title: Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration.
abstract: Type III RNase Dicer is responsible for the maturation and function of microRNA (miRNA) molecules in the cell. It is now well-documented that Dicer and the fine-tuning of the miRNA gene network are important for neuronal integrity. However, the underlying mechanisms involved in neuronal death, particularly in the adult brain, remain poorly defined. Here we show that the absence of Dicer in the adult forebrain is accompanied by a mixed neurodegenerative phenotype. Although neuronal loss is observed in the hippocampus, cellular shrinkage is predominant in the cortex. Interestingly, neuronal degeneration coincides with the hyperphosphorylation of endogenous tau at several epitopes previously associated with neurofibrillary pathology. Transcriptome analysis of enzymes involved in tau phosphorylation identified ERK1 as one of the candidate kinases responsible for this event in vivo. We further demonstrate that miRNAs belonging to the miR-15 family are potent regulators of ERK1 expression in mouse neuronal cells and co-expressed with ERK1/2 in vivo. Finally, we show that miR-15a is specifically downregulated in Alzheimer's disease brain. In summary, these results support the hypothesis that changes in the miRNA network may contribute to a neurodegenerative phenotype by affecting tau phosphorylation.
authors.affiliation: Centre de Recherche du CHUQ CHUL, Axe Neurosciences, Québec, Canada. sebastien.hebert@crchul.ulaval.ca
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Hébert
authors.forename: Aikaterini S
authors.initials: AS
authors.lastname: Papadopoulou
authors.forename: Pascal
authors.initials: P
authors.lastname: Smith
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Galas
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
authors.forename: Asli N
authors.initials: AN
authors.lastname: Silahtaroglu
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000939:Epitopes; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008474:Medial Forebrain Bundle; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000503:physiopathology; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012323:RNA Processing, Post-Transcriptional; D043244:Ribonuclease III / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000939:Epitopes; D035683:MicroRNAs; C544301:Mirn15a microRNA, mouse; D016875:tau Proteins; D048052:Mitogen-Activated Protein Kinase 3; D043244:Ribonuclease III