RESUMEN
MicroRNAs have essential functional roles in brain development and neuronal specification but their roles in neurodegenerative diseases such as Alzheimer's disease (AD) is unknown. Using a sensitive qRT-PCR platform we identified regional and stage-specific deregulation of miRNA expression in AD patient brains. We used experimental validation in addition to literature to reveal how the deregulated brain microRNAs are biomarkers for known and novel pathways in AD pathogenesis related to amyloid processing, neurogenesis, insulin resistance, and innate immunity. We additionally recovered miRNAs from cerebrospinal fluid and discovered AD-specific miRNA changes consistent with their role as potential biomarkers of disease.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Encéfalo/patología , Marcadores Genéticos/genética , MicroARNs/líquido cefalorraquídeo , MicroARNs/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/fisiopatología , Amiloide/metabolismo , Biomarcadores/líquido cefalorraquídeo , Línea Celular Tumoral , Cerebelo/patología , Femenino , Lóbulo Frontal/patología , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/fisiología , Hipocampo/patología , Humanos , Inmunidad Innata/fisiología , Resistencia a la Insulina/fisiología , Masculino , Persona de Mediana Edad , Neuronas/fisiología , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónAsunto(s)
Proteínas de Ciclo Celular/metabolismo , Reacción en Cadena de la Polimerasa/métodos , Receptores Acoplados a Proteínas G/metabolismo , Animales , Células Sanguíneas/química , Proteínas de Ciclo Celular/genética , Humanos , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Ratas , Receptores Acoplados a Proteínas G/genéticaRESUMEN
Studies from eukaryotic model systems, ranging from yeast to human, indicate that Polo and Polo-like kinases (Plks) are essential for the activity of the microtubule organization center. Polo/Plks localize to centrosomes or spindle pole bodies and undergo dramatic subcellular relocation during the cell cycle. Deregulated activities of Plks often result in abnormalities in centrosome duplication, maturation, and/or microtubule dynamics. Genetic and biochemical approaches have identified several candidate genes that either lie in the same pathway as POLO/PLKs or whose products are direct targets of Polo/Plks during the centrosome cycle. Recent studies have demonstrated that mammalian Plks also regulate the function of the Golgi complex, a cellular organelle closely associated with the centrosome and also having microtubule organization activity. Furthermore, deregulated expression of human PLK1 and PLK3 is strongly correlated with the development of many types of malignancies, and ectopic expression of kinase-active Plk3 or Plk1 dominant negative protein leads to rapid cell death. Given that several effective anti-tumor drugs directly interfere with microtubule dynamics, mammalian Plks are excellent targets for the development of anticancer drugs.