Dicer and microRNAs protect adult dopamine neurons

Piotr Chmielarz,Holger Erfle,Andrii Domanskyi,Kai C Sonntag,Timo Petteri Piepponen,Günther Schütz,Ilya A Vinnikov,Julia Konovalova,Heike Alter,Syeda Sadia Najam

doi:10.1038/cddis.2017.214

Abstract

MicroRNAs (miRs) are important post-transcriptional regulators of gene expression implicated in neuronal development, differentiation, aging and neurodegenerative diseases, including Parkinson’s disease (PD). Several miRs have been linked to PD-associated genes, apoptosis and stress response pathways, suggesting that deregulation of miRs may contribute to the development of the neurodegenerative phenotype. Here, we investigate the cell-autonomous role of miR processing RNAse Dicer in the functional maintenance of adult dopamine (DA) neurons. We demonstrate a reduction of Dicer in the ventral midbrain and altered miR expression profiles in laser-microdissected DA neurons of aged mice. Using a mouse line expressing tamoxifen-inducible CreERT2 recombinase under control of the DA transporter promoter, we show that a tissue-specific conditional ablation of Dicer in DA neurons of adult mice led to decreased levels of striatal DA and its metabolites without a reduction in neuronal body numbers in hemizygous mice (DicerHET) and to progressive loss of DA neurons with severe locomotor deficits in nullizygous mice (DicerCKO). Moreover, we show that pharmacological stimulation of miR biosynthesis promoted survival of cultured DA neurons and reduced their vulnerability to thapsigargin-induced endoplasmic reticulum stress. Our data demonstrate that Dicer is crucial for maintenance of adult DA neurons, whereas a stimulation of miR production can promote neuronal survival, which may have direct implications for PD treatment.

Highlights

Dopamine (DA) neurons in the ventral midbrain project to striatal, limbic and cortical areas forming neuronal networks that regulate complex behaviors, emotions and controlled voluntary motion.[1]
We assessed the expression of Dicer[1] and several other genes involved in the development and physiology of DA neurons by analyzing ventral midbrain samples from young (6.5 weeks) and old (87 weeks) wild-type C57Bl/6 N mice
In our previous studies on post-mortem laser-microdissected DA neurons, we observed a reduction of DICER1 gene expression in Parkinson’s disease (PD) patients (–1.9 fold, Po0.05) compared with age-matched healthy individuals, which was even more pronounced in the male population (–2.7 fold, Po0.05).[32]

Summary

Introduction

Dopamine (DA) neurons in the ventral midbrain project to striatal, limbic and cortical areas forming neuronal networks that regulate complex behaviors, emotions and controlled voluntary motion.[1]. MicroRNAs (miRs) are approximately 22 nucleotides long non-coding RNA molecules that bind to complementary sites in target mRNAs and promote their degradation or suppress translation.[7] MiRs can mediate a formation of large-scale regulatory networks and enable crosstalk between different cellular pathways.[8] They have crucial roles in neuronal cell development and differentiation,[9] and in the maintenance or age-related degeneration of neuronal cell systems, including. MiRs are processed from precursor molecules by two protein complexes containing double-stranded RNA-specific nucleases, Drosha and Dicer. (TRBP) to produce mature miRs, which direct RNA-induced silencing complex to target mRNAs.[7,18,19] During aging, Dicer is downregulated in the heart, adipose tissue and the brain.[20,21]. The age-related decline in its expression, possibly caused by long-term cellular stress,[22,23] results in diminished miR processing and downregulation of mature miR levels.[20,24]

Methods

Results

Conclusion