RESUMEN
In humans, aggregation of polyglutamine repeat (polyQ) proteins causes disorders such as Huntington's disease. Although plants express hundreds of polyQ-containing proteins, no pathologies arising from polyQ aggregation have been reported. To investigate this phenomenon, we expressed an aggregation-prone fragment of human huntingtin (HTT) with an expanded polyQ stretch (Q69) in Arabidopsis thaliana plants. In contrast to animal models, we find that Arabidopsis sp. suppresses Q69 aggregation through chloroplast proteostasis. Inhibition of chloroplast proteostasis diminishes the capacity of plants to prevent cytosolic Q69 aggregation. Moreover, endogenous polyQ-containing proteins also aggregate on chloroplast dysfunction. We find that Q69 interacts with the chloroplast stromal processing peptidase (SPP). Synthetic Arabidopsis SPP prevents polyQ-expanded HTT aggregation in human cells. Likewise, ectopic SPP expression in Caenorhabditis elegans reduces neuronal Q67 aggregation and subsequent neurotoxicity. Our findings suggest that synthetic plant proteins, such as SPP, hold therapeutic potential for polyQ disorders and other age-related diseases involving protein aggregation.
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Arabidopsis , Agregado de Proteínas , Animales , Humanos , Arabidopsis/genética , Péptidos/genética , Neuronas/metabolismo , Caenorhabditis elegans/genéticaRESUMEN
Stress granules are membrane-less ribonucleoprotein organelles that assemble upon exposure to stress conditions, but rapidly disassemble upon removal of stress. However, chronic stress can lead to persistent stress granules, a feature of distinct age-related neurodegenerative disorders. Among them, Huntington's disease (HD), which is caused by mutant expansion of the polyglutamine (polyQ) repeats of huntingtin protein (HTT), leading to its aggregation. To identify modulators of mutant HTT aggregation, we define its interactome in striatal neurons differentiated from patient-derived induced pluripotent stem cells (HD-iPSCs). We find that HTT interacts with G3BP1, a characteristic component of stress granules. Knockdown of G3BP1 increases mutant HTT protein levels and abolishes the ability of iPSCs as well as their differentiated neural counterparts to suppress mutant HTT aggregation. Moreover, loss of G3BP1 hastens polyQ-expanded aggregation and toxicity in the neurons of HD C. elegans models. Likewise, the assembly of G3BP1 into stress granules upon distinct stress conditions also reduces its interaction with HTT in human cells, promoting mutant HTT aggregation. Notably, enhancing the levels of G3BP1 is sufficient to induce proteasomal degradation of mutant HTT and prevent its aggregation, whereas the formation of stress granules blocks these ameliorative effects. In contrast, a mutant G3BP1 variant that cannot accumulate into granules retains its capacity to prevent mutant HTT aggregation even when the cells assemble stress granules. Thus, our findings indicate a direct role of G3BP1 and stress granule assembly in mutant HTT aggregation that may have implications for HD.
Asunto(s)
Enfermedad de Huntington , Agregado de Proteínas , Animales , Humanos , ADN Helicasas/metabolismo , Gránulos de Estrés , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/genética , ARN Helicasas/metabolismo , Proteínas con Motivos de Reconocimiento de ARN/genética , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , MutaciónRESUMEN
The first case of a placental tumor composed of benign hepatic tissue was published in 1986 and considered a placental benign hepatocellular adenoma. Since then, this lesion is better known as ectopic liver, and a total of 12 cases have been published. The ectopic liver located in the umbilical cord is an even rarer alteration, with only nine cases described to date. We report another case of ectopic liver, this time in an embryo of only five weeks of gestational age.
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Adenoma , Hepatopatías , Femenino , Humanos , Hígado , Placenta , Embarazo , Cordón UmbilicalRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Pluripotent stem cells are invaluable resources to study development and disease, holding a great promise for regenerative medicine. Here we use human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) from patients with Huntington's disease (HD-iPSCs) to shed light into the normal function of huntingtin (HTT) and its demise in disease. We find that HTT binds ATF7IP, a regulator of the histone H3 methyltransferase SETDB1. HTT inhibits the interaction of the ATF7IP-SETDB1 complex with other heterochromatin regulators and transcriptional repressors, maintaining low levels of H3K9 trimethylation (H3K9me3) in hESCs. Loss of HTT promotes global increased H3K9me3 levels and enrichment of H3K9me3 marks at distinct genes, including transcriptional regulators of neuronal differentiation. Although these genes are normally expressed at low amounts in hESCs, HTT knockdown (KD) reduces their induction during neural differentiation. Notably, mutant expanded polyglutamine repeats in HTT diminish its interaction with ATF7IP-SETDB1 complex and trigger H3K9me3 in HD-iPSCs. Conversely, KD of ATF7IP in HD-iPSCs reduces H3K9me3 alterations and ameliorates gene expression changes in their neural counterparts. Taken together, our results indicate ATF7IP as a potential target to correct aberrant H3K9me3 levels induced by mutant HTT.
Asunto(s)
Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Proteína Metiltransferasas/genética , Factores de Transcripción/genética , Diferenciación Celular/genética , Células Madre Embrionarias/metabolismo , Células Madre Embrionarias/patología , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Heterocromatina/genética , Histona Metiltransferasas/genética , N-Metiltransferasa de Histona-Lisina , Humanos , Enfermedad de Huntington/patología , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Lentivirus/genética , Neuronas/metabolismo , Neuronas/patología , Péptidos/genética , Proteínas RepresorasRESUMEN
Induced pluripotent stem cells (iPSCs) undergo unlimited self-renewal while maintaining their potential to differentiate into post-mitotic cells with an intact proteome. As such, iPSCs suppress the aggregation of polyQ-expanded huntingtin (HTT), the mutant protein underlying Huntington's disease (HD). Here we show that proteasome activity determines HTT levels, preventing polyQ-expanded aggregation in iPSCs from HD patients (HD-iPSCs). iPSCs exhibit high levels of UBR5, a ubiquitin ligase required for proteasomal degradation of both normal and mutant HTT. Conversely, loss of UBR5 increases HTT levels and triggers polyQ-expanded aggregation in HD-iPSCs. Moreover, UBR5 knockdown hastens polyQ-expanded aggregation and neurotoxicity in invertebrate models. Notably, UBR5 overexpression induces polyubiquitination and degradation of mutant HTT, reducing polyQ-expanded aggregates in HD-cell models. Besides HTT levels, intrinsic enhanced UBR5 expression determines global proteostasis of iPSCs preventing the aggregation of misfolded proteins ensued from normal metabolism. Thus, our findings indicate UBR5 as a modulator of super-vigilant proteostasis of iPSCs.
Asunto(s)
Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Células Madre Pluripotentes/metabolismo , Ubiquitina-Proteína Ligasas/genética , Péptidos beta-Amiloides/metabolismo , Animales , Caenorhabditis elegans , Diferenciación Celular , Variación Genética , Genotipo , Células HEK293 , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Mutación , Neuronas/metabolismo , Péptidos/metabolismo , Polimorfismo de Nucleótido Simple , Complejo de la Endopetidasa Proteasomal/metabolismo , Desnaturalización Proteica , Pliegue de Proteína , Proteómica , ProteostasisRESUMEN
PURPOSE: We are conducting a prospective study trying to determine, in both sexes, the frequency of appearance of ectopic Leydig cells, their preferred location, their relationship with nerve structures and the possible causes of their appearance. METHODS: We have studied 86 cases that were removed according to different clinical indications for pathological study: uterine leyomiomas (n = 12), ovarian cystadenoma (n = 4), endometrial hyperplasia (n = 8), endometrial carcinoma (n = 12), cervical carcinoma (n = 4), seminoma (n = 4), fallopian tube ligatures (n = 24), vasectomies (n = 8), nonspecific orchiepididymitis (n = 2), and unknown (n = 8). RESULTS: We have observed ectopic Leydig cells in 13/86 cases (15.11%), 9/72 in the female samples (12.50%) and 4/14 in male samples (28.57%). The most frequent location was the mesosalpinx (4 of 13: 30.76%). CONCLUSIONS: These high figures lead us to believe that the ectopia of Leydig cells is not really a pathologic entity, but a finding related to specific functions yet to be determined.
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Células Intersticiales del Testículo/citología , Neoplasias Ováricas/patología , Testículo/citología , Trompas Uterinas , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
Human embryonic stem cells (hESCs) exhibit high levels of proteasome activity, an intrinsic characteristic required for their self-renewal, pluripotency and differentiation. However, the mechanisms by which enhanced proteasome activity maintains hESC identity are only partially understood. Besides its essential role for the ability of hESCs to suppress misfolded protein aggregation, we hypothesize that enhanced proteasome activity could also be important to degrade endogenous regulatory factors. Since E3 ubiquitin ligases are responsible for substrate selection, we first define which E3 enzymes are increased in hESCs compared with their differentiated counterparts. Among them, we find HECT-domain E3 ligases such as HERC2 and UBE3A as well as several RING-domain E3s, including UBR7 and RNF181. Systematic characterization of their interactome suggests a link with hESC identity. Moreover, loss of distinct up-regulated E3s triggers significant changes at the transcriptome and proteome level of hESCs. However, these alterations do not dysregulate pluripotency markers and differentiation ability. On the contrary, global proteasome inhibition impairs diverse processes required for hESC identity, including protein synthesis, rRNA maturation, telomere maintenance and glycolytic metabolism. Thus, our data indicate that high proteasome activity is coupled with other determinant biological processes of hESC identity.
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Células Madre Embrionarias Humanas/enzimología , Complejo de la Endopetidasa Proteasomal/análisis , Ubiquitina-Proteína Ligasas/análisis , Ubiquitina/análisis , Células Cultivadas , Perfilación de la Expresión Génica , Células Madre Embrionarias Humanas/química , Humanos , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas , ProteómicaAsunto(s)
Coristoma , Neoplasias Ováricas , Femenino , Humanos , Células Intersticiales del Testículo , MasculinoRESUMEN
Protein homeostasis, or proteostasis, is essential for cell function, development, and organismal viability. The composition of the proteome is adjusted to the specific requirements of a particular cell type and status. Moreover, multiple metabolic and environmental conditions challenge the integrity of the proteome. To maintain the quality of the proteome, the proteostasis network monitors proteins from their synthesis through their degradation. Whereas somatic stem cells lose their ability to maintain proteostasis with age, immortal pluripotent stem cells exhibit a stringent proteostasis network associated with their biological function and intrinsic characteristics. Moreover, growing evidence indicates that enhanced proteostasis mechanisms play a central role in immortality and cell fate decisions of pluripotent stem cells. Here, we will review new insights into the melding fields of proteostasis and pluripotency and their implications for the understanding of organismal development and survival.
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Estrés del Retículo Endoplásmico , Células Madre Pluripotentes/metabolismo , Proteoma/metabolismo , Proteostasis , Animales , Diferenciación Celular , Supervivencia Celular , Humanos , Modelos Biológicos , Células Madre Pluripotentes/citología , Respuesta de Proteína DesplegadaRESUMEN
Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by motor dysfunction, cognitive deficits and psychosis. HD is caused by mutations in the Huntingtin (HTT) gene, resulting in the expansion of polyglutamine (polyQ) repeats in the HTT protein. Mutant HTT is prone to aggregation, and the accumulation of polyQ-expanded fibrils as well as intermediate oligomers formed during the aggregation process contribute to neurodegeneration. Distinct protein homeostasis (proteostasis) nodes such as chaperone-mediated folding and proteolytic systems regulate the aggregation and degradation of HTT. Moreover, polyQ-expanded HTT fibrils and oligomers can lead to a global collapse in neuronal proteostasis, a process that contributes to neurodegeneration. The ability to maintain proteostasis of HTT declines during the aging process. Conversely, mechanisms that preserve proteostasis delay the onset of HD. Here we will review the link between proteostasis, aging and HD-related changes.
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Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Proteostasis , Envejecimiento/metabolismo , Chaperonas de Histonas , Humanos , Proteína Huntingtina/química , Enfermedad de Huntington/genética , Chaperonas Moleculares/metabolismo , Mutación , Pliegue de Proteína , ProteolisisRESUMEN
Embryonic stem cells (ESCs) exhibit a striking ability to replicate continuously in the absence of senescence. Despite the knowledge gained into ESC biology and cell reprogramming, the mechanisms that regulate their pluripotency, self-renewal, and differentiation remain largely unknown. Recently, cumulative evidence has highlighted the importance of protein homeostasis, or proteostasis, in the maintenance of ESC function. These findings indicate that ESCs exhibit intrinsic differences in the regulation and activity of key nodes of the proteostasis network such as global protein synthesis, folding, and degradation rates. Here, we review new insights into proteostasis of ESCs and the questions raised by these findings. In addition, we discuss the potential of these discoveries to be applied into aging and cancer research.
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Envejecimiento/genética , Células Madre Embrionarias/metabolismo , Homeostasis/genética , Neoplasias/metabolismo , Proteoma/metabolismo , Envejecimiento/metabolismo , Animales , Diferenciación Celular , Proliferación Celular , Reprogramación Celular , Células Madre Embrionarias/citología , Humanos , Terapia Molecular Dirigida , Neoplasias/genética , Neoplasias/patología , Neoplasias/terapia , Complejo de la Endopetidasa Proteasomal/metabolismo , Biosíntesis de Proteínas , Pliegue de Proteína , Estabilidad Proteica , Proteolisis , Proteoma/genéticaRESUMEN
Human embryonic stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity may demand avoidance of any imbalance in protein homeostasis (proteostasis) that would otherwise compromise stem cell identity. Here we show that human pluripotent stem cells exhibit enhanced assembly of the TRiC/CCT complex, a chaperonin that facilitates the folding of 10% of the proteome. We find that ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly. Moreover, increased TRiC/CCT complex is required to avoid aggregation of mutant Huntingtin protein. We further show that increased expression of CCT8 in somatic tissues extends Caenorhabditis elegans lifespan in a TRiC/CCT-dependent manner. Ectopic expression of CCT8 also ameliorates the age-associated demise of proteostasis and corrects proteostatic deficiencies in worm models of Huntington's disease. Our results suggest proteostasis is a common principle that links organismal longevity with hESC immortality.
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Caenorhabditis elegans/fisiología , Chaperonina con TCP-1/metabolismo , Longevidad , Células Madre Pluripotentes/metabolismo , Proteostasis , Animales , Diferenciación Celular , Técnicas de Silenciamiento del Gen , Células HEK293 , Células Madre Embrionarias Humanas/citología , Células Madre Embrionarias Humanas/metabolismo , Humanos , Mutación/genética , Fenotipo , Agregado de Proteínas , Subunidades de Proteína/metabolismo , Estrés FisiológicoRESUMEN
Accurate quantification depends on normalization of the measured gene expression data. In particular, gene expression studies with exposure to metals are challenging due their toxicity and redox-active properties. Here, we assessed the stability of potential reference genes in three cell lines commonly used to study metal cell metabolism: Caco-2 (colon), HepG2 (liver) and THP-1 (peripheral blood) under copper (Cu) or zinc (Zn) exposure. We used combined statistical tools to identify the best reference genes from a set of eleven candidates, which included traditional "housekeeping" genes such as GAPDH and B-ACTIN, in cell lines exposed to high and low, Zn and Cu concentrations. The expression stabilities of ATP5B (ATP synthase) and CYC1 (subunits of the cytochrome) were the highest considering the effect of Zn and Cu treatments whereas SDHA (succinate dehydrogenase) was found to be the most unstable gene. Even though the transcriptional effect of Zn and Cu is very different in term of redox properties, the same best reference genes were identified when Zn or Cu treatments were analyzed together. Our results indicate that ATP5B/CYC1 are the best candidates for reference genes after metal exposure, which can be used as a suitable starting point to evaluate gene expression with other metals or in different cell types in human models.
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Cobre/farmacología , Grupo Citocromo c/genética , ATPasas de Translocación de Protón Mitocondriales/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Zinc/farmacología , Línea Celular , Grupo Citocromo c/metabolismo , Grupo Citocromo c/normas , Perfilación de la Expresión Génica , Humanos , ATPasas de Translocación de Protón Mitocondriales/metabolismo , ATPasas de Translocación de Protón Mitocondriales/normas , Reacción en Cadena en Tiempo Real de la Polimerasa/normas , Estándares de ReferenciaRESUMEN
Copper is an essential cofactor of complex IV of the electron transfer chain, and it is directly involved in the generation of mitochondrial membrane potential. Its deficiency induces the formation of ROS, large mitochondria and anemia. Thus, there is a connection between copper metabolism and bioenergetics, mitochondrial dynamics and erythropoiesis. Copper depletion might end in cellular apoptosis or necrosis. However, before entering into those irreversible processes, mitochondria may execute a series of adaptive responses. Mitochondrial adaptive responses (MAR) may involve multiple and diverse mechanisms for preserving cell life, such as mitochondrial dynamics, OXPHOS remodeling and bioenergetics output. In this study, a mild copper deficiency was produced in an animal model through intraperitoneal injections of bathocuproine disulfonate in order to study the MAR. Under these conditions, a new type of mitochondrial morphology was discovered in the liver. Termed the "butternut squash" mitochondria, it coexisted with normal and swollen mitochondria. Western blot analyses of mitochondrial dynamics proteins showed an up-regulation of MFN-2 and OPA1 fusion proteins. Furthermore, isolated liver mitochondria displayed OXPHOS remodeling through a decrease in supercomplex activity with a concomitant increase at an individual level of complexes I and IV, higher respiratory rates at complex I and II levels, higher oligomycin-insensitive respiration, and lower respiratory control ratio values when compared to the control group. As expected, total ATP and ATP/ADP values were not significantly different, since animal's health was not compromised. As a whole, these results describe a compensatory and adaptive response of metabolism and bioenergetics under copper deprivation.
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Adaptación Fisiológica/fisiología , Cobre/deficiencia , Metabolismo Energético/fisiología , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Fosforilación Oxidativa , Adenosina Trifosfato/metabolismo , Animales , Quelantes/farmacología , Cobre/metabolismo , Masculino , Ratones , Fenantrolinas/farmacología , Especies Reactivas de OxígenoRESUMEN
El presente artículo surge de la revisión documental del concepto violencias escolares en bases de datos, artículos de revista, bibliotecas y demás medios de información, dentro de la investigación: "Violencias escolares presentes en las ins tituciones educativas católicas. Una aproximación a los discursos y prácticas en el Colegio Parroquial Emaús de la ciudad de Medellín", de la Maestría en Intervenciones Psicosociales de la Fundación Universitaria Luis Amigó. La búsqueda documental arrojó tres categorías: Bullying, violencias de los escolares y conflicto escolar, que alimentaron la construcción en torno a la violencia escolar, evidenciando la necesidad de pluralizar el concepto, más allá de tipificarlo en el bullying, para abarcar sus diversas manifestaciones.
This article comes from the review of documents in databases, journal articles, libraries and other ways, in research "School Violence present in Catholic educational institutions. An approach to the discourses and practices in Emaús Parish School of Medellin", within the Maestría en Intervenciones Psicosociales de la Fundación Universitaria Luis Amigó. During the search we found three theoretical framework: Bullying, School Violence, and Conflict School, which fueled construction around school violence evidencing the need to pluralize the concept beyond typify in Bullying, to cover its various manifestations.
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Humanos , Acoso Escolar , Estudiantes/psicología , Psicología del Adolescente , Agresión/éticaRESUMEN
Copper is an essential micronutrient that functions as an enzymatic cofactor in a wide range of cellular processes. Although adequate Cu levels are essential for normal metabolism, excess Cu can be toxic to cells. Cellular responses to copper deficiency and overload involve changes in the expression of genes directly and indirectly involved in copper metabolism. However little is known on the effect of physiological copper concentration on gene expression changes. In the current study we aimed to establish whether the expression of genes encoding enzymes related to cholesterol (hmgcs1, hmgcr, fdft) and fatty acid biosynthesis and LDL receptor can be induced by an iso-physiological copper concentration. The iso-physiological copper concentration was determined as the bioavailable plasmatic copper in a healthy adult population. In doing so, two blood cell lines (Jurkat and THP-1) were exposed for 6 or 24 h to iso- or supraphysiological copper concentrations. Our results indicated that in cells exposed to an iso-physiological copper concentration the early induction of genes involved in lipid metabolism was not mediated by copper itself but by the modification of the cellular redox status. Thus our results contributed to understand the involvement of copper in the regulation of cholesterol metabolism under physiological conditions.
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Colesterol/biosíntesis , Cobre/farmacología , Expresión Génica/efectos de los fármacos , Histidina/análogos & derivados , Compuestos Organometálicos/farmacología , ARN Mensajero/genética , Colesterol/genética , Farnesil Difosfato Farnesil Transferasa/genética , Farnesil Difosfato Farnesil Transferasa/metabolismo , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/metabolismo , Histidina/farmacología , Humanos , Hidroximetilglutaril-CoA Reductasas/genética , Hidroximetilglutaril-CoA Reductasas/metabolismo , Hidroximetilglutaril-CoA Sintasa/genética , Hidroximetilglutaril-CoA Sintasa/metabolismo , Células Jurkat , Metabolismo de los Lípidos/efectos de los fármacos , Oxidación-Reducción , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismoRESUMEN
OBJECTIVE: Report of one case of desmoid tumor in a patient who had been treated of a testicular seminoma 26 months before, with excision of a retroperitoneal mass and chemotherapy. On followup he presented with a mesenteric abdominal mass which was clinically labeleled as a recurrence of the seminoma. RESULTS: Histologically it was reported as a mesenteric desmoid tumor. Differential diagnosis with gastrointestinal stromal tumor was performed with immunohistochemical studies. CONCLUSIONS: Desmoid tumor is rare. There are few cases reported in patients with history of previous testicular tumor. It should be included in the differential diagnosis of testicular tumor recurrences.
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Fibromatosis Agresiva/diagnóstico , Mesenterio , Neoplasias Peritoneales/diagnóstico , Seminoma/diagnóstico , Neoplasias Testiculares/diagnóstico , Adulto , Diagnóstico Diferencial , Humanos , Masculino , Recurrencia Local de Neoplasia/diagnósticoRESUMEN
OBJECTIVES: To report one case of an exceptional benign prostatic pathology and its differential diagnosis with malignant tumors. METHODS: 67-year-old male who suffers an acute urinary retention requiring bladder catheterization and subsequent negative catheter removal tests. Digital rectal examination showed a small prostate, adenomatous, without nodules. PSA was 1.01 ng/ml. The patient underwent transurethral resection of the prostate because of the persistence of urinary retention. RESULTS: Pathologic study reported a hypercellular stroma, with a perivascularly distributed inflammatory infiltrate and myxoid stromal background with slightly atypical fusiform cells. Immunohistochemical studies showed positive staining of fusiform cells for vimentin and histiocytes in the lesion for CD68, and negative staining for cytokeratin. The final diagnosis was prostatic inflammatory pseudotumor. CONCLUSIONS: In spite of being an unfrequent presentation it is important to take this benign lesion under consideration to avoid unnecessary aggressive radical complementary treatments.