Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.787
Filtrar
1.
Nat Commun ; 11(1): 4183, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826893

RESUMO

We describe a human single-nuclei transcriptomic atlas for the substantia nigra (SN), generated by sequencing approximately 17,000 nuclei from matched cortical and SN samples. We show that the common genetic risk for Parkinson's disease (PD) is associated with dopaminergic neuron (DaN)-specific gene expression, including mitochondrial functioning, protein folding and ubiquitination pathways. We identify a distinct cell type association between PD risk and oligodendrocyte-specific gene expression. Unlike Alzheimer's disease (AD), we find no association between PD risk and microglia or astrocytes, suggesting that neuroinflammation plays a less causal role in PD than AD. Beyond PD, we find associations between SN DaNs and GABAergic neuron gene expression and multiple neuropsychiatric disorders. Conditional analysis reveals that distinct neuropsychiatric disorders associate with distinct sets of neuron-specific genes but converge onto shared loci within oligodendrocytes and oligodendrocyte precursors. This atlas guides our aetiological understanding by associating SN cell type expression profiles with specific disease risk.


Assuntos
Expressão Gênica , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Encéfalo , Neurônios Dopaminérgicos/metabolismo , Humanos , Microglia/metabolismo , Mitocôndrias/metabolismo , Doenças do Sistema Nervoso/patologia , Substância Negra/patologia , Transcriptoma
2.
Vet Clin North Am Equine Pract ; 36(2): 255-272, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32654782

RESUMO

Neurologic disease in horses can be particularly challenging to diagnose and treat. These diseases can result in economic losses, emotional distress to owners, and injury to the horse or handlers. To date, there are 5 neurologic diseases caused by known genetic mutations and several more are suspected to be heritable: lethal white foal syndrome, lavender foal syndrome, cerebellar abiotrophy, occipitoatlantoaxial malformation, and Friesian hydrocephalus. Genetic testing allows owners, breeders, and veterinarians to make informed decisions when selecting dams and sires for breeding or deciding the treatment or prognosis of a neurologic animal.


Assuntos
Doenças dos Cavalos/genética , Doenças do Sistema Nervoso/veterinária , Animais , Testes Genéticos/veterinária , Cavalos , Doenças do Sistema Nervoso/genética
3.
ACS Chem Neurosci ; 11(15): 2361-2369, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32627524

RESUMO

Spike protein (S protein) is the virus "key" to infect cells and is able to strongly bind to the human angiotensin-converting enzyme2 (ACE2), as has been reported. In fact, Spike structure and function is known to be highly important for cell infection as well as for entering the brain. Growing evidence indicates that different types of coronaviruses not only affect the respiratory system, but they might also invade the central nervous system (CNS). However, very little evidence has been so far reported on the presence of COVID-19 in the brain, and the potential exploitation, by this virus, of the lung to brain axis to reach neurons has not been completely understood. In this Article, we assessed the SARS-CoV and SARS-CoV-2 Spike protein sequence, structure, and electrostatic potential using computational approaches. Our results showed that the S proteins of SARS-CoV-2 and SARS-CoV are highly similar, sharing a sequence identity of 77%. In addition, we found that the SARS-CoV-2 S protein is slightly more positively charged than that of SARS-CoV since it contains four more positively charged residues and five less negatively charged residues which may lead to an increased affinity to bind to negatively charged regions of other molecules through nonspecific and specific interactions. Analysis the S protein binding to the host ACE2 receptor showed a 30% higher binding energy for SARS-CoV-2 than for the SARS-CoV S protein. These results might be useful for understanding the mechanism of cell entry, blood-brain barrier crossing, and clinical features related to the CNS infection by SARS-CoV-2.


Assuntos
Betacoronavirus/genética , Encéfalo/virologia , Infecções por Coronavirus/genética , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/virologia , Pneumonia Viral/genética , Glicoproteína da Espícula de Coronavírus/genética , Sequência de Aminoácidos , Betacoronavirus/química , Humanos , Pandemias , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Glicoproteína da Espícula de Coronavírus/química
4.
Artigo em Inglês | MEDLINE | ID: mdl-32645824

RESUMO

Environmental lead (Pb) exposure is closely associated with pathogenesis of a range of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), attention deficit/hyperactivity disorder (ADHD), etc. Epigenetic machinery modulates neural development and activities, while faulty epigenetic regulation contributes to the diverse forms of CNS (central nervous system) abnormalities and diseases. As a potent epigenetic modifier, lead is thought to cause neurological disorders through modulating epigenetic mechanisms. Specifically, increasing evidence linked aberrant DNA methylations, histone modifications as well as ncRNAs (non-coding RNAs) with AD cases, among which circRNA (circular RNA) stands out as a new and promising field for association studies. In 23-year-old primates with developmental lead treatment, Zawia group discovered a variety of epigenetic changes relating to AD pathogenesis. This is a direct evidence implicating epigenetic basis in lead-induced AD animals with an entire lifespan. Additionally, some epigenetic molecules associated with AD etiology were also known to respond to chronic lead exposure in comparable disease models, indicating potentially interlaced mechanisms with respect to the studied neurotoxic and pathological events. Of note, epigenetic molecules acted via globally or selectively influencing the expression of disease-related genes. Compared to AD, the association of lead exposure with other neurological disorders were primarily supported by epidemiological survey, with fewer reports connecting epigenetic regulators with lead-induced pathogenesis. Some pharmaceuticals, such as HDAC (histone deacetylase) inhibitors and DNA methylation inhibitors, were developed to deal with CNS disease by targeting epigenetic components. Still, understandings are insufficient regarding the cause-consequence relations of epigenetic factors and neurological illness. Therefore, clear evidence should be provided in future investigations to address detailed roles of novel epigenetic factors in lead-induced neurological disorders, and efforts of developing specific epigenetic therapeutics should be appraised.


Assuntos
Doença de Alzheimer , DNA/genética , Chumbo/efeitos adversos , Doenças do Sistema Nervoso/induzido quimicamente , Animais , Metilação de DNA/efeitos dos fármacos , Epigênese Genética , Inibidores de Histona Desacetilases , Doenças do Sistema Nervoso/genética , Doenças Neurodegenerativas/genética
5.
Adv Exp Med Biol ; 1194: 455, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468561

RESUMO

The majority of risk genetic variants for common and complex neuropsychiatric traits lie within noncoding regions. Previous efforts have linked risk variants to specific genes by leveraging transcriptome data and expression quantitative trait loci. Most recently, the generation of large-scale epigenome data and the availability of epigenome quantitative trait loci provide a powerful discovery tool for assigning a functional role to the genetic variation in neuropsychiatric traits. In this talk, we will focus on advances in integration of epigenome datasets with the risk of common and complex neuropsychiatric traits.


Assuntos
Análise de Dados , Epigenoma , Transtornos Mentais , Doenças do Sistema Nervoso , Locos de Características Quantitativas , Epigenoma/genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/genética , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética
6.
Am J Hum Genet ; 106(6): 885-892, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32413284

RESUMO

Leveraging high-dimensional molecular datasets can help us develop mechanistic insight into associations between genetic variants and complex traits. In this study, we integrated human proteome data derived from brain tissue to evaluate whether targeted proteins putatively mediate the effects of genetic variants on seven neurological phenotypes (Alzheimer disease, amyotrophic lateral sclerosis, depression, insomnia, intelligence, neuroticism, and schizophrenia). Applying the principles of Mendelian randomization (MR) systematically across the genome highlighted 43 effects between genetically predicted proteins derived from the dorsolateral prefrontal cortex and these outcomes. Furthermore, genetic colocalization provided evidence that the same causal variant at 12 of these loci was responsible for variation in both protein and neurological phenotype. This included genes such as DCC, which encodes the netrin-1 receptor and has an important role in the development of the nervous system (p = 4.29 × 10-11 with neuroticism), as well as SARM1, which has been previously implicated in axonal degeneration (p = 1.76 × 10-08 with amyotrophic lateral sclerosis). We additionally conducted a phenome-wide MR study for each of these 12 genes to assess potential pleiotropic effects on 700 complex traits and diseases. Our findings suggest that genes such as SNX32, which was initially associated with increased risk of Alzheimer disease, may potentially influence other complex traits in the opposite direction. In contrast, genes such as CTSH (which was also associated with Alzheimer disease) and SARM1 may make worthwhile therapeutic targets because they did not have genetically predicted effects on any of the other phenotypes after correcting for multiple testing.


Assuntos
Encéfalo/metabolismo , Variação Genética/genética , Doenças do Sistema Nervoso/genética , Fenômica , Proteoma/genética , Proteômica , Doença de Alzheimer/genética , Esclerose Amiotrófica Lateral/genética , Proteínas do Domínio Armadillo/genética , Proteínas de Transporte/genética , Catepsina H/genética , Proteínas do Citoesqueleto/genética , Depressão/genética , Estudo de Associação Genômica Ampla , Humanos , Inteligência/genética , Doenças do Sistema Nervoso/metabolismo , Neuroticismo , Proteínas Nucleares/genética , Fenótipo , Proteoma/metabolismo , Esquizofrenia/genética , Distúrbios do Início e da Manutenção do Sono/genética , Nexinas de Classificação/genética
8.
PLoS Genet ; 16(4): e1008734, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32310941

RESUMO

Genome-wide association studies (GWASs) have identified many SNPs associated with various common diseases. Understanding the biological functions of these identified SNP associations requires identifying disease/trait relevant tissues or cell types. Here, we develop a network method, CoCoNet, to facilitate the identification of trait-relevant tissues or cell types. Different from existing approaches, CoCoNet incorporates tissue-specific gene co-expression networks constructed from either bulk or single cell RNA sequencing (RNAseq) studies with GWAS data for trait-tissue inference. In particular, CoCoNet relies on a covariance regression network model to express gene-level effect measurements for the given GWAS trait as a function of the tissue-specific co-expression adjacency matrix. With a composite likelihood-based inference algorithm, CoCoNet is scalable to tens of thousands of genes. We validate the performance of CoCoNet through extensive simulations. We apply CoCoNet for an in-depth analysis of four neurological disorders and four autoimmune diseases, where we integrate the corresponding GWASs with bulk RNAseq data from 38 tissues and single cell RNAseq data from 10 cell types. In the real data applications, we show how CoCoNet can help identify specific glial cell types relevant for neurological disorders and identify disease-targeted colon tissues as relevant for autoimmune diseases.


Assuntos
Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla/métodos , Software , Transcriptoma , Doenças Autoimunes/genética , Humanos , Doenças do Sistema Nervoso/genética , Especificidade de Órgãos , Característica Quantitativa Herdável , RNA-Seq/métodos
9.
Gene ; 749: 144709, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32339621

RESUMO

BACKGROUND: Mutations in the ATP1A3 gene are known to be the cause of three distinct neurological syndromes including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP) and cerebellar ataxia, arefexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS). Recent studies have suggested the broader diversity of ATP1A3-related disorders. This study aimed to investigate the clinical spectrum in patients carrying causative mutations within the ATP1A3 gene. METHOD: The medical histories of nine unrelated patients with diverse phenotypes harboring variants in ATP1A3 were retrospectively analyzed after they were referred to a tertiary epilepsy center in one of the two different health care systems (Germany or Thailand). Clinical features, neurophysiological data, imaging results, genetic characteristics and treatments were reviewed. RESULTS: Three patients harbor novel mutations in the ATP1A3 gene. Atypical clinical features and imaging findings were observed in two cases, one with hemiplegia-hemiconvulsion-epilepsy syndrome, and the other with neurodegeneration with brain iron accumulation. All nine patients presented with intellectual impairment. Alternating hemiplegia of childhood (AHC) was the most common phenotype (67%). Flunarizine and topiramate led to symptom reduction in 83% and 25% of AHC cases administered, respectively. CONCLUSION: The present case series expands the clinical and genetic spectrum of ATP1A3-related disorders.


Assuntos
Mutação , Doenças do Sistema Nervoso/genética , Fenótipo , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Criança , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/genética , Eletroencefalografia , Feminino , Hemiplegia/diagnóstico , Hemiplegia/genética , Humanos , Masculino , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/diagnóstico por imagem , Neuroimagem , Adulto Jovem
10.
Biochim Biophys Acta Gene Regul Mech ; 1863(7): 194545, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32194213

RESUMO

Histone lysine methyltransferase 2 (KMT2) proteins form multimeric enzymatic complexes that methylate lysine 4 on histone H3 (H3K4) at transcription regulatory elements in the genome. A strong association of H3K4 methylation with active transcription has led to intense efforts to reveal the functional involvement of KMT2 complexes in transcriptional regulation. A number of biochemical and cellular studies have shown that KMT2 complexes regulate transcription of target genes via H3K4 methylation. However, in many cases, loss of KMT2 complex enzymatic activity fails to fully account for observed transcriptional defects. Accumulating evidence indicates that, in certain contexts, KMT2 complex-mediated transcriptional regulation can occur in an H3K4 methylation-independent manner. Here, we comprehensively review functions of KMT2 complexes in gene expression, focusing on what we currently know about the molecular mechanisms by which the KMT2 complexes regulate transcription. We also discuss how aberrant transcriptional regulation by KMT2 complexes contributes to different human diseases, such as cancer.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Ativação Transcricional , Animais , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/genética , Humanos , Hepatopatias/genética , Neoplasias/genética , Doenças do Sistema Nervoso/genética
11.
Artigo em Inglês | MEDLINE | ID: mdl-32041280

RESUMO

Neurological diseases (NDs) are progressive disorders, the progression of which can be significantly affected by a range of common diseases that present as comorbidities. Clinical studies, including epidemiological and neuropathological analyses, indicate that patients with type 2 diabetes (T2D) have worse progression of NDs, suggesting pathogenic links between NDs and T2D. However, finding causal or predisposing factors that link T2D and NDs remains challenging. To address these problems, we developed a high-throughput network-based quantitative pipeline using agnostic approaches to identify genes expressed abnormally in both T2D and NDs, to identify some of the shared molecular pathways that may underpin T2D and ND interaction. We employed gene expression transcriptomic datasets from control and disease-affected individuals and identified differentially expressed genes (DEGs) in tissues of patients with T2D and ND when compared to unaffected control individuals. One hundred and ninety seven DEGs (99 up-regulated and 98 down-regulated in affected individuals) that were common to both the T2D and the ND datasets were identified. Functional annotation of these identified DEGs revealed the involvement of significant cell signaling associated molecular pathways. The overlapping DEGs (i.e., seen in both T2D and ND datasets) were then used to extract the most significant GO terms. We performed validation of these results with gold benchmark databases and literature searching, which identified which genes and pathways had been previously linked to NDs or T2D and which are novel. Hub proteins in the pathways were identified (including DNM2, DNM1, MYH14, PACSIN2, TFRC, PDE4D, ENTPD1, PLK4, CDC20B, and CDC14A) using protein-protein interaction analysis which have not previously been described as playing a role in these diseases. To reveal the transcriptional and post-transcriptional regulators of the DEGs we used transcription factor (TF) interactions analysis and DEG-microRNAs (miRNAs) interaction analysis, respectively. We thus identified the following TFs as important in driving expression of our T2D/ND common genes: FOXC1, GATA2, FOXL1, YY1, E2F1, NFIC, NFYA, USF2, HINFP, MEF2A, SRF, NFKB1, USF2, HINFP, MEF2A, SRF, NFKB1, PDE4D, CREB1, SP1, HOXA5, SREBF1, TFAP2A, STAT3, POU2F2, TP53, PPARG, and JUN. MicroRNAs that affect expression of these genes include mir-335-5p, mir-16-5p, mir-93-5p, mir-17-5p, mir-124-3p. Thus, our transcriptomic data analysis identifies novel potential links between NDs and T2D pathologies that may underlie comorbidity interactions, links that may include potential targets for therapeutic intervention. In sum, our neighborhood-based benchmarking and multilayer network topology methods identified novel putative biomarkers that indicate how type 2 diabetes (T2D) and these neurological diseases interact and pathways that, in the future, may be targeted for treatment.


Assuntos
Diabetes Mellitus Tipo 2/genética , Doenças do Sistema Nervoso/genética , Biomarcadores , Biologia Computacional , Progressão da Doença , Redes Reguladoras de Genes , Humanos , MicroRNAs , Fatores de Transcrição/genética , Transcriptoma
12.
Nat Commun ; 11(1): 1041, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32098967

RESUMO

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/.


Assuntos
Putamen/fisiologia , Locos de Características Quantitativas , Processamento de RNA , Substância Negra/fisiologia , Alelos , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Doenças do Sistema Nervoso/genética , Neurônios/fisiologia , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Esquizofrenia/genética , Transcriptoma
13.
J Neurosci ; 40(1): 101-106, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896564

RESUMO

On the 50th anniversary of the Society for Neuroscience, we reflect on the remarkable progress that the field has made in understanding the nervous system, and look forward to the contributions of the next 50 years. We predict a substantial acceleration of our understanding of the nervous system that will drive the development of new therapeutic strategies to treat diseases over the course of the next five decades. We also see neuroscience at the nexus of many societal topics beyond medicine, including education, consumerism, and the justice system. In combination, advances made by basic, translational, and clinical neuroscience research in the next 50 years have great potential for lasting improvements in human health, the economy, and society.


Assuntos
Neurociências/tendências , Animais , Comportamento Animal , Previsões , Edição de Genes , História do Século XX , História do Século XXI , Humanos , Comunicação Interdisciplinar , Transtornos Mentais/diagnóstico , Transtornos Mentais/genética , Transtornos Mentais/terapia , Rede Nervosa/fisiologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/terapia , Neurogênese , Neurociências/história , Organoides , Pesquisa , Mudança Social
14.
Science ; 367(6476)2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31974223

RESUMO

Forebrain development is characterized by highly synchronized cellular processes, which, if perturbed, can cause disease. To chart the regulatory activity underlying these events, we generated a map of accessible chromatin in human three-dimensional forebrain organoids. To capture corticogenesis, we sampled glial and neuronal lineages from dorsal or ventral forebrain organoids over 20 months in vitro. Active chromatin regions identified in human primary brain tissue were observed in organoids at different developmental stages. We used this resource to map genetic risk for disease and to explore evolutionary conservation. Moreover, we integrated chromatin accessibility with transcriptomics to identify putative enhancer-gene linkages and transcription factors that regulate human corticogenesis. Overall, this platform brings insights into gene-regulatory dynamics at previously inaccessible stages of human forebrain development, including signatures of neuropsychiatric disorders.


Assuntos
Montagem e Desmontagem da Cromatina/fisiologia , Cromatina/metabolismo , Neurogênese , Prosencéfalo/embriologia , Animais , Linhagem da Célula , Montagem e Desmontagem da Cromatina/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Transtornos Mentais/embriologia , Transtornos Mentais/genética , Camundongos , Doenças do Sistema Nervoso/embriologia , Doenças do Sistema Nervoso/genética , Organoides/embriologia , Células-Tronco Pluripotentes/fisiologia , Transcriptoma
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 25-27, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922590

RESUMO

OBJECTIVE: To explore the genetic etiology of a pedigree affected with Norrie disease. METHODS: Four individuals from the core family of the proband were subjected to whole exome sequencing in order to identify the pathological variant. Sanger sequencing was used to verify the finding among 7 additional members from the pedigree. RESULTS: The proband and other 3 male patients have all carried a hemizygote c.361C>T (p.Arg121Trp) missense variant of the NDP gene, for which his mother, grandmother and two younger female cousins were heterozygous carriers. The same variant was not detected among unaffected males. Above results conformed to a X-linked recessive pattern of inheritance. CONCLUSION: The missense variant c.361C>T of the NDP gene probably underlies the Norrie disease in this pedigree.


Assuntos
Cegueira/congênito , Proteínas do Olho , Doenças Genéticas Ligadas ao Cromossomo X , Proteínas do Tecido Nervoso , Doenças do Sistema Nervoso , Degeneração Retiniana , Espasmos Infantis , Cegueira/genética , Proteínas do Olho/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Doenças do Sistema Nervoso/genética , Linhagem , Degeneração Retiniana/genética , Espasmos Infantis/genética
16.
Life Sci ; 244: 117329, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954747

RESUMO

MicroRNAs (miRs) are small non-coding pieces of RNA that are involved in a variety of physiologic processes such as apoptosis, cell proliferation, cell differentiation, cell cycle and cell survival. These multifunctional nucleotides are also capable of preventing oxidative damages by modulating antioxidant defense systems in a variety of milieu, such as in diabetes. Although the exact molecular mechanisms by which miRs modulate the antioxidant defense elements are unclear, some evidence suggests that they may exert these effects via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This intracellular mechanism is crucial in the maintenance of the physiologic redox balance by regulating the expression and activity of various cellular antioxidative defense elements and thereby plays a pivotal role in the development of oxidative stress. Any impairment in the Nrf2 signaling pathway may result in oxidative damage-dependent complications such as various diabetic complications, neurological disorders and cancer. In the current review, we discuss the modulatory effects of miRs on the Nrf2 signaling pathway, which can potentially be novel therapeutic targets.


Assuntos
Complicações do Diabetes/prevenção & controle , Regulação da Expressão Gênica , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias/prevenção & controle , Doenças do Sistema Nervoso/prevenção & controle , Estresse Oxidativo , Animais , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Transdução de Sinais
17.
Mol Cells ; 42(12): 828-835, 2019 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-31838836

RESUMO

PIWI Argonaute proteins and Piwi-interacting RNAs (piRNAs) are expressed in all animal species and play a critical role in cellular defense by inhibiting the activation of transposable elements in the germline. Recently, new evidence suggests that PIWI proteins and piRNAs also play important roles in various somatic tissues, including neurons. This review summarizes the neuronal functions of the PIWI-piRNA pathway in multiple animal species, including their involvement in axon regeneration, behavior, memory formation, and transgenerational epigenetic inheritance of adaptive memory. This review also discusses the consequences of dysregulation of neuronal PIWI-piRNA pathways in certain neurological disorders, including neurodevelopmental and neurodegenerative diseases. A full understanding of neuronal PIWI-piRNA pathways will ultimately provide novel insights into small RNA biology and could potentially provide precise targets for therapeutic applications.


Assuntos
Proteínas Argonauta/metabolismo , Neurônios/fisiologia , RNA Interferente Pequeno/metabolismo , Animais , Proteínas Argonauta/química , Proteínas Argonauta/genética , Epigênese Genética , Regulação da Expressão Gênica , Humanos , Aprendizagem , Regeneração Nervosa , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Neurônios/metabolismo , RNA Interferente Pequeno/genética
18.
Am J Hum Genet ; 105(6): 1237-1253, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31785787

RESUMO

We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.


Assuntos
Atrofia/patologia , Doenças Cerebelares/patologia , Lisossomos/patologia , Proteínas Mitocondriais/metabolismo , Doenças do Sistema Nervoso/patologia , Estresse Oxidativo , Adolescente , Adulto , Animais , Atrofia/genética , Atrofia/metabolismo , Doenças Cerebelares/genética , Doenças Cerebelares/metabolismo , Criança , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Lisossomos/metabolismo , Masculino , Proteínas Mitocondriais/genética , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Linhagem , Fenótipo , Adulto Jovem
19.
BMC Med Genet ; 20(1): 199, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852446

RESUMO

BACKGROUND: Neurological disorders are a common cause of morbidity and mortality within Pakistani populations. It is one of the most important challenges in healthcare, with significant life-long socio-economic burden. METHODS: We investigated the cause of disease in three Pakistani families in individuals with unexplained autosomal recessive neurological conditions, using both genome-wide SNP mapping and whole exome sequencing (WES) of affected individuals. RESULTS: We identified a homozygous splice site variant (NM_000521:c.445 + 1G > T) in the hexosaminidase B (HEXB) gene confirming a diagnosis of Sandhoff disease (SD; type II GM2-gangliosidosis), an autosomal recessive lysosomal storage disorder caused by deficiency of hexosaminidases in a single family. In two further unrelated families, we identified a homozygous frameshift variant (NM_024298.3:c.758_778del; p.Glu253_Ala259del) in membrane-bound O-acyltransferase family member 7 (MBOAT7) as the likely cause of disease. MBOAT7 gene variants have recently been identified as a cause of intellectual disability (ID), seizures and autistic features. CONCLUSIONS: We identified two metabolic disorders of lipid biosynthesis within three Pakistani families presenting with undiagnosed neurodevelopmental conditions. These findings enabled an accurate neurological disease diagnosis to be provided for these families, facilitating disease management and genetic counselling within this population. This study consolidates variation within MBOAT7 as a cause of neurodevelopmental disorder, broadens knowledge of the clinical outcomes associated with MBOAT7-related disorder, and confirms the likely presence of a regionally prevalent founder variant (c.758_778del; p.Glu253_Ala259del) in Pakistan.


Assuntos
Aciltransferases/genética , Homozigoto , Proteínas de Membrana/genética , Doenças do Sistema Nervoso/genética , Cadeia beta da beta-Hexosaminidase/genética , Consanguinidade , Eletroencefalografia , Feminino , Genes Recessivos , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Mutação , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/fisiopatologia , Paquistão , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA