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.

MicroRNA-9

“…MiR-9 contributes to drug adaptation and adult brain plasticity by downregulating specific mRNA splice variants of this channel. 39 The potential involvement of miRNAs in age-dependent neurodegeneration is suggested by findings in conditional dicer knockout mice in which specific types of neurons are lost; [40][41][42] however, the exact mechanisms are unclear. In principle, loss of miRNAs can cause accumulation of toxic proteins and subsequent neuronal loss and might affect neuronal survival by changing the levels of trophic or prosurvival factors.…”

Noncoding RNAs in Neural Stem Cell Development

“…miRNAs play essential roles in NSC differentiation and the cell fate switch between neurons and glia Hebert et al, 2010;Zheng et al, 2010). We have found that Dicer-deficient NSCs display abnormal differentiation, with shorter neurites in neurons and fewer processes in glial cells (Kawase-Koga et al, 2010) (Fig.…”

“…2B). Conditional deletion of Dicer from the mouse forebrain neurons using CamKII-Cre line results in neuronal degeneration and an increase in glial fibrillary acidic protein (GFAP)-positive astrocytes (Hebert et al, 2010). Dicer ablation in the dopaminoceptive neurons in the basal ganglia using a dopamine receptor-1 ( DR-1)-Cre line leads to astrogliogenesis, but not neurodegeneration .…”

Constructing and characterizing a bioactive small molecule and microRNA association network for Alzheimer's disease

“…Many researchers have observed that amantadine is associated with the treatment of behavioural disturbances, synaptic and cholinergic receptors, neurotransmitter deficits and improving neurorecovery [54,55]. MiR-15a was identified as an SA-miRNA (senescence-associated miRNA) and was downregulated in AD patients' brains [56]. This miRNA is a member of the miR15/107 group, which has been implicated in neuronal degenerative diseases, including AD [57].…”