Journal of neurochemistry, 2012-01, Vol.120 (2), p.259-268
2012
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Dendrimer-mediated siRNA delivery knocks down Beclin 1 and potentiates NMDA-mediated toxicity in rat cortical neurons
- Ist Teil von
- Journal of neurochemistry, 2012-01, Vol.120 (2), p.259-268
- Ort / Verlag
- Oxford, UK: Blackwell Publishing Ltd
- Erscheinungsjahr
- 2012
- Quelle
- Wiley-Blackwell Journals
- Beschreibungen/Notizen
- J. Neurochem. (2012) 120, 259–268. Autophagy is an important process which plays a key role in cellular homeostasis by degrading cytoplasmic components in the lysosomes, which facilitates recycling. Alterations to normal autophagy have been linked to excitotoxicity, but the mechanisms governing its signal transduction remain unclear. The aim of this study was to explore the role of autophagy in neuronal excitotoxic death by delivering small interfering RNA (siRNA) to rat cortical neurons, using a dendrimer to silence the autophagy‐related gene 6 (beclin 1) and to determine the role of autophagy in excitotoxicity. We have found that the dendrimer is very efficient to deliver siRNA to rat cortical neurons, leading to almost complete removal of the target protein Beclin 1. In addition, NMDA increases autophagy markers, such as the protein levels of Beclin 1, the microtubule‐associated light chain 3 (LC3) B‐II/LC3B‐I ratio, and monodansylcadaverine (MDC) labeling in rat cortical neurons. Moreover, NMDA also increases the formation of autophagosomes observed under a transmission electron microscope. Silencing beclin 1 expression blocked NMDA‐induced autophagy. Moreover, Beclin 1 removal potentiated NMDA‐induced neuronal death indicating that autophagy plays a protective role during excitotoxicity and suggesting that targeting autophagy might be a helpful therapeutic strategy in neurodegenerative diseases. siRNA unveils the role of autophagy in excitotoxic deathThis study was performed to identify the role of autophagy in excitotoxic death by knocking down autophagic proteins using dendrimer‐delivered siRNA. The most relevant finding is that autophagy plays a neuroprotective role during excitotoxicity and that it is possible to knock down neuronal proteins using a dendrimer‐delivered siRNA. The conclusion is relevant because it indicates that the autophagic pathway might be a therapeutic target in neurodegenerative diseases and that it is possible to dissect neuronal signaling pathways using dendrimer‐delivered specific siRNA.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-3042eISSN: 1471-4159DOI: 10.1111/j.1471-4159.2011.07556.xTitel-ID: cdi_proquest_miscellaneous_920791553
- Format
- –
- Schlagworte
- Adenine - analogs & derivatives, Adenine - pharmacology, Animals, Apoptosis Regulatory Proteins - genetics, Apoptosis Regulatory Proteins - metabolism, Autophagy, Autophagy - drug effects, Beclin 1, Biological and medical sciences, Calcium - metabolism, Cells, Cultured, Central nervous system, Central neurotransmission. Neuromudulation. Pathways and receptors, Cerebral Cortex - cytology, Cytoplasm, Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases, dendrimer, Dendrites - drug effects, Dendrites - metabolism, Dendrites - ultrastructure, Dose-Response Relationship, Drug, Excitatory Amino Acid Agonists - toxicity, excitotoxicity, Fundamental and applied biological sciences. Psychology, Homeostasis, Intracellular Fluid - drug effects, Intracellular Fluid - metabolism, L-Lactate Dehydrogenase - metabolism, Medical sciences, Microscopy, Electron, Transmission, Microtubule-Associated Proteins - metabolism, N-Methylaspartate - toxicity, Neurochemistry, Neurology, Neurons - cytology, Neurons - drug effects, Rats, Ribonucleic acid, RNA, RNA, Small Interfering - metabolism, Signal transduction, siRNA, Transfection - methods, Vertebrates: nervous system and sense organs