opportunity to identify new biomarker candidates.


Assuntos
Técnicas de Diagnóstico Molecular/métodos , Doenças do Sistema Nervoso/genética , Proteogenômica/métodos , Animais , Biomarcadores/metabolismo , Humanos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/metabolismo
17.
Science ; 362(6420)2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30545854

RESUMO

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.


Assuntos
Encéfalo/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Transtornos Mentais/genética , Doenças do Sistema Nervoso/genética , Neurogênese/genética , Encéfalo/crescimento & desenvolvimento , Epigênese Genética , Epigenômica , Redes Reguladoras de Genes , Humanos , Análise de Célula Única , Transcriptoma
18.
Genome Med ; 10(1): 98, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30577867

RESUMO

The gut microbiome contributes to the development and function of the immune, metabolic, and nervous systems. Furthermore, commensal bacteria modulate symptoms and pathology in mouse models of neuropsychiatric and neurodevelopmental diseases. Uncovering mechanisms that are utilized by the microbiome to mediate gut-brain connections may provide novel opportunities to target therapies to the gut in order to treat neurologic disorders.


Assuntos
Bactérias , Microbioma Gastrointestinal , Doenças do Sistema Nervoso/microbiologia , Animais , Encéfalo , Predisposição Genética para Doença , Humanos , Camundongos , Doenças do Sistema Nervoso/genética , Polimorfismo de Nucleotídeo Único
19.
Int J Nanomedicine ; 13: 8137-8151, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555231

RESUMO

Purpose: The objective of this study is to develop a facile tool for the absolute detection and quantification of nucleic acid transcripts, using a gold nanoparticle-based optical biosensor. Topoisomerase 1 (TOP1) and tyrosyl DNA phosphodiesterase 2 (TDP2) were among the nucleic acid transcripts of choice due to their role as genomic instability biomarkers and their implication in various cancers and neurologic disorders. This opens the door to develop a simple tool that can be used for diagnosing and monitoring treatment response for such diseases, overcoming the requirements for high cost, time, and complexity of the existing technologies for the absolute quantification of transcripts of interest. Materials and methods: The TOP1 and TDP2 mRNA transcripts were first captured specifically using magnetic nanoparticles that were functionalized with TOP1- and TDP2-specific probes, respectively. The captured mRNA was then directly detected and quantified using the gold aggregating gold (GAG) assay, without the need for amplification as in existing technologies used for the quantification of transcripts. Results: A linear correlation exists between the GAG assay and the qPCR for the quantification of the TOP1 and TDP2 mRNA transcripts (101-104 copies). The detection limit of the GAG assay in mRNA quantification was up to 10 copies per reaction. Wild-type and TDP2-deficient cell lines confirmed the assay specificity and reproducibility in distinguishing between different transcripts. Conclusion: The GAG assay can be utilized as an inexpensive, rapid, simple, and sensitive tool for the absolute quantification of RNA for different applications, instead of the laborious, expensive, and sophisticated real-time PCR.


Assuntos
Técnicas Biossensoriais , DNA Topoisomerases Tipo I/genética , Ouro/química , Nanopartículas Metálicas/química , Neoplasias/diagnóstico , Doenças do Sistema Nervoso/diagnóstico , Proteínas Nucleares/genética , RNA Mensageiro/análise , Fatores de Transcrição/genética , Bioensaio , Humanos , Neoplasias/genética , Doenças do Sistema Nervoso/genética , RNA Mensageiro/genética
20.
Rev Sci Tech ; 37(1): 151-160, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30209421

RESUMO

Skeletal and neurological problems consistently rank among the top health conditions necessitating the withdrawal or retirement of guide dogs and other working dogs from their service roles. Management practices such as weight management and physical conditioning may help to reduce the incidence of such conditions. However, where there is at least partial genetic aetiology, selective breeding strategies are the only way to produce a lasting reduction in their incidence in future generations. The management of single gene disorders is relatively simple through the judicious use of DNA test results. Breeding strategies to tackle complex diseases, into which category many skeletal and neurological diseases fall, are more challenging but can be successful through the use of data collected through screening schemes and, most efficiently, through the use of estimated breeding values.


Assuntos
Doenças do Cão/prevenção & controle , Predisposição Genética para Doença , Displasia Pélvica Canina/genética , Doenças do Sistema Nervoso/veterinária , Animais , Doenças do Cão/genética , Cães , Doenças do Sistema Nervoso/genética
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