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Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Sébastien S Hébert
  • Aikaterini S Papadopoulou
  • Pascal Smith
  • Marie-Christine Galas
  • Emmanuel Planel
  • Silahtaroglu, Asli
  • Nicolas Sergeant
  • Luc Buée
  • Bart De Strooper
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.
OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind19
Udgave nummer20
Sider (fra-til)3959-69
Antal sider11
ISSN0964-6906
DOI
StatusUdgivet - 15 okt. 2010

ID: 33504984