RESUMEN
Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are neurodegenerative "tauopathies" characterized by hyperphosphorylated tau accumulation and neurofibrillary tangles. The P301S mutation of tau, a causal mutation of a familial type of FTLD, is believed to be involved in neurodegenerative progression. We developed a transgenic mouse, named TPR50, harboring human P301S tau. Tau phosphorylation in the hippocampus of TPR50 mice increased with age, particularly at S202/T205. Insolubilization and intracellular accumulation of tau were detected in the hippocampus by 9 months of age. Expression of calbindin was significantly reduced in 6- and 9-month-old TPR50 mice but not in 3-month-old mice. TPR50 mice demonstrated cognitive dysfunction at 5 months. At this age or earlier, although no intracellular tau accumulation was observed in the hippocampus, abnormally increased microtubule (MT)-related proteins and MT hyperdynamics in the hippocampus, and impaired axonal transport in the septo-hippocampal pathway were already observed. Therefore, cognitive dysfunction in TPR50 mice may result from early MT dysfunction and impaired axonal transport rather than accumulation of insoluble tau and neurodegeneration. TPR50 mice are a valuable new model to study progression of tauopathies at both the behavioral and neurocellular levels and may also prove useful for testing new therapies for neurodegenerative diseases.
Asunto(s)
Transporte Axonal/genética , Trastornos del Conocimiento/genética , Mutación/genética , Prolina/genética , Serina/genética , Proteínas tau/genética , Factores de Edad , Animales , Trastornos del Conocimiento/patología , Progresión de la Enfermedad , Conducta Exploratoria/fisiología , Regulación de la Expresión Génica/genética , Humanos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Actividad Motora/genética , Proteínas del Tejido Nervioso/metabolismo , Fosforilación , Reconocimiento en Psicología/fisiología , Proteínas tau/metabolismoRESUMEN
The mechanisms of docetaxel resistance in PC (prostate cancer) are unclear because of the lack of suitable experimental models, and no effective treatment exists for docetaxel-resistant PC. We established a docetaxel-resistant cell line, LNDCr, from an androgen-refractory PC cell line, LNCaP-hr, by intermittent exposure to docetaxel in vitro. The LNDCr cells harboured an F270I mutation in class I beta-tubulin, and demonstrated impaired tubulin polymerization by docetaxel. AR signalling was sustained in LNDCr cells, and AR knockdown suppressed the growth of LNDCr cells. These results suggest that an acquired mutation in beta-tubulin is associated with docetaxel resistance in PC and that a novel AR-targeted therapy is effective for docetaxel-resistant PC.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal , Taxoides/farmacología , Tubulina (Proteína)/genética , Línea Celular Tumoral , Docetaxel , Resistencia a Antineoplásicos , Humanos , Masculino , Mutación , Interferencia de ARN , ARN Interferente Pequeño , Receptores Androgénicos/genética , Tubulina (Proteína)/metabolismoRESUMEN
Human LCAT-like lysophospholipase (LLPL), or lysophospholipase 3, was first identified in vitro, in foam cells derived from THP-1 cells. We demonstrated that LLPL was present in foam cells in the severe atherosclerotic lesions that develop in apolipoprotein E-null (apoE(-/-)) mice. This indicated that LLPL might affect lipid metabolisms in foam cells and, therefore, atherogenesis. Accordingly, we created LLPL-knockout mice by gene targeting and crossed them with apoE(-/-) mice. We showed that the absence of LLPL increased lesion formation markedly in apoE(-/-) mice but had little effect on the plasma-lipid profile. In addition, LLPL-deficient peritoneal macrophages were more sensitive to apoptosis induced by exposure to oxidized low-density lipoprotein. LLPL might provide a link between apoptosis in macrophages and atherogenesis. Our data demonstrate that LLPL activity is anti-atherogenic and indicate that the regulation of this enzyme might be a novel drug target for the treatment of atherosclerosis.
Asunto(s)
Apolipoproteínas E/fisiología , Arteriosclerosis/genética , Lisofosfolipasa/fisiología , Acilación , Animales , Apolipoproteínas E/genética , Apoptosis , Lipoproteínas LDL/metabolismo , Lisofosfolipasa/genética , Macrófagos/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Metastin is encoded by a putative human metastasis suppressor gene KiSS-1, and is the cognate ligand of a G-protein-coupled receptor designated OT7T175. To study the physiological function(s) of metastin, we cloned rat and mouse KiSS-1 cDNAs both encoding 130-amino acid KiSS-1 proteins. Sequence analysis suggested that processing of the rat and mouse KiSS-1 proteins produces 52-amino-acid peptides, each with an amidated carboxyl terminal and with a single possible disulfide bond, corresponding to rat and mouse metastins. The carboxyl-terminal sequence of metastin, known to be essential for functional receptor interaction, was found to be highly conserved among humans and rodents. Real-time PCR analysis indicated that rat KiSS-1 mRNA showed the highest expression level in the cecum and colon. Since KiSS-1 mRNA and metastin are known to be abundant in human placenta, we further studied the localization of KiSS-1 and OT7T175 mRNAs in rat placenta by in situ hybridization. KiSS-1 and OT7T175 mRNAs were specifically detected in trophoblast giant cells at embryonic day 12.5, and the transcripts in the cells gradually decreased during placental maturation. These results suggest that metastin/OT7T175 signaling may participate in implantation of the mammalian embryo, placenta formation, and maintenance of pregnancy.
