المؤلفون: Yoel Sadovsky, Tianjiao Chu, Adrian E. Morelli, Carolyn B. Coyne, Elizabeth Delorme-Axford, Yingshi Ouyang, Avraham Bayer, Donna B. Stolz, Jean-Francois Mouillet, Rogier B. Donker, Saumendra N. Sarkar, Tianyi Wang

المصدر: Proceedings of the National Academy of Sciences. 110:12048-12053

مصطلحات موضوعية: Placenta, Green Fluorescent Proteins, Enzyme-Linked Immunosorbent Assay, Biology, Exosomes, Paracrine signalling, Pregnancy, Immunity, microRNA, Autophagy, medicine, Humans, Cells, Cultured, Disease Resistance, Analysis of Variance, Multidisciplinary, Effector, Biological Sciences, Virology, Microvesicles, Trophoblasts, Cell biology, MicroRNAs, medicine.anatomical_structure, Viral replication, Virus Diseases, embryonic structures, Female, Chromosomes, Human, Pair 19

الوصف: Placental trophoblasts form the interface between the fetal and maternal environments and serve to limit the maternal–fetal spread of viruses. Here we show that cultured primary human placental trophoblasts are highly resistant to infection by a number of viruses and, importantly, confer this resistance to nonplacental recipient cells by exosome-mediated delivery of specific microRNAs (miRNAs). We show that miRNA members of the chromosome 19 miRNA cluster, which are almost exclusively expressed in the human placenta, are packaged within trophoblast-derived exosomes and attenuate viral replication in recipient cells by the induction of autophagy. Together, our findings identify an unprecedented paracrine and/or systemic function of placental trophoblasts that uses exosome-mediated transfer of a unique set of placental-specific effector miRNAs to directly communicate with placental or maternal target cells and regulate their immunity to viral infections.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0ac339ea8137358db5448e99e5f6bd6dTest
https://doi.org/10.1073/pnas.1304718110Test

المؤلفون: Hannes Vogel, Angus McQuibban, Lichuan Yang, Bingwei Lu, M. Flint Beal, Yingshi Ouyang, Yufeng Yang

المصدر: Proceedings of the National Academy of Sciences. 105:7070-7075

مصطلحات موضوعية: FIS1, Fission, Dopamine, Cell, Genes, Insect, PINK1, Biology, Mitochondrion, GTP-Binding Proteins, Chlorocebus aethiops, medicine, Animals, Drosophila Proteins, Neurons, Multidisciplinary, Biological Sciences, Mitochondria, Cell biology, Cytoskeletal Proteins, Drosophila melanogaster, Phenotype, medicine.anatomical_structure, mitochondrial fusion, COS Cells, DNAJA3, Mitochondrial fission, Protein Kinases, Protein Binding

الوصف: Mitochondria form dynamic tubular networks that undergo frequent morphological changes through fission and fusion, the imbalance of which can affect cell survival in general and impact synaptic transmission and plasticity in neurons in particular. Some core components of the mitochondrial fission/fusion machinery, including the dynamin-like GTPases Drp1, Mitofusin, Opa1, and the Drp1-interacting protein Fis1, have been identified. How the fission and fusion processes are regulated under normal conditions and the extent to which defects in mitochondrial fission/fusion are involved in various disease conditions are poorly understood. Mitochondrial malfunction tends to cause diseases with brain and skeletal muscle manifestations and has been implicated in neurodegenerative diseases such as Parkinson's disease (PD). Whether abnormal mitochondrial fission or fusion plays a role in PD pathogenesis has not been shown. Here, we show that Pink1, a mitochondria-targeted Ser/Thr kinase linked to familial PD, genetically interacts with the mitochondrial fission/fusion machinery and modulates mitochondrial dynamics. Genetic manipulations that promote mitochondrial fission suppress Drosophila Pink1 mutant phenotypes in indirect flight muscle and dopamine neurons, whereas decreased fission has opposite effects. In Drosophila and mammalian cells, overexpression of Pink1 promotes mitochondrial fission, whereas inhibition of Pink1 leads to excessive fusion. Our genetic interaction results suggest that Fis1 may act in-between Pink1 and Drp1 in controlling mitochondrial fission. These results reveal a cell biological role for Pink1 and establish mitochondrial fission/fusion as a paradigm for PD research. Compounds that modulate mitochondrial fission/fusion could have therapeutic value in PD intervention.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4ff1092769d2fb31a35ef0e9d97a82a4Test
https://doi.org/10.1073/pnas.0711845105Test

المؤلفون: M. Flint Beal, Yingshi Ouyang, Hannes Vogel, Yufeng Yang, Lichuan Yang, Stephan Gehrke, Ji-Wu Wang, Zhinong Huang, Bingwei Lu, Yuzuru Imai

المصدر: Proceedings of the National Academy of Sciences. 103:10793-10798

مصطلحات موضوعية: Ubiquitin-Protein Ligases, Mutant, PINK1, Biology, Parkin, Animals, Genetically Modified, RNA interference, medicine, Animals, Drosophila Proteins, Humans, Gene Silencing, Neurons, Genetics, Multidisciplinary, Kinase, Muscles, Neurodegeneration, Dopaminergic, Wild type, Parkinson Disease, Biological Sciences, medicine.disease, nervous system diseases, Mitochondria, Cell biology, Drosophila melanogaster, Nerve Degeneration, RNA Interference, Protein Kinases, Signal Transduction

الوصف: Mutations in Pink1 , a gene encoding a Ser/Thr kinase with a mitochondrial-targeting signal, are associated with Parkinson’s disease (PD), the most common movement disorder characterized by selective loss of dopaminergic neurons. The mechanism by which loss of Pink1 leads to neurodegeneration is not understood. Here we show that inhibition of Drosophila Pink1 (dPink1) function results in energy depletion, shortened lifespan, and degeneration of select indirect flight muscles and dopaminergic neurons. The muscle pathology was preceded by mitochondrial enlargement and disintegration. These phenotypes could be rescued by the wild type but not the pathogenic C-terminal deleted form of human Pink1 (hPink1). The muscle and dopaminergic phenotypes associated with dPink1 inactivation show similarity to that seen in parkin mutant flies and could be suppressed by the overexpression of Parkin but not DJ-1. Consistent with the genetic rescue results, we find that, in dPink1 RNA interference (RNAi) animals, the level of Parkin protein is significantly reduced. Together, these results implicate Pink1 and Parkin in a common pathway that regulates mitochondrial physiology and cell survival in Drosophila .

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::efe12e03ba5ad0536551d1c5ff2c2afcTest
https://doi.org/10.1073/pnas.0602493103Test