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1.
Brain ; 143(12): 3776-3792, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33439986

RESUMO

Alzheimer's disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer's disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer's disease (defined as having abnormal amyloid, n = 425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n = 127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer's disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer's disease (all P > 0.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer's disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer's disease heterogeneity. Compared to controls, all non-demented Alzheimer's disease individuals had increased risk of showing clinical progression (all P < 0.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P = 0.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P = 0.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer's disease patients, and suggest that subtypes may require tailored therapy.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/classificação , Secretases da Proteína Precursora do Amiloide/líquido cefalorraquidiano , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/genética , Ácido Aspártico Endopeptidases/líquido cefalorraquidiano , Ácido Aspártico Endopeptidases/genética , Barreira Hematoencefálica/patologia , Análise por Conglomerados , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/genética , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/genética , Proteômica , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genética
2.
Cereb Cortex ; 30(4): 2144-2156, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32142100

RESUMO

Sleep problems are related to the elevated levels of the Alzheimer's disease (AD) biomarker ß-amyloid (Aß). Hypotheses about the causes of this relationship can be generated from molecular markers of sleep problems identified in rodents. A major marker of sleep deprivation is Homer1a, a neural protein coded by the HOMER1 gene, which has also been implicated in brain Aß accumulation. Here, we tested whether the relationship between cortical Aß accumulation and self-reported sleep quality, as well as changes in sleep quality over 3 years, was stronger in cortical regions with high HOMER1 mRNA expression levels. In a sample of 154 cognitively healthy older adults, Aß correlated with poorer sleep quality cross-sectionally and longitudinally (n = 62), but more strongly in the younger than in older individuals. Effects were mainly found in regions with high expression of HOMER1. The anatomical distribution of the sleep-Aß relationship followed closely the Aß accumulation pattern in 69 patients with mild cognitive impairment or AD. Thus, the results indicate that the relationship between sleep problems and Aß accumulation may involve Homer1 activity in the cortical regions, where harbor Aß deposits in AD. The findings may advance our understanding of the relationship between sleep problems and AD risk.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral/metabolismo , Disfunção Cognitiva/metabolismo , Proteínas de Arcabouço Homer/biossíntese , Transtornos do Sono-Vigília/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Córtex Cerebral/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Estudos Transversais , Feminino , Expressão Gênica , Proteínas de Arcabouço Homer/genética , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Autorrelato , Transtornos do Sono-Vigília/diagnóstico por imagem , Transtornos do Sono-Vigília/genética
3.
Nucleic Acids Res ; 47(1): 168-183, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30329130

RESUMO

Cortical development is controlled by transcriptional programs, which are orchestrated by transcription factors. Yet, stable inheritance of spatio-temporal activity of factors influencing cell fate and localization in different layers is only partly understood. Here we find that deletion of Dot1l in the murine telencephalon leads to cortical layering defects, indicating DOT1L activity and chromatin methylation at H3K79 impact on the cell cycle, and influence transcriptional programs conferring upper layer identity in early progenitors. Specifically, DOT1L prevents premature differentiation by increasing expression of genes that regulate asymmetric cell division (Vangl2, Cenpj). Loss of DOT1L results in reduced numbers of progenitors expressing genes including SoxB1 gene family members. Loss of DOT1L also leads to altered cortical distribution of deep layer neurons that express either TBR1, CTIP2 or SOX5, and less activation of transcriptional programs that are characteristic for upper layer neurons (Satb2, Pou3f3, Cux2, SoxC family members). Data from three different mouse models suggest that DOT1L balances transcriptional programs necessary for proper neuronal composition and distribution in the six cortical layers. Furthermore, because loss of DOT1L in the pre-neurogenic phase of development impairs specifically generation of SATB2-expressing upper layer neurons, our data suggest that DOT1L primes upper layer identity in cortical progenitors.


Assuntos
Proteínas de Ligação à Região de Interação com a Matriz/genética , Metiltransferases/genética , Neurogênese/genética , Neurônios/metabolismo , Fatores de Transcrição/genética , Animais , Diferenciação Celular/genética , Divisão Celular/genética , Proliferação de Células/genética , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Cromatina/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Histona-Lisina N-Metiltransferase , Metilação , Camundongos , Neurônios/patologia , Proteínas Repressoras/genética , Fatores de Transcrição SOXD/genética , Proteínas com Domínio T , Telencéfalo/crescimento & desenvolvimento , Telencéfalo/metabolismo , Telencéfalo/patologia , Proteínas Supressoras de Tumor/genética
4.
Bioinformatics ; 35(22): 4757-4759, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31134269

RESUMO

SUMMARY: Due to the rapidly increasing scale and diversity of epigenomic data, modular and scalable analysis workflows are of wide interest. Here we present snakePipes, a workflow package for processing and downstream analysis of data from common epigenomic assays: ChIP-seq, RNA-seq, Bisulfite-seq, ATAC-seq, Hi-C and single-cell RNA-seq. snakePipes enables users to assemble variants of each workflow and to easily install and upgrade the underlying tools, via its simple command-line wrappers and yaml files. AVAILABILITY AND IMPLEMENTATION: snakePipes can be installed via conda: `conda install -c mpi-ie -c bioconda -c conda-forge snakePipes'. Source code (https://github.com/maxplanck-ie/snakepipes) and documentation (https://snakepipes.readthedocs.io/en/latest/) are available online. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Epigenômica , Software , RNA-Seq , Sequenciamento do Exoma , Fluxo de Trabalho
5.
Alzheimers Dement ; 15(11): 1478-1488, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31495601

RESUMO

INTRODUCTION: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. METHODS: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. RESULTS: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. DISCUSSION: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.


Assuntos
Doença de Alzheimer , Amiloide/metabolismo , Biomarcadores/sangue , Encéfalo/metabolismo , Proteômica , Fatores Etários , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
Nucleic Acids Res ; 44(W1): W160-5, 2016 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-27079975

RESUMO

We present an update to our Galaxy-based web server for processing and visualizing deeply sequenced data. Its core tool set, deepTools, allows users to perform complete bioinformatic workflows ranging from quality controls and normalizations of aligned reads to integrative analyses, including clustering and visualization approaches. Since we first described our deepTools Galaxy server in 2014, we have implemented new solutions for many requests from the community and our users. Here, we introduce significant enhancements and new tools to further improve data visualization and interpretation. deepTools continue to be open to all users and freely available as a web service at deeptools.ie-freiburg.mpg.de The new deepTools2 suite can be easily deployed within any Galaxy framework via the toolshed repository, and we also provide source code for command line usage under Linux and Mac OS X. A public and documented API for access to deepTools functionality is also available.


Assuntos
Biologia Computacional/estatística & dados numéricos , Drosophila melanogaster/genética , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência de DNA/estatística & dados numéricos , Software , Animais , Sequência de Bases , Biologia Computacional/métodos , Gráficos por Computador , Humanos , Armazenamento e Recuperação da Informação , Internet , Alinhamento de Sequência
7.
Nat Commun ; 15(1): 7665, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39227614

RESUMO

Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect FGF14 expansions from short-read genome data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare FGF14 expansion alleles, including interruptions and flanking regions. Uninterrupted AAG expansions are significantly enriched in patients with ataxia from a lower threshold (180-200 repeats) than previously reported based on expansion size alone. Conversely, AAGGAG hexameric expansions are equally frequent in patients and controls. Distinct 5' flanking regions, interruptions and pre-repeat sequences correlate with repeat size. Furthermore, pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats form different secondary structures. Regardless of expansion size, SCA27B is a recognizable clinical entity characterized by frequent episodic ataxia and downbeat nystagmus, similar to the presentation observed in a family with a previously unreported nonsense variant (SCA27A). Overall, this study suggests that SCA27B is a major overlooked cause of adult-onset ataxia, accounting for 23-31% of unsolved patients. We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process.


Assuntos
Fatores de Crescimento de Fibroblastos , Humanos , Masculino , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Pessoa de Meia-Idade , Ataxia Cerebelar/genética , Idoso , Alelos , Adulto , Expansão das Repetições de DNA/genética , Expansão das Repetições de Trinucleotídeos/genética
8.
Mol Phylogenet Evol ; 64(1): 106-17, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22491068

RESUMO

In this study, we analyse the evolutionary dynamics and phylogenetic implications of gene order rearrangements in five newly sequenced mitochondrial (mt) genomes and four published mt genomes of isopod crustaceans. The sequence coverage is nearly complete for four of the five newly sequenced species, with only the control region and some tRNA genes missing, while in Janira maculosa only two thirds of the genome could be determined. Mitochondrial gene order in isopods seems to be more plastic than that in other crustacean lineages, making all nine known mt gene orders different. Especially the asellote Janira is characterized by many autapomorphies. The following inferred ancestral isopod mt gene order exists slightly modified in modern isopods: nad1, tnrL1, rrnS, control region, trnS1, cob, trnT, nad5, trnF. We consider the inferred gene translocation events leading to gene rearrangements as valuable characters in phylogenetic analyses. In this first study covering major isopod lineages, potential apomorphies were identified, e.g., a shared relative position of trnR in Valvifera. We also report one of the first findings of homoplasy in mitochondrial gene order, namely a shared relative position of trnV in unrelated isopod lineages. In addition to increased taxon sampling secondary structure, modification in tRNAs and GC-skew inversion may be potentially fruitful subjects for future mt genome studies in a phylogenetic context.


Assuntos
Evolução Molecular , Ordem dos Genes/genética , Rearranjo Gênico/genética , Genoma Mitocondrial/genética , Isópodes/genética , Filogenia , Animais , Regiões Antárticas , Sequência de Bases , Teorema de Bayes , Primers do DNA/genética , França , Alemanha , Isópodes/classificação , Modelos Genéticos , Dados de Sequência Molecular , Análise de Sequência de DNA
9.
Cancers (Basel) ; 14(9)2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35565295

RESUMO

Retinoblastoma is a tumor of the eye in children under the age of five caused by biallelic inactivation of the RB1 tumor suppressor gene in maturing retinal cells. Cancer models are essential for understanding tumor development and in preclinical research. Because of the complex organization of the human retina, such models were challenging to develop for retinoblastoma. Here, we present an organoid model based on differentiation of human embryonic stem cells into neural retina after inactivation of RB1 by CRISPR/Cas9 mutagenesis. Wildtype and RB1 heterozygous mutant retinal organoids were indistinguishable with respect to morphology, temporal development of retinal cell types and global mRNA expression. However, loss of pRB resulted in spatially disorganized organoids and aberrant differentiation, indicated by disintegration of organoids beyond day 130 of differentiation and depletion of most retinal cell types. Only cone photoreceptors were abundant and continued to proliferate, supporting these as candidate cells-of-origin for retinoblastoma. Transcriptome analysis of RB1 knockout organoids and primary retinoblastoma revealed gain of a retinoblastoma expression signature in the organoids, characterized by upregulation of RBL1 (p107), MDM2, DEK, SYK and HELLS. In addition, genes related to immune response and extracellular matrix were specifically upregulated in RB1-negative organoids. In vitro retinal organoids therefore display some features associated with retinoblastoma and, so far, represent the only valid human cancer model for the development of this disease.

10.
Leukemia ; 35(8): 2311-2324, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33526861

RESUMO

The transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4+ T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4+ T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4+ T cells, that is enriched in genes typical for T regulatory type 1 (TR1) cells. The TR1 cell identity of these CD4+ T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. TR1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4+ T cells control TCL1 leukemia development after adoptive transfer in leukopenic Rag2-/- mice, EOMES-deficient CD4+ T cells failed to do so. We further show that TR1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as Il10rb-deficient CD4+ T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic TR1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-10/metabolismo , Leucemia Linfocítica Crônica de Células B/prevenção & controle , Proteínas com Domínio T/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Animais , Diferenciação Celular , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Interferon gama , Interleucina-10/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , Camundongos Endogâmicos C57BL , Prognóstico , Transdução de Sinais , Proteínas com Domínio T/genética , Transcriptoma , Células Tumorais Cultivadas
11.
Nat Commun ; 12(1): 3216, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34050153

RESUMO

X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (p < 5 × 10-8). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2, the genes that were recently implicated in modifying age at onset in Huntington's disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway.


Assuntos
Distúrbios Distônicos/genética , Genes Modificadores , Doenças Genéticas Ligadas ao Cromossomo X/genética , Loci Gênicos , Penetrância , Adulto , Idade de Início , Idoso , Alelos , Estudos de Casos e Controles , Reparo de Erro de Pareamento de DNA , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Proteção , Adulto Jovem
12.
Neurobiol Aging ; 86: 202.e1-202.e3, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31685236

RESUMO

The role of microRNAs (miRNAs) in the pathogenesis of Alzheimer's disease (AD) is currently extensively investigated. In this study, we assessed the potential impact of AD genetic risk variants on miRNA expression by performing large-scale bioinformatic data integration. Our analysis was based on genetic variants from 3 AD genome-wide association studies (GWASs). Association with miRNA expression was tested by expression quantitative trait locus analysis using next-generation miRNA sequencing data generated in lymphoblastoid cell lines. Although, overall, we did not identify a strong effect of AD GWAS variants on miRNA expression in this cell type, we highlight 2 notable outliers, that is, miR-29c-5p and miR-6840-5p. MiR-29c-5p was recently reported to be involved in the regulation of BACE1 and SORL1 expression. In conclusion, despite 2 exceptions, our large-scale assessment provides only limited support for the hypothesis that AD GWAS variants act as miRNA expression quantitative trait loci.


Assuntos
Doença de Alzheimer/genética , Expressão Gênica , Linfócitos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Linhagem Celular , Estudo de Associação Genômica Ampla , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Resultados Negativos , Locos de Características Quantitativas/genética , Risco
13.
Neurol Genet ; 6(5): e506, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33134508

RESUMO

OBJECTIVE: To test the hypothesis that genetic risk for Alzheimer disease (AD) may represent a stable influence on the brain from early in life, rather than being primarily age dependent, we investigated in a lifespan sample of 1,181 persons with a total of 2,690 brain scans, whether higher polygenic risk score (PGS) for AD and presence of APOE ε4 was associated with lower hippocampal volumes to begin with, as an offset effect, or possibly faster decline in older age. METHODS: Using general additive mixed models, we assessed the relations of PGS for AD, including variants in APOE with hippocampal volume and its change in a cognitively healthy longitudinal lifespan sample (age range: 4-95 years, mean visit age 39.7 years, SD 26.9 years), followed for up to 11 years. RESULTS: AD-PGS and APOE ε4 in isolation showed a significant negative effect on hippocampal volume. The effect of a 1 sample SD increase in AD-PGS on hippocampal volume was estimated to -36.4 mm3 (confidence interval [CI]: -71.8, -1.04) and the effect of carrying ε4 allele(s) -107.0 mm3 (CI: -182.0, -31.5). Offset effects of AD-PGS and APOE ε4 were present in hippocampal development, and interactions between age and genetic risk on volume change were not consistently observed. CONCLUSIONS: Endophenotypic manifestation of polygenic risk for AD may be seen across the lifespan in cognitively healthy persons, not being confined to clinical populations or older age. This emphasizes that a broader population and age range may be relevant targets for attempts to prevent AD.

14.
J Alzheimers Dis ; 77(3): 1353-1368, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32831200

RESUMO

BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Idoso , Doença de Alzheimer/genética , Biomarcadores/sangue , Feminino , Expressão Gênica , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Pessoa de Meia-Idade
15.
Transl Psychiatry ; 10(1): 403, 2020 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-33223526

RESUMO

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aß) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aß42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aß38 and CSF-Aß40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aß and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.


Assuntos
Doença de Alzheimer , Idoso , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Biomarcadores , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fragmentos de Peptídeos , Proteínas tau/genética
16.
Mol Neurobiol ; 56(6): 4273-4287, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30302725

RESUMO

The disruptor of telomeric silencing 1-like (DOT1L) mediates methylation of histone H3 at position lysine 79 (H3K79). Conditional knockout of Dot1l in mouse cerebellar granule cells (Dot1l-cKOAtoh1) led to a smaller external granular layer with fewer precursors of granule neurons. Dot1l-cKOAtoh1 mice had impaired proliferation and differentiation of granular progenitors, which resulted in a smaller cerebellum. Mutant mice showed mild ataxia in motor behavior tests. In contrast, Purkinje cell-specific conditional knockout mice showed no obvious phenotype. Genome-wide transcription analysis of Dot1l-cKOAtoh1 cerebella using microarrays revealed changes in genes that function in cell cycle, cell migration, axon guidance, and metabolism. To identify direct DOT1L target genes, we used genome-wide profiling of H3K79me2 and transcriptional analysis. Analysis of differentially methylated regions (DR) and differentially expressed genes (DE) revealed in total 12 putative DOT1L target genes in Dot1l-cKOAtoh1 affecting signaling (Tnfaip8l3, B3galt5), transcription (Otx1), cell migration and axon guidance (Sema4a, Sema5a, Robo1), cholesterol and lipid metabolism (Lss, Cyp51), cell cycle (Cdkn1a), calcium-dependent cell-adhesion or exocytosis (Pcdh17, Cadps2), and unknown function (Fam174b). Dysregulated expression of these target genes might be implicated in the ataxia phenotype observed in Dot1l-cKOAtoh1.


Assuntos
Cerebelo/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Metiltransferases/metabolismo , Animais , Orientação de Axônios/genética , Ciclo Celular , Diferenciação Celular , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Colesterol/metabolismo , Regulação da Expressão Gênica , Histona-Lisina N-Metiltransferase , Metilação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Estresse Fisiológico , Transcriptoma/genética
17.
Epigenomics ; 11(8): 885-897, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31169416

RESUMO

Aim: Validation of epigenome-wide association studies is sparse. Therefore, we evaluated the methylation markers cg06500161 (ABCG1) and cg11024682 (SREBF1) as classifiers for diabetes stratification. Patients & methods: DNA methylation was measured in blood (n = 167), liver (n = 99) and visceral adipose tissue (n = 99) of nondiabetic or Type 2 diabetic subjects by bisulfite pyrosequencing. Results: DNA methylation at cg11024682 in blood and liver correlated with BMI. Methylation at cg06500161 was influenced by the adjacent SNP rs9982016. Insulin-resistant and sensitive subjects could be stratified by DNA methylation status in blood or visceral adipose tissue. Conclusion: DNA methylation at both loci in blood presents a promising approach for risk group stratification and could be valuable for personalized Type 2 diabetes risk prediction in the future.


Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Diabetes Mellitus Tipo 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Metilação de DNA , Diabetes Mellitus Tipo 2/sangue , Marcadores Genéticos/genética , Humanos , Insulina/metabolismo
18.
Science ; 357(6347): 212-216, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28706074

RESUMO

Gametes carry parental genetic material to the next generation. Stress-induced epigenetic changes in the germ line can be inherited and can have a profound impact on offspring development. However, the molecular mechanisms and consequences of transgenerational epigenetic inheritance are poorly understood. We found that Drosophila oocytes transmit the repressive histone mark H3K27me3 to their offspring. Maternal contribution of the histone methyltransferase Enhancer of zeste, the enzymatic component of Polycomb repressive complex 2, is required for active propagation of H3K27me3 during early embryogenesis. H3K27me3 in the early embryo prevents aberrant accumulation of the active histone mark H3K27ac at regulatory regions and precocious activation of lineage-specific genes at zygotic genome activation. Disruption of the germ line-inherited Polycomb epigenetic memory causes embryonic lethality that cannot be rescued by late zygotic reestablishment of H3K27me3. Thus, maternally inherited H3K27me3, propagated in the early embryo, regulates the activation of enhancers and lineage-specific genes during development.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/embriologia , Elementos Facilitadores Genéticos , Epigênese Genética , Histonas/metabolismo , Herança Materna , Oócitos/metabolismo , Zigoto/metabolismo , Animais , Drosophila melanogaster/genética , Perda do Embrião , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/metabolismo , Complexo Repressor Polycomb 2/metabolismo
19.
BMC Genomics ; 7: 241, 2006 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-16987408

RESUMO

BACKGROUND: Sequence data and other characters from mitochondrial genomes (gene translocations, secondary structure of RNA molecules) are useful in phylogenetic studies among metazoan animals from population to phylum level. Moreover, the comparison of complete mitochondrial sequences gives valuable information about the evolution of small genomes, e.g. about different mechanisms of gene translocation, gene duplication and gene loss, or concerning nucleotide frequency biases. The Peracarida (gammarids, isopods, etc.) comprise about 21,000 species of crustaceans, living in many environments from deep sea floor to arid terrestrial habitats. Ligia oceanica is a terrestrial isopod living at rocky seashores of the european North Sea and Atlantic coastlines. RESULTS: The study reveals the first complete mitochondrial DNA sequence from a peracarid crustacean. The mitochondrial genome of Ligia oceanica is a circular double-stranded DNA molecule, with a size of 15,289 bp. It shows several changes in mitochondrial gene order compared to other crustacean species. An overview about mitochondrial gene order of all crustacean taxa yet sequenced is also presented. The largest non-coding part (the putative mitochondrial control region) of the mitochondrial genome of Ligia oceanica is unexpectedly not AT-rich compared to the remainder of the genome. It bears two repeat regions (4x 10 bp and 3x 64 bp), and a GC-rich hairpin-like secondary structure. Some of the transfer RNAs show secondary structures which derive from the usual cloverleaf pattern. While some tRNA genes are putative targets for RNA editing, trnR could not be localized at all. CONCLUSION: Gene order is not conserved among Peracarida, not even among isopods. The two isopod species Ligia oceanica and Idotea baltica show a similarly derived gene order, compared to the arthropod ground pattern and to the amphipod Parhyale hawaiiensis, suggesting that most of the translocation events were already present the last common ancestor of these isopods. Beyond that, the positions of three tRNA genes differ in the two isopod species. Strand bias in nucleotide frequency is reversed in both isopod species compared to other Malacostraca. This is probably due to a reversal of the replication origin, which is further supported by the fact that the hairpin structure typically found in the control region shows a reversed orientation in the isopod species, compared to other crustaceans.


Assuntos
DNA Mitocondrial/genética , Regulação da Expressão Gênica , Ordem dos Genes , Isópodes/genética , Animais , Composição de Bases , Crustáceos/classificação , Crustáceos/genética , Evolução Molecular , Genes Reguladores , Genoma , Isópodes/classificação , Conformação de Ácido Nucleico , Filogenia , RNA de Transferência/genética , Sequências Repetitivas de Ácido Nucleico , Especificidade da Espécie
20.
ISME J ; 9(11): 2537-40, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25885562

RESUMO

Ice-binding proteins (IBPs) have been isolated from various sea-ice organisms. Their characterisation points to a crucial role in protecting the organisms in sub-zero environments. However, their in situ abundance and diversity in natural sea-ice microbial communities is largely unknown. In this study, we analysed the expression and phylogenetic diversity of eukaryotic IBP transcripts from microbial communities of Arctic and Antarctic sea ice. IBP transcripts were found in abundances similar to those of proteins involved in core cellular processes such as photosynthesis. Eighty-nine percent of the IBP transcripts grouped with known IBP sequences from diatoms, haptophytes and crustaceans, but the majority represented novel sequences not previously characterized in cultured organisms. The observed high eukaryotic IBP expression in natural eukaryotic sea ice communities underlines the essential role of IBPs for survival of many microorganisms in communities living under the extreme conditions of polar sea ice.


Assuntos
Camada de Gelo/microbiologia , Regiões Antárticas , Regiões Árticas , Diatomáceas/genética , Ecossistema , Geografia , Haptófitas , Camada de Gelo/química , Fotossíntese , Filogenia , Transcriptoma
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