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1.
Mol Psychiatry ; 28(3): 1327-1336, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36577842

RESUMEN

Polygenic risk scores (PRS) have been widely adopted as a tool for measuring common variant liability and they have been shown to predict lifetime risk of Alzheimer's disease (AD) development. However, the relationship between PRS and AD pathogenesis is largely unknown. To this end, we performed a differential gene-expression and associated disrupted biological pathway analyses of AD PRS vs. case/controls in human brain-derived cohort sample (cerebellum/temporal cortex; MayoRNAseq). The results highlighted already implicated mechanisms: immune and stress response, lipids, fatty acids and cholesterol metabolisms, endosome and cellular/neuronal death, being disrupted biological pathways in both case/controls and PRS, as well as previously less well characterised processes such as cellular structures, mitochondrial respiration and secretion. Despite heterogeneity in terms of differentially expressed genes in case/controls vs. PRS, there was a consensus of commonly disrupted biological mechanisms. Glia and microglia-related terms were also significantly disrupted, albeit not being the top disrupted Gene Ontology terms. GWAS implicated genes were significantly and in their majority, up-regulated in response to different PRS among the temporal cortex samples, suggesting potential common regulatory mechanisms. Tissue specificity in terms of disrupted biological pathways in temporal cortex vs. cerebellum was observed in relation to PRS, but limited tissue specificity when the datasets were analysed as case/controls. The largely common biological mechanisms between a case/control classification and in association with PRS suggests that PRS stratification can be used for studies where suitable case/control samples are not available or the selection of individuals with high and low PRS in clinical trials.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Factores de Riesgo , Herencia Multifactorial , Mitocondrias/genética , Retículo Endoplásmico , Aparato de Golgi , Análisis de Secuencia de ARN , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad
2.
Proc Natl Acad Sci U S A ; 118(8)2021 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-33593901

RESUMEN

Reduced activity of insulin/insulin-like growth factor signaling (IIS) increases healthy lifespan among diverse animal species. Downstream of IIS, multiple evolutionarily conserved transcription factors (TFs) are required; however, distinct TFs are likely responsible for these effects in different tissues. Here we have asked which TFs can extend healthy lifespan within distinct cell types of the adult nervous system in Drosophila Starting from published single-cell transcriptomic data, we report that forkhead (FKH) is endogenously expressed in neurons, whereas forkhead-box-O (FOXO) is expressed in glial cells. Accordingly, we find that neuronal FKH and glial FOXO exert independent prolongevity effects. We have further explored the role of neuronal FKH in a model of Alzheimer's disease-associated neuronal dysfunction, where we find that increased neuronal FKH preserves behavioral function and reduces ubiquitinated protein aggregation. Finally, using transcriptomic profiling, we identify Atg17, a member of the Atg1 autophagy initiation family, as one FKH-dependent target whose neuronal overexpression is sufficient to extend healthy lifespan. Taken together, our results underscore the importance of cell type-specific mapping of TF activity to preserve healthy function with age.


Asunto(s)
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crecimiento & desarrollo , Factores de Transcripción Forkhead/metabolismo , Regulación del Desarrollo de la Expresión Génica , Longevidad , Neuroglía/metabolismo , Neuronas/metabolismo , Animales , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Femenino , Factores de Transcripción Forkhead/genética , Perfilación de la Expresión Génica , Masculino , Neuroglía/citología , Neuronas/citología , Transcriptoma
3.
PLoS Genet ; 13(3): e1006593, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28253260

RESUMEN

Nrf2, a transcriptional activator of cell protection genes, is an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer's disease (AD). Current Nrf2 activators, however, may exert toxicity and pathway over-activation can induce detrimental effects. An understanding of the mechanisms mediating Nrf2 inhibition in neurodegenerative conditions may therefore direct the design of drugs targeted for the prevention of these diseases with minimal side-effects. Our study provides the first in vivo evidence that specific inhibition of Keap1, a negative regulator of Nrf2, can prevent neuronal toxicity in response to the AD-initiating Aß42 peptide, in correlation with Nrf2 activation. Comparatively, lithium, an inhibitor of the Nrf2 suppressor GSK-3, prevented Aß42 toxicity by mechanisms independent of Nrf2. A new direct inhibitor of the Keap1-Nrf2 binding domain also prevented synaptotoxicity mediated by naturally-derived Aß oligomers in mouse cortical neurons. Overall, our findings highlight Keap1 specifically as an efficient target for the re-activation of Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors for the prevention of neurodegeneration in vivo.


Asunto(s)
Enfermedad de Alzheimer/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Perfilación de la Expresión Génica/métodos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Factor 2 Relacionado con NF-E2/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/farmacología , Animales , Animales Modificados Genéticamente , Western Blotting , Línea Celular Tumoral , Células Cultivadas , Modelos Animales de Enfermedad , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Cloruro de Litio/farmacología , Longevidad/efectos de los fármacos , Longevidad/genética , Ratones , Microscopía Confocal , Factor 2 Relacionado con NF-E2/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacología , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/farmacología , Unión Proteica/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tiadiazoles/farmacología , Triazoles/farmacología
4.
Bioinformatics ; 31(23): 3878-80, 2015 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-26249811

RESUMEN

UNLABELLED: Understanding the biology of ageing is an important and complex challenge. Survival experiments are one of the primary approaches for measuring changes in ageing. Here, we present a major update to SurvCurv, a database and online resource for survival data in animals. As well as a substantial increase in data and additions to existing graphical and statistical survival analysis features, SurvCurv now includes extended mathematical mortality modelling functions and survival density plots for more advanced representation of groups of survival cohorts. AVAILABILITY AND IMPLEMENTATION: The database is freely available at https://www.ebi.ac.uk/thornton-srv/databases/SurvCurv/. All data are published under the Creative Commons Attribution License. CONTACT: matthias.ziehm@ebi.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Bases de Datos Factuales , Análisis de Supervivencia , Animales
5.
Hum Mol Genet ; 22(4): 816-24, 2013 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-23148125

RESUMEN

We assessed the role of rare copy number variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlapping APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between single nucleotide polymorphisms and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbours significantly fewer deletions >1 Mb than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 × 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and attention deficit/hyperactivity disorder, CNVs do not appear to make a significant contribution to the development of AD.


Asunto(s)
Enfermedad de Alzheimer/genética , Variaciones en el Número de Copia de ADN , Duplicación de Gen , Anciano , Precursor de Proteína beta-Amiloide/genética , Estudios de Casos y Controles , Sitios Genéticos , Predisposición Genética a la Enfermedad , Genoma Humano , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Receptores de Complemento 3b/genética , Factores de Riesgo
6.
Elife ; 122024 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-38285009

RESUMEN

Increasing evidence supports a role for deficient Wnt signaling in Alzheimer's disease (AD). Studies reveal that the secreted Wnt antagonist Dickkopf-3 (DKK3) colocalizes to amyloid plaques in AD patients. Here, we investigate the contribution of DKK3 to synapse integrity in healthy and AD brains. Our findings show that DKK3 expression is upregulated in the brains of AD subjects and that DKK3 protein levels increase at early stages in the disease. In hAPP-J20 and hAPPNL-G-F/NL-G-F mouse AD models, extracellular DKK3 levels are increased and DKK3 accumulates at dystrophic neuronal processes around plaques. Functionally, DKK3 triggers the loss of excitatory synapses through blockade of the Wnt/GSK3ß signaling with a concomitant increase in inhibitory synapses via activation of the Wnt/JNK pathway. In contrast, DKK3 knockdown restores synapse number and memory in hAPP-J20 mice. Collectively, our findings identify DKK3 as a novel driver of synaptic defects and memory impairment in AD.


Alzheimer's disease is the most common form of dementia worldwide. The cognitive decline typically observed in this condition is associated with the weakening and eventually the loss of synapses, the structures that allow neurons to communicate. Increasing evidence points to this deterioration being linked to deficiency in the Wnt signalling pathway, a cascade of molecular events crucial for brain function and development. The DKK protein family helps to tightly regulate the Wnt pathway by dampening its activity. Previous work suggests that DKK proteins could also be connected to Alzheimer's disease. For example, an elevated amount of DKK1 leads to synapse and memory defects in mice, while brain production of DKK1 is increased in individuals with late Alzheimer's. More recent studies show high levels of another DKK protein, DKK3, in Alzheimer's patients. This protein is also present in the harmful amyloid-ß aggregates, named 'plaques', that typically form in the brain in this condition. Despite these findings, how DKK3 participates in synaptic health remains unclear. To address this question, Martin-Flores, Podpolny et al. tracked DKK3 levels in the brains of Alzheimer's patients, revealing that they increase early in the disease. Additional experiments in Alzheimer's mouse models suggested that DKK3 secretion rise before amyloid-ß plaques form, with the protein then accumulating in abnormal neuronal structures present in the surroundings of these toxic deposits. Martin-Flores, Podpolny et al. then examined the impact of DKK3 on the Wnt pathway, and ultimately, on the balance between synapses that control neuronal activity. These experiments showed that elevated DKK3 levels are linked to a loss of synapses which are excitatory, with a concomitant increase in those that are inhibitory. Crucially, reducing DKK3 levels in a mouse model of Alzheimer's restored this synaptic balance and improved memory, highlighting DKK3 as a potential driver of cognitive impairment. Overall, these findings help to refine our understanding of the molecular mechanisms that contribute to synaptic impairment in Alzheimer's disease. They may also be relevant for researchers studying other conditions that involve aberrant activity of the Wnt pathway, such as cancer.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Enfermedad de Alzheimer , Animales , Humanos , Ratones , Enfermedad de Alzheimer/genética , Transporte Biológico , Modelos Animales de Enfermedad , Regulación hacia Abajo , Placa Amiloide , Sinapsis , Proteínas Adaptadoras Transductoras de Señales/genética
7.
Biogerontology ; 14(1): 21-45, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23100172

RESUMEN

Serotonin is a monoamine neurotransmitter, which is phylogenetically conserved in a wide range of species from nematodes to humans. In mammals, age-related changes in serotonin systems are known risk factors of age-related diseases, such as diabetes, faecal incontinence and cardiovascular diseases. A decline in serotonin function with aging would be consistent with observations of age-related changes in behaviours, such as sleep, sexual behaviour and mood all of which are linked to serotonergic function. Despite this little is known about serotonin in relation to aging. This review aims to give a comprehensive analysis of the distribution, function and interactions of serotonin in the brain; gastrointestinal tract; skeletal; vascular and immune systems. It also aims to demonstrate how the function of serotonin is linked to aging and disease pathology in these systems. The regulation of serotonin via microRNAs is also discussed, as are possible applications of serotonergic drugs in aging research and age-related diseases. Furthermore, this review demonstrates that serotonin is potentially involved in whole organism aging through its links with multiple organs, the immune system and microRNA regulation. Methods to investigate these links are discussed.


Asunto(s)
Envejecimiento/fisiología , Serotonina/fisiología , Envejecimiento/inmunología , Animales , Plaquetas/fisiología , Remodelación Ósea/fisiología , Encéfalo/fisiología , Fenómenos Fisiológicos Cardiovasculares , Tracto Gastrointestinal/fisiología , Humanos , Regeneración Hepática/fisiología , Longevidad/fisiología , MicroARNs/genética , MicroARNs/metabolismo , Receptores de Serotonina/fisiología , Fenómenos Fisiológicos Respiratorios , Serotonina/inmunología
8.
Hum Mutat ; 32(6): 620-32, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21432943

RESUMEN

Mutations associated with tumorigenesis may either arise somatically or can be inherited through the germline. We performed a comparison of somatic, germline, shared (found in both soma and germline) and somatic recurrent mutational spectra for 17 human tumor suppressor genes, which focused upon missense single base-pair substitutions and microdeletions/microinsertions. Somatic and germline mutational spectra were similar in relation to C.G>T.A transitions but differed with respect to the frequency of A.T>G.C, A.T>T.A, and C.G>A.T substitutions. Shared missense mutations were characterized by higher mutability rates, greater physicochemical differences between wild-type and mutant residues, and a tendency to occur in evolutionarily conserved residues and within CpG/CpHpG oligonucleotides. Mononucleotide runs (≥4 bp) were identified as hotspots for shared microdeletions/microinsertions. Both germline and somatic microdeletions/microinsertions were found to be significantly overrepresented within the "indel-hotspot" motif, GTAAGT. Using a naïve Bayes' classifier trained to discriminate between five missense mutation groups, 63% of mutations in our dataset were on average correctly recognized. Applying this classifier to an independent dataset of probable driver mutations, we concluded that ∼50% of these somatic missense mutations possess features consistent with their being either shared or recurrent, suggesting that a disproportionate number of such lesions are likely to be drivers of tumorigenesis.


Asunto(s)
Transformación Celular Neoplásica/genética , Mutación de Línea Germinal/genética , Mutación/genética , Neoplasias/genética , Proteínas Supresoras de Tumor/genética , Biología Computacional , Análisis Mutacional de ADN , Humanos , Mutación INDEL
9.
Hum Mol Genet ; 18(8): 1497-503, 2009 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-19181681

RESUMEN

We investigated the involvement of rare (<1%) copy number variants (CNVs) in 471 cases of schizophrenia and 2792 controls that had been genotyped using the Affymetrix GeneChip 500K Mapping Array. Large CNVs >1 Mb were 2.26 times more common in cases (P = 0.00027), with the effect coming mostly from deletions (odds ratio, OR = 4.53, P = 0.00013) although duplications were also more common (OR = 1.71, P = 0.04). Two large deletions were found in two cases each, but in no controls: a deletion at 22q11.2 known to be a susceptibility factor for schizophrenia and a deletion on 17p12, at 14.0-15.4 Mb. The latter is known to cause hereditary neuropathy with liability to pressure palsies. The same deletion was found in 6 of 4618 (0.13%) cases and 6 of 36 092 (0.017%) controls in the re-analysed data of two recent large CNV studies of schizophrenia (OR = 7.82, P = 0.001), with the combined significance level for all three studies achieving P = 5 x 10(-5). One large duplication on 16p13.1, which has been previously implicated as a susceptibility factor for autism, was found in three cases and six controls (0.6% versus 0.2%, OR = 2.98, P = 0.13). We also provide the first support for a recently reported association between deletions at 15q11.2 and schizophrenia (P = 0.026). This study confirms the involvement of rare CNVs in the pathogenesis of schizophrenia and contributes to the growing list of specific CNVs that are implicated.


Asunto(s)
Dosificación de Gen , Esquizofrenia/genética , Femenino , Eliminación de Gen , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Reino Unido
10.
Hum Hered ; 70(2): 141-9, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20616560

RESUMEN

AIMS: We sought to examine the magnitude of the differences in SNP allele frequencies between five European populations (Scotland, Ireland, Sweden, Bulgaria and Portugal) and to identify the loci with the greatest differences. METHODS: We performed a population-based genome-wide association analysis with Affymetrix 6.0 and 5.0 arrays. We used a 4 degrees of freedom χ(2) test to determine the magnitude of stratification for each SNP. We then examined the genes within the most stratified regions, using a highly conservative cutoff of p < 10(-45). RESULTS: We found 40,593 SNPs which are genome-wide significantly (p ≤ 10(-8)) stratified between these populations. The largest differences clustered in gene ontology categories for immunity and pigmentation. Some of the top loci span genes that have already been reported as highly stratified: genes for hair color and pigmentation (HERC2, EXOC2, IRF4), the LCT gene, genes involved in NAD metabolism, and in immunity (HLA and the Toll-like receptor genes TLR10, TLR1, TLR6). However, several genes have not previously been reported as stratified within European populations, indicating that they might also have provided selective advantages: several zinc finger genes, two genes involved in glutathione synthesis or function, and most intriguingly, FOXP2, implicated in speech development. CONCLUSION: Our analysis demonstrates that many SNPs show genome-wide significant differences within European populations and the magnitude of the differences correlate with the geographical distance. At least some of these differences are due to the selective advantage of polymorphisms within these loci.


Asunto(s)
Genética de Población , Población Blanca/genética , Humanos , Lactasa/genética , Polimorfismo de Nucleótido Simple/genética
11.
Am J Med Genet B Neuropsychiatr Genet ; 156B(7): 764-71, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21812096

RESUMEN

We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no individual run of homozygosity showed association to Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad , Homocigoto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Cromosomas Humanos Par 8/genética , Femenino , Genes/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino
12.
J Alzheimers Dis ; 84(1): 141-149, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34487047

RESUMEN

BACKGROUND: The rate of cognitive decline in Alzheimer's disease (AD) has been found to vary widely between individuals, with numerous factors driving this heterogeneity. OBJECTIVE: This study aimed to compute a measure of cognitive decline in patients with AD based on clinical information and to utilize this measure to explore the genetic architecture of cognitive decline in AD. METHODS: An in-house cohort of 616 individuals, hereby termed the Cardiff Genetic Resource for AD, as well as a subset of 577 individuals from the publicly available ADNI dataset, that have been assessed at multiple timepoints, were used in this study. Measures of cognitive decline were computed using various mixed effect linear models of Mini-Mental State Examination (MMSE). After an optimal model was selected, a metric of cognitive decline for each individual was estimated as the random slope derived from this model. This metric was subsequently used for testing the association of cognitive decline with apolipoprotein E (APOE) genotype. RESULTS: No association was found between the number of APOEɛ2 or ɛ4 alleles and the rate of cognitive decline in either of the datasets examined. CONCLUSION: Further exploration is required to uncover possible genetic variants that affect the rate of decline in patients with AD.


Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Disfunción Cognitiva/psicología , Pruebas de Estado Mental y Demencia/estadística & datos numéricos , Anciano de 80 o más Años , Alelos , Estudios de Cohortes , Femenino , Genotipo , Humanos , Estudios Longitudinales , Masculino
13.
Brain Commun ; 3(4): fcab246, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34805994

RESUMEN

Alzheimer's disease is a neurodegenerative disorder and the most common form of dementia. Early diagnosis may assist interventions to delay onset and reduce the progression rate of the disease. We systematically reviewed the use of machine learning algorithms for predicting Alzheimer's disease using single nucleotide polymorphisms and instances where these were combined with other types of data. We evaluated the ability of machine learning models to distinguish between controls and cases, while also assessing their implementation and potential biases. Articles published between December 2009 and June 2020 were collected using Scopus, PubMed and Google Scholar. These were systematically screened for inclusion leading to a final set of 12 publications. Eighty-five per cent of the included studies used the Alzheimer's Disease Neuroimaging Initiative dataset. In studies which reported area under the curve, discrimination varied (0.49-0.97). However, more than half of the included manuscripts used other forms of measurement, such as accuracy, sensitivity and specificity. Model calibration statistics were also found to be reported inconsistently across all studies. The most frequent limitation in the assessed studies was sample size, with the total number of participants often numbering less than a thousand, whilst the number of predictors usually ran into the many thousands. In addition, key steps in model implementation and validation were often not performed or unreported, making it difficult to assess the capability of machine learning models.

14.
Brain Commun ; 3(2): fcab053, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33977265

RESUMEN

Accumulation of amyloid beta peptides is thought to initiate the pathogenesis of Alzheimer's disease. However, the precise mechanisms mediating their neurotoxicity are unclear. Our microarray analyses show that, in Drosophila models of amyloid beta 42 toxicity, genes involved in the unfolded protein response and metabolic processes are upregulated in brain. Comparison with the brain transcriptome of early-stage Alzheimer's patients revealed a common transcriptional signature, but with generally opposing directions of gene expression changes between flies and humans. Among these differentially regulated genes, lactate dehydrogenase (Ldh) was up-regulated by the greatest degree in amyloid beta 42 flies and the human orthologues (LDHA and LDHB) were down-regulated in patients. Functional analyses revealed that either over-expression or inhibition of Ldh by RNA interference (RNAi) slightly exacerbated climbing defects in both healthy and amyloid beta 42-induced Drosophila. This suggests that metabolic responses to lactate dehydrogenase must be finely-tuned, and that its observed upregulation following amyloid beta 42 production could potentially represent a compensatory protection to maintain pathway homeostasis in this model, with further manipulation leading to detrimental effects. The increased Ldh expression in amyloid beta 42 flies was regulated partially by unfolded protein response signalling, as ATF4 RNAi diminished the transcriptional response and enhanced amyloid beta 42-induced climbing phenotypes. Further functional studies are required to determine whether Ldh upregulation provides compensatory neuroprotection against amyloid beta 42-induced loss of activating transcription factor 4 activity and endoplasmatic reticulum stress. Our study thus reveals dysregulation of lactate dehydrogenase signalling in Drosophila models and patients with Alzheimer's disease, which may lead to a detrimental loss of metabolic homeostasis. Importantly, we observed that down-regulation of ATF4-dependent endoplasmic reticulum-stress signalling in this context appears to prevent Ldh compensation and to exacerbate amyloid beta 42-dependent neuronal toxicity. Our findings, therefore, suggest caution in the use of therapeutic strategies focussed on down-regulation of this pathway for the treatment of Alzheimer's disease, since its natural response to the toxic peptide may induce beneficial neuroprotective effects.

15.
PLoS One ; 15(10): e0240824, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33104720

RESUMEN

Many research teams perform numerous genetic, transcriptomic, proteomic and other types of omic experiments to understand molecular, cellular and physiological mechanisms of disease and health. Often (but not always), the results of these experiments are deposited in publicly available repository databases. These data records often include phenotypic characteristics following genetic and environmental perturbations, with the aim of discovering underlying molecular mechanisms leading to the phenotypic responses. A constrained set of phenotypic characteristics is usually recorded and these are mostly hypothesis driven of possible to record within financial or practical constraints. We present a novel proof-of-principal computational approach for combining publicly available gene-expression data from control/mutant animal experiments that exhibit a particular phenotype, and we use this approach to predict unobserved phenotypic characteristics in new experiments (data derived from EBI's ArrayExpress and ExpressionAtlas respectively). We utilised available microarray gene-expression data for two phenotypes (starvation-sensitive and sterile) in Drosophila. The data were combined using a linear-mixed effects model with the inclusion of consecutive principal components to account for variability between experiments in conjunction with Gene Ontology enrichment analysis. We present how available data can be ranked in accordance to a phenotypic likelihood of exhibiting these two phenotypes using random forest. The results from our study show that it is possible to integrate seemingly different gene-expression microarray data and predict a potential phenotypic manifestation with a relatively high degree of confidence (>80% AUC). This provides thus far unexplored opportunities for inferring unknown and unbiased phenotypic characteristics from already performed experiments, in order to identify studies for future analyses. Molecular mechanisms associated with gene and environment perturbations are intrinsically linked and give rise to a variety of phenotypic manifestations. Therefore, unravelling the phenotypic spectrum can help to gain insights into disease mechanisms associated with gene and environmental perturbations. Our approach uses public data that are set to increase in volume, thus providing value for money.


Asunto(s)
Biología Computacional/métodos , Perfilación de la Expresión Génica/métodos , Transcriptoma/genética , Animales , Bases de Datos Genéticas , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Ontología de Genes , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Fenotipo , Proteómica
16.
PLoS One ; 14(7): e0218111, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31283791

RESUMEN

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.


Asunto(s)
Enfermedad de Alzheimer/genética , Genoma Humano , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Polimorfismo de Nucleótido Simple , Proteínas/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Centrosoma/metabolismo , Centrosoma/patología , Colesterol/genética , Colesterol/metabolismo , Ritmo Circadiano/genética , Daño del ADN/genética , Reparación del ADN/genética , Metabolismo Energético/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Masculino , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Proteínas/metabolismo
17.
Hum Mutat ; 29(8): 1037-47, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18454449

RESUMEN

Nonsense mutations account for approximately 11% of all described gene lesions causing human inherited disease and approximately 20% of disease-associated single-basepair substitutions affecting gene coding regions. Pathological nonsense mutations resulting in TGA (38.5%), TAG (40.4%), and TAA (21.1%) occur in different proportions to naturally occurring stop codons. Of the 23 different nucleotide substitutions giving rise to nonsense mutations, the most frequent are CGA --> TGA (21%; resulting from methylation-mediated deamination) and CAG --> TAG (19%). The differing nonsense mutation frequencies are largely explicable in terms of variable nucleotide substitution rates such that it is unnecessary to invoke differential translational termination efficiency or differential codon usage. Some genes are characterized by numerous nonsense mutations but relatively few if any missense mutations (e.g., CHM) whereas other genes exhibit many missense mutations but few if any nonsense mutations (e.g., PSEN1). Genes in the latter category have a tendency to encode proteins characterized by multimer formation. Consistent with the operation of a clinical selection bias, genes exhibiting an excess of nonsense mutations are also likely to display an excess of frameshift mutations. Tumor suppressor (TS) genes exhibit a disproportionate number of nonsense mutations while most mutations in oncogenes are missense. A total of 12% of somatic nonsense mutations in TS genes were found to occur recurrently in the hypermutable CpG dinucleotide. In a comparison of somatic and germline mutational spectra for 17 TS genes, approximately 43% of somatic nonsense mutations had counterparts in the germline (rising to 98% for CpG mutations). Finally, the proportion of disease-causing nonsense mutations predicted to elicit nonsense-mediated mRNA decay (NMD) is significantly higher (P=1.56 x 10(-9)) than among nonobserved (potential) nonsense mutations, implying that nonsense mutations that elicit NMD are more likely to come to clinical attention.


Asunto(s)
Codón sin Sentido , Bases de Datos Genéticas , Enfermedades Genéticas Congénitas , Codón , Humanos , Estabilidad del ARN
18.
Aging Cell ; 16(5): 1006-1015, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28620943

RESUMEN

Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against aging, despite many genes and pathways shown to be important in the aging process and numerous studies demonstrating that genetic interventions can lead to a healthier aging phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate aging in the invertebrates Caenorhabditis elegans and Drosophila. Our approach combines information on genetic effects on aging, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate aging. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating aging, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates for in vivo testing of their effects on lifespan in C. elegans or Drosophila. As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human aging.


Asunto(s)
Envejecimiento/efectos de los fármacos , Caenorhabditis elegans/efectos de los fármacos , Drosophila melanogaster/efectos de los fármacos , Reposicionamiento de Medicamentos/métodos , Drogas en Investigación/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Envejecimiento/genética , Envejecimiento/metabolismo , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/crecimiento & desarrollo , Caenorhabditis elegans/metabolismo , Bases de Datos Farmacéuticas , Drosophila melanogaster/genética , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Drogas en Investigación/química , Expresión Génica , Envejecimiento Saludable/efectos de los fármacos , Envejecimiento Saludable/genética , Envejecimiento Saludable/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 14 Activada por Mitógenos/química , Proteína Quinasa 14 Activada por Mitógenos/genética , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Simulación del Acoplamiento Molecular , Ratas , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad
19.
Cell Rep ; 21(3): 641-653, 2017 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-29045833

RESUMEN

Reduced activity of nutrient-sensing signaling networks can extend organismal lifespan, yet the underlying biology remains unclear. We show that the anti-aging effects of rapamycin and reduced intestinal insulin/insulin growth factor (IGF) signaling (IIS) require the Drosophila FoxA transcription factor homolog Fork Head (FKH). Intestinal FKH induction extends lifespan, highlighting a role for the gut. FKH binds to and is phosphorylated by AKT and Target of Rapamycin. Gut-specific FKH upregulation improves gut barrier function in aged flies. Additionally, it increases the expression of nutrient transporters, as does lowered IIS. Evolutionary conservation of this effect of lowered IIS is suggested by the upregulation of related nutrient transporters in insulin receptor substrate 1 knockout mouse intestine. Our study highlights a critical role played by FKH in the gut in mediating anti-aging effects of reduced IIS. Malnutrition caused by poor intestinal absorption is a major problem in the elderly, and a better understanding of the mechanisms involved will have important therapeutic implications for human aging.


Asunto(s)
Drosophila melanogaster/metabolismo , Drosophila melanogaster/fisiología , Alimentos , Factores de Transcripción Forkhead/metabolismo , Absorción Intestinal , Mucosa Intestinal/metabolismo , Longevidad , Proteínas Nucleares/metabolismo , Animales , Restricción Calórica , Diferenciación Celular/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Enterocitos/efectos de los fármacos , Enterocitos/metabolismo , Femenino , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Absorción Intestinal/efectos de los fármacos , Intestinos/citología , Longevidad/efectos de los fármacos , Proteínas de Transporte de Membrana/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sirolimus/farmacología , Somatomedinas/metabolismo , Transcripción Genética/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos
20.
Cell Rep ; 15(3): 638-650, 2016 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-27068460

RESUMEN

The quest to extend healthspan via pharmacological means is becoming increasingly urgent, both from a health and economic perspective. Here we show that lithium, a drug approved for human use, promotes longevity and healthspan. We demonstrate that lithium extends lifespan in female and male Drosophila, when administered throughout adulthood or only later in life. The life-extending mechanism involves the inhibition of glycogen synthase kinase-3 (GSK-3) and activation of the transcription factor nuclear factor erythroid 2-related factor (NRF-2). Combining genetic loss of the NRF-2 repressor Kelch-like ECH-associated protein 1 (Keap1) with lithium treatment revealed that high levels of NRF-2 activation conferred stress resistance, while low levels additionally promoted longevity. The discovery of GSK-3 as a therapeutic target for aging will likely lead to more effective treatments that can modulate mammalian aging and further improve health in later life.


Asunto(s)
Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/fisiología , Glucógeno Sintasa Quinasa 3/metabolismo , Hormesis/efectos de los fármacos , Litio/farmacología , Longevidad/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Autofagia/efectos de los fármacos , Restricción Calórica , Carbohidratos de la Dieta , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Femenino , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Modelos Biológicos , Estrés Fisiológico/efectos de los fármacos , Análisis de Supervivencia , Transcripción Genética/efectos de los fármacos , Xenobióticos/farmacología
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