RESUMEN
BACKGROUND: Parkinson's disease (PD) is affecting 5 million people worldwide, but the response mechanisms of the striatum are still unclear. Therefore, identification of gene expression alterations in the striatum will greatly assist the development of novel therapy strategies. METHODS: We performed a comprehensive gene expression analysis in 15 PD patients and 15 normal controls to identify differentially expressed genes (DEGs) using the expression profile GSE20291 from Gene Expression Omnibus (GEO). Gene Ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis were used to define functions and pathways altered in PD. Protein-protein interaction network was constructed to find out the modules with close interactions. RESULTS: Total715 DEGs including 268 up-regulated and 447 down-regulated genes were obtained. GO functional enrichment analysis indicated that the genes related with neurons function and cell morphogenesis might be changed upon PD. KEGG pathway enrichment analysis showed that most of the genes were enriched in the nodes of Gap junction, calcium signaling pathway, phosphatidylinositol signaling system, long-term potentiation, Alzheimer's disease and GnRH signaling pathway. Protein-protein interaction network and module analysis suggested that some apoptosis related genes, such as PRKCA, CDC42 and BCL2 may play critical roles in striatal neurons growth. CONCLUSION: Intrinsic striatal tyrosine hydroxylase interneurons growth may be promoted by changes in several genes expression and thus reduce the functional excitatory synapses.
Asunto(s)
Regulación de la Expresión Génica/fisiología , Enfermedad de Parkinson/patología , Putamen/metabolismo , Femenino , Uniones Comunicantes/metabolismo , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Genoma , Humanos , Masculino , Neuronas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Mapas de Interacción de Proteínas/genética , Proteína Quinasa C-alfa/genética , Proteína Quinasa C-alfa/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Putamen/patología , Transducción de Señal/genética , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Chronic hypoxia has been reported to contribute to the development of Alzheimer's disease (AD). However, the mechanism of hypoxia in the pathogenesis of AD remains unclear. The purpose of this study was to investigate the effects of chronic hypoxia treatment on ß-amyloid, tau pathologies, and the behavioral consequences in the double transgenic (APP/PS1) mice. Double transgenic mice (APP/PS1 mice) were treated with hypoxia, and spatial learning and memory abilities of mice were assessed in the Morris water maze. ß-amyloid level and plaque level in APP/PS1 double transgenic mice were detected by immunohistochemistry. Protein tau, p35/p25, cyclin-dependent kinase 5 (CDK5), and calpain were detected by western blotting analysis. Chronic hypoxia treatment decreased memory and cognitive function in AD mice. In addition, chronic hypoxia treatment resulted in increased senile plaques, accompanying with increased tau phosphorylation. The hypoxia-induced increase in the tau phosphorylation was associated with a significant increase in the production of p35 and p25 and upregulation of calpain, suggesting that hypoxia induced aberrant CDK5/p25 activation via upregulation of calpain. Our results showed that chronic hypoxia exposure accelerates not only amyloid pathology but also tau pathology via calpain-mediated tau hyperphosphorylation in an AD mouse model. These pathological changes possibly contribute to the hypoxia-induced behavioral change in AD mice.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Calpaína/metabolismo , Hipoxia/metabolismo , Aprendizaje por Laberinto , Proteínas tau/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Calpaína/genética , Quinasa 5 Dependiente de la Ciclina/genética , Quinasa 5 Dependiente de la Ciclina/metabolismo , Hipoxia/fisiopatología , Memoria , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Fosforilación , Fosfotransferasas/genética , Fosfotransferasas/metabolismo , Regulación hacia ArribaRESUMEN
Fibulin-3 has been considered as a regulator of glioma cell invasion, but little is known about the molecules regulating fibulin-3 expression. Metformin, an oral antidiabetic drug in the biguanide class, is known to inhibit proliferation and metastasis in a variety of cancer cells. In the present study, we determined the effect of metformin on the expression of fibulin-3 in U251 Human glioma cells. Metformin potently suppressed U251 cell adhesion and invasion. Metformin inhibited the expression of fibulin-3 at the transcriptional level. Moreover, metformin abolished the protein expression of fibulin-3 in a concentration-dependent manner. Furthermore, this compound suppressed the expression of matrix metalloproteinase-2, a key effector of glioma cell invasion, regulated by fibulin-3. Taken together, our results suggest that metformin abolishes fibulin-3 expression and subsequently inhibits invasion of glioma cells.