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1.
Cell ; 160(3): 477-88, 2015 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-25619689

RESUMEN

MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc(+/-)) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc(+/-) mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.


Asunto(s)
Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Envejecimiento , Animales , Tamaño Corporal , Femenino , Longevidad , Linfoma/genética , Masculino , Redes y Vías Metabólicas , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Transcriptoma
2.
Nature ; 588(7838): 459-465, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32866962

RESUMEN

Aberrant aggregation of the RNA-binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by haploinsufficiency in the gene encoding progranulin1,2. However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA sequencing to show that progranulin deficiency promotes microglial transition from a homeostatic to a disease-specific state that causes endolysosomal dysfunction and neurodegeneration in mice. These defects persist even when Grn-/- microglia are cultured ex vivo. In addition, single-nucleus RNA sequencing reveals selective loss of excitatory neurons at disease end-stage, which is characterized by prominent nuclear and cytoplasmic TDP-43 granules and nuclear pore defects. Remarkably, conditioned media from Grn-/- microglia are sufficient to promote TDP-43 granule formation, nuclear pore defects and cell death in excitatory neurons via the complement activation pathway. Consistent with these results, deletion of the genes encoding C1qa and C3 mitigates microglial toxicity and rescues TDP-43 proteinopathy and neurodegeneration. These results uncover previously unappreciated contributions of chronic microglial toxicity to TDP-43 proteinopathy during neurodegeneration.


Asunto(s)
Microglía/metabolismo , Microglía/patología , Neuronas/metabolismo , Neuronas/patología , Progranulinas/deficiencia , Proteinopatías TDP-43/metabolismo , Proteinopatías TDP-43/patología , Envejecimiento/genética , Envejecimiento/patología , Animales , Núcleo Celular/genética , Núcleo Celular/patología , Activación de Complemento/efectos de los fármacos , Activación de Complemento/inmunología , Complemento C1q/antagonistas & inhibidores , Complemento C1q/inmunología , Complemento C3b/antagonistas & inhibidores , Complemento C3b/inmunología , Medios de Cultivo Condicionados/química , Medios de Cultivo Condicionados/farmacología , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Poro Nuclear/metabolismo , Poro Nuclear/patología , Progranulinas/genética , RNA-Seq , Análisis de la Célula Individual , Proteinopatías TDP-43/tratamiento farmacológico , Proteinopatías TDP-43/genética , Tálamo/metabolismo , Tálamo/patología , Transcriptoma
3.
Acta Neuropathol ; 140(6): 907-917, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32892244

RESUMEN

Paragangliomas are neuroendocrine tumors of the autonomic nervous system that are variably clinically functional and have a potential for metastasis. Up to 40% occur in the setting of a hereditary syndrome, most commonly due to germline mutations in succinate dehydrogenase (SDHx) genes. Immunohistochemically, paragangliomas are characteristically GATA3-positive and cytokeratin-negative, with loss of SDHB expression in most hereditary cases. In contrast, the rare paragangliomas arising in the cauda equina (CEP) or filum terminale region have been shown to be hormonally silent, clinically indolent, and have variable keratin expression, suggesting these tumors may represent a separate pathologic entity. We retrospectively evaluated 17 CEPs from 11 male and 6 female patients with a median age of 38 years (range 21-82), none with a family history of neuroendocrine neoplasia. Six of the 17 tumors demonstrated prominent gangliocytic or ganglioneuromatous differentiation. By immunohistochemistry, none of the CEPs showed GATA3 positivity or loss of SDHB staining; all 17 CEPs were cytokeratin positive. Genome-wide DNA methylation profiling was performed on 12 of the tumors and compared with publicly available genome-wide DNA methylation data. Clustering analysis showed that CEPs form a distinct epigenetic group, separate from paragangliomas of extraspinal sites, pheochromocytomas, and other neuroendocrine neoplasms. Copy number analysis revealed diploid genomes in the vast majority of CEPs, whereas extraspinal paragangliomas were mostly aneuploid with recurrent trisomy 1q and monosomies of 1p, 3, and 11, none of which were present in the cohort of CEP. Together, these findings indicate that CEPs likely represent a distinct entity. Future genomic studies are needed to further elucidate the molecular pathogenesis of these tumors.


Asunto(s)
Cauda Equina/patología , Neoplasias del Sistema Nervioso Central/genética , Variaciones en el Número de Copia de ADN/fisiología , Metilación de ADN/fisiología , Inmunohistoquímica , Paraganglioma/patología , Adulto , Anciano , Anciano de 80 o más Años , Cauda Equina/metabolismo , Femenino , Mutación de Línea Germinal/genética , Mutación de Línea Germinal/fisiología , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Paraganglioma/genética , Adulto Joven
4.
BMC Neurol ; 20(1): 106, 2020 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-32199449

RESUMEN

BACKGROUND: Psoriasis is the most common chronic inflammatory condition involving the T helper cell system. Population studies have demonstrated that patients with psoriasis and/or psoriatic arthritis have an increased risk of developing vascular risk factors, including diabetes, hypertension, and obesity, and increased risk of adverse vascular events, including myocardial infarction and stroke. Population studies have generally investigated the individual contributions of psoriasis and psoriatic arthritis to development of vascular risk factors; fewer studies have investigated the additive contribution of comorbid inflammatory disorders. We present a case of a woman with psoriasis, psoriatic arthritis, and comorbid vascular risk factors. CASE PRESENTATION: A 49 year-old Caucasian woman with a history of severe psoriasis and psoriatic arthritis since adolescence presented with bilateral lower extremity weakness. She was found to have acute bilateral watershed infarcts and multifocal subacute infarcts. Her evaluation revealed vascular risk factors and elevated non-specific systemic inflammatory markers; serum and cerebral spinal fluid did not reveal underlying infection, hypercoagulable state, or vasculitis. Over the course of days, she exhibited precipitous clinical deterioration related to multiple large vessel occlusions, including the bilateral anterior cerebral arteries and the left middle cerebral artery. Autopsy revealed acute thrombi and diffuse, severe atherosclerosis. CONCLUSION: Patients with early onset inflammatory disease activity or comorbid inflammatory disorders may have an even higher risk of developing metabolic syndrome and adverse vascular events compared to patients with late-onset disease activity or with a single inflammatory condition. The described case illustrates the complex relationship between inflammatory disorders and vascular risk factors. The degree of systemic inflammation, as measured by severity of disease activity, has been shown to have a dose-response relationship with comorbid vascular risk factors and vascular events. Dysregulation of the Th1 and Th17 system has been implicated in the development of atherosclerosis and may explain the severe atherosclerosis seen in such chronic inflammatory conditions. Further research will help refine screening and management guidelines to account for comorbid inflammatory disorders and related disease severity.


Asunto(s)
Artritis Psoriásica/complicaciones , Psoriasis/complicaciones , Accidente Cerebrovascular/epidemiología , Artritis Psoriásica/inmunología , Aterosclerosis/epidemiología , Aterosclerosis/etiología , Comorbilidad , Resultado Fatal , Femenino , Humanos , Síndrome Metabólico/epidemiología , Síndrome Metabólico/etiología , Persona de Mediana Edad , Psoriasis/inmunología , Factores de Riesgo
5.
Bioessays ; 35(12): 1035-43, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24129940

RESUMEN

Here we present and develop the hypothesis that the derepression of endogenous retrotransposable elements (RTEs) - "genomic parasites" - is an important and hitherto under-unexplored molecular aging process that can potentially occur in most tissues. We further envision that the activation and continued presence of retrotransposition contribute to age-associated tissue degeneration and pathology. Chromatin is a complex and dynamic structure that needs to be maintained in a functional state throughout our lifetime. Studies of diverse species have revealed that chromatin undergoes extensive rearrangements during aging. Cellular senescence, an important component of mammalian aging, has recently been associated with decreased heterochromatinization of normally silenced regions of the genome. These changes lead to the expression of RTEs, culminating in their transposition. RTEs are common in all kingdoms of life, and comprise close to 50% of mammalian genomes. They are tightly controlled, as their activity is highly destabilizing and mutagenic to their resident genomes.


Asunto(s)
Senescencia Celular/genética , Retroelementos/genética , Envejecimiento/genética , Envejecimiento/fisiología , Animales , Senescencia Celular/fisiología , Humanos , Retroelementos/fisiología
7.
Brain Pathol ; 31(4): e12918, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33141488

RESUMEN

Intracranial mesenchymal tumors with FET-CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET-CREB fusion by next-generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4-70). Tumors were uniformly extra-axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1-ATF1 fusion, seven had EWSR1-CREB1, four had EWSR1-CREM, and one had FUS-CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1-CREB1 fusions more often featured stellate/spindle cell morphology, mucin-rich stroma, and hemangioma-like vasculature compared to tumors with EWSR1-ATF1 fusions that most often featured sheets of epithelioid cells with mucin-poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression-free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1-ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET-CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma-like neoplasms.


Asunto(s)
Neoplasias Encefálicas/patología , Histiocitoma Fibroso Benigno/patología , Histiocitoma Fibroso Maligno/patología , Proteínas de Fusión Oncogénica/metabolismo , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Niño , Preescolar , Femenino , Fusión Génica/genética , Histiocitoma Fibroso Benigno/diagnóstico , Histiocitoma Fibroso Benigno/metabolismo , Histiocitoma Fibroso Maligno/diagnóstico , Histiocitoma Fibroso Maligno/genética , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Adulto Joven
8.
Acta Neuropathol Commun ; 8(1): 151, 2020 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-32859279

RESUMEN

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.


Asunto(s)
Neoplasias Neuroepiteliales/clasificación , Neoplasias Neuroepiteliales/genética , Neoplasias Neuroepiteliales/patología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neoplasias de la Médula Espinal/clasificación , Neoplasias de la Médula Espinal/genética , Neoplasias de la Médula Espinal/patología , Adulto Joven
9.
J Mol Evol ; 69(1): 94-114, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19533212

RESUMEN

To gain insight on mitochondrial DNA (mtDNA) evolution, we assembled and analyzed the mitochondrial genomes of Drosophila erecta, D. ananassae, D. persimilis, D. willistoni, D. mojavensis, D. virilis and D. grimshawi together with the sequenced mtDNAs of the melanogaster subgroup. Genomic comparisons across the well-defined Drosophila phylogeny impart power for detecting conserved mtDNA regions that maintain metabolic function and regions that evolve uniquely on lineages. Evolutionary rate varies across intergenic regions of the mtDNA. Rapidly evolving intergenic regions harbor the majority of mitochondrial indel divergence. In contrast, patterns of nearly perfect conservation within intergenic regions reveal a refined set of nucleotides underlying the binding of transcription termination factors. Sequencing of 5' cDNA ends indicates that cytochrome C oxidase I (CoI) has a novel (T/C)CG start codon and that perfectly conserved regions upstream of two NADH dehydrogenase (ND) genes are transcribed and likely extend these protein sequences. Substitutions at synonymous sites in the Drosophila mitochondrial proteomes reflect a mutation process that is biased toward A and T nucleotides and differs between mtDNA strands. Differences in codon usage bias across genes reveal that weak selection at silent sites may offset the mutation bias. The mutation-selection balance at synonymous sites has also diverged between the Drosophila and Sophophora lineages. Rates of evolution are highly heterogeneous across the mitochondrial proteome, with ND accumulating many more amino acid substitutions than CO. These oxidative phosphorylation complex-specific rates of evolution vary across lineages and may reflect physiological and ecological change across the Drosophila phylogeny.


Asunto(s)
ADN Mitocondrial/genética , Drosophila/genética , Evolución Molecular , Genoma Mitocondrial , Genómica/métodos , Secuencia de Aminoácidos , Animales , Composición de Base , Secuencia de Bases , Teorema de Bayes , Secuencia Conservada , ADN Intergénico , Proteínas del Complejo de Cadena de Transporte de Electrón/genética , Proteínas Mitocondriales/genética , Modelos Genéticos , Datos de Secuencia Molecular , Mutación , Filogenia , ARN de Transferencia/genética , Selección Genética , Alineación de Secuencia , Transcripción Genética
10.
Annu Rev Pathol ; 14: 469-495, 2019 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-30355151

RESUMEN

Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype-phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid-liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights into the pathogenesis and potential therapeutic targets of FTLD.


Asunto(s)
Proteínas de Unión al ADN/genética , Degeneración Lobar Frontotemporal/metabolismo , Mutación , Proteína FUS de Unión a ARN/genética , Esclerosis Amiotrófica Lateral , Animales , Proteínas de Unión al ADN/metabolismo , Demencia Frontotemporal , Degeneración Lobar Frontotemporal/etiología , Degeneración Lobar Frontotemporal/genética , Humanos , Proteína FUS de Unión a ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteinopatías TDP-43 , Proteínas tau
11.
Virchows Arch ; 471(2): 257-269, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28674742

RESUMEN

This article reviews the histologic and molecular characterization of gliomas, including the new "integrated diagnoses" of the World Health Organization Classification, 2016 edition. The entities reviewed within include diffuse gliomas (astrocytoma, oligodendroglioma, glioblastoma), as well as circumscribed and low-grade gliomas (angiocentric glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, ependymoma, myxopapillary ependymoma, and subependymoma). Diagnostic, prognostic, and predictive biomarkers are discussed for each entity. We review how molecular testing for IDH1 and ATRX and detection of chromosome 1p/19q codeletion can be used to categorize glioblastomas as IDH-wildtype or IDH-mutant, and lower grade diffuse gliomas into three molecular groups that correlate better with patient outcomes than histologic subtyping. Pediatric diffuse gliomas are highlighted, including diffuse midline glioma, H3 K27M-mutant, and inherited germline mutations that predispose to pediatric gliomas. The utility of genomic profiling of certain gliomas is discussed, including identifying candidates for experimental therapies. This review is meant to be a concise summary of glioma characterization for the practicing pathologist.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glioma/genética , Glioma/patología , Neoplasias Encefálicas/clasificación , Glioma/clasificación , Humanos , Patología Clínica/métodos , Patología Clínica/tendencias , Patología Molecular/métodos , Patología Molecular/tendencias
14.
Age (Dordr) ; 36(3): 9618, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24488586

RESUMEN

The Wnt signaling pathway is involved in the regulation of tissue patterning and organ development during embryogenesis and continues to contribute to the maintenance of tissue homeostasis in adulthood. Recently, Wnt signaling has also been implicated in the establishment and progression of replicative cellular senescence. Given the known roles of tissue homeostasis and cellular senescence in aging, we sought to determine whether Wnt signaling changes with age. We examined the expression of 84 Wnt pathway-related genes in the liver, lung, skeletal muscle, and brain tissue from young and old mice. Expression changes were compared with those seen in cellular senescence, and transcription factors that might mediate these changes were predicted bioinformatically. In aggregate, our data are indicative of a general decrease in Wnt signaling with age, especially in the lung and brain. Furthermore, the set of genes that are differentially expressed with age is distinct from the genes differentially expressed in cellular senescence. The transcription factors predicted to regulate these changes, Nf-κB, Myb, Nkx2-1, Nr5a2, and Ep300, are known to regulate inflammation, differentiation, lipid metabolism, and chromatin remodeling, all of which have previously been implicated in aging. Although our study does not address whether altered Wnt signaling is a cause or an effect of aging, the presence of a relationship between the two provides a starting point for further investigation.


Asunto(s)
Envejecimiento/genética , Encéfalo/metabolismo , Hígado/metabolismo , Pulmón/metabolismo , Músculo Esquelético/metabolismo , ARN/genética , Proteínas Wnt/genética , Animales , Encéfalo/citología , Supervivencia Celular , Senescencia Celular/fisiología , Hígado/citología , Pulmón/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/citología , Polimorfismo de Nucleótido Simple , Proteínas Wnt/metabolismo , Vía de Señalización Wnt
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