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1.
Cell ; 186(4): 786-802.e28, 2023 02 16.
Article in English | MEDLINE | ID: mdl-36754049

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results from many diverse genetic causes. Although therapeutics specifically targeting known causal mutations may rescue individual types of ALS, these approaches cannot treat most cases since they have unknown genetic etiology. Thus, there is a pressing need for therapeutic strategies that rescue multiple forms of ALS. Here, we show that pharmacological inhibition of PIKFYVE kinase activates an unconventional protein clearance mechanism involving exocytosis of aggregation-prone proteins. Reducing PIKFYVE activity ameliorates ALS pathology and extends survival of animal models and patient-derived motor neurons representing diverse forms of ALS including C9ORF72, TARDBP, FUS, and sporadic. These findings highlight a potential approach for mitigating ALS pathogenesis that does not require stimulating macroautophagy or the ubiquitin-proteosome system.


Subject(s)
Amyotrophic Lateral Sclerosis , Phosphatidylinositol 3-Kinases , Animals , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Motor Neurons , Mutation , RNA-Binding Protein FUS/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Disease Models, Animal
2.
Cell ; 184(3): 689-708.e20, 2021 02 04.
Article in English | MEDLINE | ID: mdl-33482083

ABSTRACT

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction also rescued axonal degeneration caused by poly(glycine-arginine), increased survival of C9orf72 ALS/FTD-patient-induced pluripotent stem cell (iPSC)-derived motor neurons, and mitigated neurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription-factor-binding events and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.


Subject(s)
C9orf72 Protein/metabolism , DNA Repeat Expansion/genetics , Nerve Degeneration/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Apoptosis Regulatory Proteins/metabolism , Axons/metabolism , C9orf72 Protein/genetics , Cell Death , Cells, Cultured , Cerebral Cortex/pathology , Chromatin/metabolism , DNA Damage , Disease Models, Animal , Drosophila , Mice, Inbred C57BL , Nerve Degeneration/pathology , Protein Stability , Transcription, Genetic , Tumor Suppressor Proteins/metabolism
3.
Neuron ; 111(9): 1381-1390.e6, 2023 05 03.
Article in English | MEDLINE | ID: mdl-36931278

ABSTRACT

GGGGCC repeat expansion in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat RNAs can be translated into dipeptide repeat proteins, including poly(GR), whose mechanisms of action remain largely unknown. In an RNA-seq analysis of poly(GR) toxicity in Drosophila, we found that several antimicrobial peptide genes, such as metchnikowin (Mtk), and heat shock protein (Hsp) genes are activated. Mtk knockdown in the fly eye or in all neurons suppresses poly(GR) neurotoxicity. These findings suggest a cell-autonomous role of Mtk in neurodegeneration. Hsp90 knockdown partially rescues both poly(GR) toxicity in flies and neurodegeneration in C9ORF72 motor neurons derived from induced pluripotent stem cells (iPSCs). Topoisomerase II (TopoII) regulates poly(GR)-induced upregulation of Hsp90 and Mtk. TopoII knockdown also suppresses poly(GR) toxicity in Drosophila and improves survival of C9ORF72 iPSC-derived motor neurons. These results suggest potential novel therapeutic targets for C9ORF72-ALS/FTD.


Subject(s)
Amyotrophic Lateral Sclerosis , Frontotemporal Dementia , Animals , Amyotrophic Lateral Sclerosis/genetics , C9orf72 Protein/genetics , C9orf72 Protein/metabolism , Dipeptides/genetics , DNA Repeat Expansion , Down-Regulation , Drosophila/metabolism , Frontotemporal Dementia/genetics , Frontotemporal Dementia/metabolism , Motor Neurons/metabolism
4.
Cell Stem Cell ; 30(2): 171-187.e14, 2023 02 02.
Article in English | MEDLINE | ID: mdl-36736291

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by many diverse genetic etiologies. Although therapeutics that specifically target causal mutations may rescue individual types of ALS, such approaches cannot treat most patients since they have unknown genetic etiology. Thus, there is a critical need for therapeutic strategies that rescue multiple forms of ALS. Here, we combine phenotypic chemical screening on a diverse cohort of ALS patient-derived neurons with bioinformatic analysis of large chemical and genetic perturbational datasets to identify broadly effective genetic targets for ALS. We show that suppressing the gene-encoding, spliceosome-associated factor SYF2 alleviates TDP-43 aggregation and mislocalization, improves TDP-43 activity, and rescues C9ORF72 and causes sporadic ALS neuron survival. Moreover, Syf2 suppression ameliorates neurodegeneration, neuromuscular junction loss, and motor dysfunction in TDP-43 mice. Thus, suppression of spliceosome-associated factors such as SYF2 may be a broadly effective therapeutic approach for ALS.


Subject(s)
Amyotrophic Lateral Sclerosis , Neurodegenerative Diseases , Mice , Animals , Amyotrophic Lateral Sclerosis/genetics , Motor Neurons , Mutation , DNA-Binding Proteins/genetics
5.
Rev. venez. cir ; 46(2): 63-8, 1993. ilus, tab
Article in Spanish | LILACS | ID: lil-133132

ABSTRACT

Las lesiones de la vena cava inferior son lesiones exsanguinantes de muy difícil control quirúrgico. Presentamos 44 casos atendidos entre enero de 1988 y diciembre de 1992, los cuales presentaron una mortalidad global de 45,45 por ciento , y una morbilidad del 59,09 por ciento . La principal causa de muerte y de complicaciones post-operatorias se derivan del sangramiento producido por la lesión. Se enfatiza que la estabilización hemodinámica del paciente constituye el paso fundamental del tratamiento de estas lesiones. Las dificultades técnicas para la reparación de las lesiones según el nivel en que se encuentren, son analizadas


Subject(s)
Humans , Vena Cava, Inferior/surgery , Vena Cava, Inferior/injuries , Wounds, Gunshot/therapy
6.
Rev. venez. cir ; 47(1): 27-32, mar. 1994. ilus
Article in Spanish | LILACS | ID: lil-141376

ABSTRACT

En el presente trabajo presentamos 21 pacientes consecutivos, los cuales fueron sometidos a una toracotomía resucitadora a su ingreso a la Unidad de Politraumatizados de nuestro Hospital entre enero de 1989 y diciembre de 1992. La sobrevida global fue de 9,52 por ciento (2/21). en los pacientes con traumatismos abiertos la sobrevida se elevó al 13,33 por ciento (2/15), y en los pacientes con lesiones cardíacas la sobrevida fue del 16,67 por ciento (1/6). No hubo sobrevivientes en los pacientes con traumatismo cerrado (0/6). Nosotros creemos que la toracotomía resucitadora es una opción terapéutica viable en los pacientes en condiciones generales críticas, que presentan traumatismos abiertos, ya sean torácicos, abdominales o en lesiones vasculares de los miembros


Subject(s)
Adolescent , Adult , Humans , Male , Female , Thoracotomy/methods , Thoracotomy , Emergencies , Thoracic Injuries/surgery
7.
Centro méd ; 39(1): 36-8, ene. 1993.
Article in Spanish | LILACS | ID: lil-148169

ABSTRACT

La enfermedad de Bowen del ano es una entidad poco frecuente, la cual, es considerada como una lesión premaligna por su capacidad de transformarse en una lesión invasora. Solo habían sido descrito en la literatura 112 casos hasta 1979. En la última década, ha sido reportado un incremento en la incidencia de ésta patología, lo cual se debe, probablemente, al aumento de las infecciones venéreas de origen viral. Reporta un caso el cual, fue sometido a tratamiento quirúrgico exitoso y se revisa la literatura


Subject(s)
Middle Aged , Humans , Female , Anal Canal/pathology , Anus Neoplasms , Bowen's Disease
8.
La Paz; OPS/OMS; 1996. 60 p. (Introducción a la Metodología de la Investigación, 2).
Monography in Spanish | LILACS, LIBOCS, LIBOSP | ID: lil-183061

ABSTRACT

El documento enseña por donde iniciar la búsqueda bibliográfica. La investigación bibliográfica es la que se realiza en documentos escritos para recoger información sobre los antecedentes de un tema


Subject(s)
Rescue Work , Research , Methods , Data Collection/methods , Reading
9.
Santo Domingo; OPS; 3 ed; 1998. x,284 p.
Monography in Spanish | LILACS | ID: lil-236811

Subject(s)
Health , Periodical , Union List
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