Upregulation of a small vault RNA (svtRNA2-1a) is an early event in Parkinson disease and induces neuronal dysfunction

Miñones-Moyano, Elena; Friedländer, Marc R.; Pallares, Joan; Kagerbauer, Birgit; Porta, Sílvia; Escaramís, Geòrgia; Ferrer, Isidre; Estivill, Xavier; Martı́, Eulàlia

doi:10.4161/rna.24813

Cited by 56 publications

(64 citation statements)

References 72 publications

(86 reference statements)

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“…The findings that YsRNAs were upregulated in breast cancer patients, which would make them potential prognostic biomarkers (45), and that upregulation of a specific svRNAs is widespread in Parkinson's disease, thus suggesting potentially novel therapeutic approaches (46), significantly enhanced the interest in these small RNAs. In terms of DIS3L2, catalytic mutants could lead to svRNA and YsRNA overproduction that in turn abolishes cell homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Perlman syndrome nuclease DIS3L2 controls cytoplasmic non-coding RNAs and provides surveillance pathway for maturing snRNAs

et al. 2016

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The exosome-independent exoribonuclease DIS3L2 is mutated in Perlman syndrome. Here, we used extensive global transcriptomic and targeted biochemical analyses to identify novel DIS3L2 substrates in human cells. We show that DIS3L2 regulates pol II transcripts, comprising selected canonical and histone-coding mRNAs, and a novel FTL_short RNA from the ferritin mRNA 5′ UTR. Importantly, DIS3L2 contributes to surveillance of maturing snRNAs during their cytoplasmic processing. Among pol III transcripts, DIS3L2 particularly targets vault and Y RNAs and an Alu-like element BC200 RNA, but not Alu repeats, which are removed by exosome-associated DIS3. Using 3′ RACE-Seq, we demonstrate that all novel DIS3L2 substrates are uridylated in vivo by TUT4/TUT7 poly(U) polymerases. Uridylation-dependent DIS3L2-mediated decay can be recapitulated in vitro, thus reinforcing the tight cooperation between DIS3L2 and TUTases. Together these results indicate that catalytically inactive DIS3L2, characteristic of Perlman syndrome, can lead to deregulation of its target RNAs to disturb transcriptome homeostasis.

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Section: Discussionmentioning

confidence: 99%

Perlman syndrome nuclease DIS3L2 controls cytoplasmic non-coding RNAs and provides surveillance pathway for maturing snRNAs

et al. 2016

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“…Other brain regions investigated included the frontal cortex (Moran et al., ; Riley et al., ), Brodmann area 8 (BA8; Garcia‐Esparcia et al., ), BA9 (Zhang et al., ; Dumitriu et al., , ; Hoss et al., ), BA23 (Henderson‐Smith et al., ), putamen (Zhang et al., ; Vogt et al., ; Bossers et al., ; Naydenov et al., ; Botta‐Orfila et al., ; Nair & Ge, ), caudate nucleus (CN; Bossers et al., ), striatum (Miller et al., ; Riley et al., ), dorsal motor vagus nucleus (Lewandowski et al., ; Corradini et al., ), locus coeruleus (Botta‐Orfila et al., ; Corradini et al., ), occipital cortex (OC; Devine et al., ), posterior cingulate cortex (PCC; Stamper et al., ) and amygdala (Fig. ; Miñones‐Moyano et al., , ).…”

Section: Description Of Samples Used Across the 63 Original Studiesmentioning

confidence: 99%

“…Notably, the RNA‐Seq technique was used in only three studies (Riley et al., ; Dumitriu et al., ; Henderson‐Smith et al., ). Seven were performed using miRNA arrays or small RNA sequencing approaches (Miñones‐Moyano et al., , ; Cardo et al., ; Kim et al., ; Briggs et al., ; Hoss et al., ; Nair & Ge, ).…”

Section: Transcriptomic Platforms Usedmentioning

confidence: 99%

A review of genome‐wide transcriptomics studies in Parkinson's disease

Borrageiro

Haylett

Seedat

et al. 2017

Eur J of Neuroscience

102

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Parkinson's disease (PD) is a progressive and incurable neurodegenerative disorder. Although numerous genetic and environmental factors have been linked to the aetiology of PD the underlying pathobiology remains poorly understood, hampering the development of improved therapies. Transcriptomics has the potential to reveal significant insights into disease processes. In this review, we focused on published transcriptomics studies on PD with the aim of summarizing studies and identifying common biological pathways. A total of 96 articles were identified as follows: 12 meta-analyses, 21 re-analyses of existing data and 63 original studies. Of the 63 original studies, 33 were performed on brain tissue, 26 on blood, three on cerebrospinal fluid and one on skin. In the brain studies, altered pathways identified included those involved in dopamine metabolism, mitochondrial function, oxidative stress, protein degradation, neuroinflammation, vesicular transport and synaptic transmission. Studies on blood samples revealed alterations in pathways involved in immune function, inflammation, RNA processing, protein chaperones, mitochondrial function and programmed cell death. Limitations of these studies include small sample sizes (generally <40 cases/40 controls) and the application of widely varying statistical analysis and parameters. Only eight studies used the RNA-Seq technique. This review highlights the need for harmonization of transcriptomic approaches and the statistical analyses, and for the data to be deposited into publicly available databases in a standardized format for meta-analyses. Notably, the concordance of several pathways such as mitochondrial function, protein degradation and inflammation, identified in both blood and brain tissues, suggests that the disease process is systemic and not restricted to neurological tissues.

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“…Two prevailing functional themes currently under investigation link the vRNA to: (1) drug resistance 119,120 , and (2) neuronal differentiation. 121,122 Poor sequence conservation of vRNA complicates efforts to trace its phylogenetic depth: while it is found in the mycetozoan slime mold Dictyostelium as well as in vertebrates, it appears to have been lost in many animal lineages and appears to be absent in other crown eukaryotic lineages including plants and fungi. 123 svRNA functionality through association with the RNAi pathway may therefore represent the recent colonization of a functional niche in vertebrates, consistent with the differential gene expression patterns observed for svRNAs 32 and the terminal cell types within which vRNA and derived svRNAs are thought to function.…”

Section: Other Fragments From Larger Ncrna Precursorsmentioning

confidence: 99%

New perspectives on the diversification of the RNA interference system: insights from comparative genomics and small RNA sequencing

2013

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Our understanding of the pervasive involvement of small RNAs in regulating diverse biological processes has been greatly augmented by recent application of deep-sequencing technologies to small RNA across diverse eukaryotes. We review the currently-known small RNA classes and place them in context of the reconstructed evolutionary history of the RNAi protein machinery. This synthesis indicates the earliest versions of eukaryotic RNAi systems likely utilized small RNA processed from three types of precursors: 1) sense-antisense transcriptional products, 2) genome-encoded, imperfectly-complementary hairpin sequences, and 3) larger non-coding RNA precursor sequences. Structural dissection of PIWI proteins along with recent discovery of novel families (including Med13 of the Mediator complex) suggest that emergence of a distinct architecture with the N-terminal domains (also occurring separately fused to endoDNases in prokaryotes) formed via duplication of an ancestral unit was key to their recruitment as primary RNAi effectors and use of small RNAs of certain preferred lengths. Prokaryotic PIWI proteins are typically components of several RNA-directed DNA restriction or CRISPR/Cas systems. However, eukaryotic versions appear to have emerged from a subset that evolved RNA-directed RNA interference. They were recruited alongside RNaseIII domains and RdRP domains, also from prokaryotic systems, to form the core eukaryotic RNAi system. Like certain regulatory systems, RNAi diversified into two distinct but linked arms concomitant with eukaryotic nucleo-cytoplasmic compartmentalization. Subsequent elaboration of RNAi proceeded via diversification of the core protein machinery through lineage-specific expansions and recruitment of new components from prokaryotes (nucleases and small RNA-modifying enzymes), allowing for diversification of associating small RNAs.

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Upregulation of a small vault RNA (svtRNA2-1a) is an early event in Parkinson disease and induces neuronal dysfunction

Cited by 56 publications

References 72 publications

Perlman syndrome nuclease DIS3L2 controls cytoplasmic non-coding RNAs and provides surveillance pathway for maturing snRNAs

Perlman syndrome nuclease DIS3L2 controls cytoplasmic non-coding RNAs and provides surveillance pathway for maturing snRNAs

A review of genome‐wide transcriptomics studies in Parkinson's disease

New perspectives on the diversification of the RNA interference system: insights from comparative genomics and small RNA sequencing

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