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1.
Nat Methods ; 10(3): 221-7, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23353650

RESUMEN

Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally. If computational predictions are to be relied upon, it is crucial that the accuracy of these methods be high. Here we report the results from the first large-scale community-based critical assessment of protein function annotation (CAFA) experiment. Fifty-four methods representing the state of the art for protein function prediction were evaluated on a target set of 866 proteins from 11 organisms. Two findings stand out: (i) today's best protein function prediction algorithms substantially outperform widely used first-generation methods, with large gains on all types of targets; and (ii) although the top methods perform well enough to guide experiments, there is considerable need for improvement of currently available tools.


Asunto(s)
Biología Computacional/métodos , Biología Molecular/métodos , Anotación de Secuencia Molecular , Proteínas/fisiología , Algoritmos , Animales , Bases de Datos de Proteínas , Exorribonucleasas/clasificación , Exorribonucleasas/genética , Exorribonucleasas/fisiología , Predicción , Humanos , Proteínas/química , Proteínas/clasificación , Proteínas/genética , Especificidad de la Especie
2.
Hum Mutat ; 35(11): 1271-9, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25137622

RESUMEN

Morquio A syndrome (mucopolysaccharidosis IVA) is an autosomal recessive disorder that results from deficient activity of the enzyme N-acetylgalactosamine-6-sulfatase (GALNS) due to alterations in the GALNS gene, which causes major skeletal and connective tissue abnormalities and effects on multiple organ systems. The GALNS alterations associated with Morquio A are numerous and heterogeneous, and new alterations are continuously identified. To aid detection and interpretation of GALNS alterations, from previously published research, we provide a comprehensive and up-to-date listing of 277 unique GALNS alterations associated with Morquio A identified from 1,091 published GALNS alleles. In agreement with previous findings, most reported GALNS alterations are missense changes and even the most frequent alterations are relatively uncommon. We found that 48% of patients are assessed as homozygous for a GALNS alteration, 39% are assessed as heterozygous for two identified GALNS alterations, and in 13% of patients only one GALNS alteration is detected. We report here the creation of a locus-specific database for the GALNS gene (http://galns.mutdb.org/) that catalogs all reported alterations in GALNS to date. We highlight the challenges both in alteration detection and genotype-phenotype interpretation caused in part by the heterogeneity of GALNS alterations and provide recommendations for molecular testing of GALNS.


Asunto(s)
Condroitinsulfatasas/genética , Bases de Datos de Ácidos Nucleicos , Mucopolisacaridosis IV/genética , Mutación , Alelos , Animales , Biomarcadores , Modelos Animales de Enfermedad , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Geografía , Humanos , Recién Nacido , Mucopolisacaridosis IV/diagnóstico , Mucopolisacaridosis IV/terapia , Tamizaje Neonatal , Fenotipo , Sitios de Carácter Cuantitativo
3.
PLoS One ; 15(1): e0227887, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31945125

RESUMEN

Neurodegeneration is a major age-related pathology. Cognitive decline is characteristic of patients with Alzheimer's and related dementias and cancer patients after chemo- or radio-therapies. A recently emerged driver of these and other age-related pathologies is cellular senescence, a cell fate that entails a permanent cell cycle arrest and pro-inflammatory senescence-associated secretory phenotype (SASP). Although there is a link between inflammation and neurodegenerative diseases, there are many open questions regarding how cellular senescence affects neurodegenerative pathologies. Among the various cell types in the brain, astrocytes are the most abundant. Astrocytes have proliferative capacity and are essential for neuron survival. Here, we investigated the phenotype of primary human astrocytes made senescent by X-irradiation, and identified genes encoding glutamate and potassium transporters as specifically downregulated upon senescence. This down regulation led to neuronal cell death in co-culture assays. Unbiased RNA sequencing of transcripts expressed by non-senescent and senescent astrocytes confirmed that glutamate homeostasis pathway declines upon senescence. Our results suggest a key role for cellular senescence, particularly in astrocytes, in excitotoxicity, which may lead to neurodegeneration including Alzheimer's disease and related dementias.


Asunto(s)
Enfermedad de Alzheimer/genética , Astrocitos/metabolismo , Senescencia Celular/genética , Neuronas/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Sistema de Transporte de Aminoácidos X-AG/genética , Astrocitos/patología , Encéfalo/metabolismo , Encéfalo/patología , Puntos de Control del Ciclo Celular/efectos de la radiación , Senescencia Celular/efectos de la radiación , Regulación de la Expresión Génica/efectos de la radiación , Ácido Glutámico/genética , Ácido Glutámico/metabolismo , Humanos , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Neuronas/patología , Cultivo Primario de Células , Rayos X
4.
Cell Rep ; 28(13): 3329-3337.e5, 2019 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-31553904

RESUMEN

Cellular senescence irreversibly arrests cell proliferation, accompanied by a multi-component senescence-associated secretory phenotype (SASP) that participates in several age-related diseases. Using stable isotope labeling with amino acids (SILACs) and cultured cells, we identify 343 SASP proteins that senescent human fibroblasts secrete at 2-fold or higher levels compared with quiescent cell counterparts. Bioinformatic analysis reveals that 44 of these proteins participate in hemostasis, a process not previously linked with cellular senescence. We validated the expression of some of these SASP factors in cultured cells and in vivo. Mice treated with the chemotherapeutic agent doxorubicin, which induces widespread cellular senescence in vivo, show increased blood clotting. Conversely, selective removal of senescent cells using transgenic p16-3MR mice showed that clearing senescent cells attenuates the increased clotting caused by doxorubicin. Our study provides an in-depth, unbiased analysis of the SASP and unveils a function for cellular senescence in hemostasis.


Asunto(s)
Senescencia Celular/genética , Hemostasis , Humanos
5.
PLoS One ; 11(5): e0154890, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27191603

RESUMEN

We report generation of induced pluripotent stem cell (iPSC) lines from ten Parkinson's disease (PD) patients carrying SNCA, PARK2, LRRK2, and GBA mutations, and one age-matched control. After validation of pluripotency, long-term genome stability, and integration-free reprogramming, eight of these lines (one of each SNCA, LRRK2 and GBA, four PARK2 lines, and the control) were differentiated into neural stem cells (NSC) and subsequently to dopaminergic cultures. We did not observe significant differences in the timeline of neural induction and NSC derivation between the patient and control line, nor amongst the patient lines, although we report considerable variability in the efficiency of dopaminergic differentiation among patient lines. We performed whole genome expression analyses of the lines at each stage of differentiation (fibroblast, iPSC, NSC, and dopaminergic culture) in an attempt to identify alterations by large-scale evaluation. While gene expression profiling clearly distinguished cells at different stages of differentiation, no mutation-specific clustering or difference was observed, though consistent changes in patient lines were detected in genes associated mitochondrial biology. We further examined gene expression in a stress model (MPTP-induced dopaminergic neuronal death) using two clones from the SNCA triplication line, and detected changes in genes associated with mitophagy. Our data suggested that even a well-characterized line of a monogenic disease may not be sufficient to determine the cause or mechanism of the disease, and highlights the need to use more focused strategies for large-scale data analysis.


Asunto(s)
Neuronas Dopaminérgicas/citología , Células Madre Pluripotentes Inducidas/citología , Mutación , Células-Madre Neurales/citología , Neurogénesis , Enfermedad de Parkinson/genética , Células Cultivadas , Neuronas Dopaminérgicas/metabolismo , Genoma Humano , Glucosilceramidasa/genética , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mitocondrias/metabolismo , Mitofagia , Células-Madre Neurales/metabolismo , Enfermedad de Parkinson/patología , Ubiquitina-Proteína Ligasas/genética , alfa-Sinucleína/genética
6.
Cell Rep ; 17(5): 1227-1237, 2016 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-27783938

RESUMEN

Vitamin D has multiple roles, including the regulation of bone and calcium homeostasis. Deficiency of 25-hydroxyvitamin D, the major circulating form of vitamin D, is associated with an increased risk of age-related chronic diseases, including Alzheimer's disease, Parkinson's disease, cognitive impairment, and cancer. In this study, we utilized Caenorhabditis elegans to examine the mechanism by which vitamin D influences aging. We found that vitamin-D3-induced lifespan extension requires the stress response pathway genes skn-1, ire-1, and xbp-1. Vitamin D3 (D3) induced expression of SKN-1 target genes but not canonical targets of XBP-1. D3 suppressed an important molecular pathology of aging, that of widespread protein insolubility, and prevented toxicity caused by human ß-amyloid. Our observation that D3 improves protein homeostasis and slows aging highlights the importance of maintaining appropriate vitamin D serum levels and may explain why such a wide variety of human age-related diseases are associated with vitamin D deficiency.


Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Proteínas Portadoras/genética , Proteínas de Unión al ADN/genética , Homeostasis/efectos de los fármacos , Longevidad/fisiología , Proteínas Serina-Treonina Quinasas/genética , Estrés Fisiológico/genética , Factores de Transcripción/genética , Vitamina D/farmacología , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/fisiología , Proteínas de Caenorhabditis elegans/metabolismo , Calcitriol/metabolismo , Proteínas Portadoras/metabolismo , Colecalciferol/metabolismo , Proteínas de Unión al ADN/metabolismo , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Agregado de Proteínas , Proteínas Serina-Treonina Quinasas/metabolismo , Solubilidad , Factores de Transcripción/metabolismo , Respuesta de Proteína Desplegada/efectos de los fármacos
7.
Genome Biol ; 17(1): 184, 2016 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-27604469

RESUMEN

BACKGROUND: A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. RESULTS: We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. CONCLUSIONS: The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent.


Asunto(s)
Biología Computacional , Proteínas/química , Programas Informáticos , Relación Estructura-Actividad , Algoritmos , Bases de Datos de Proteínas , Ontología de Genes , Humanos , Anotación de Secuencia Molecular , Proteínas/genética
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