title: Upregulation of a small vault RNA (svtRNA2-1a) is an early event in Parkinson disease and induces neuronal dysfunction.
abstract: MicroRNAs (miRNAs) and other small non-coding RNAs (sncRNAs) are post-transcriptional regulators of gene expression, playing key roles in neuronal development, plasticity, and disease. Transcriptome deregulation caused by miRNA dysfunction has been associated to neurodegenerative diseases. Parkinson disease (PD) is the second most common neurodegenerative disease showing deregulation of the coding and small non-coding transcriptome. On profiling sncRNA in PD brain areas differently affected, we found that upregulation of a small vault RNA (svtRNA2-1a) is widespread in PD brains, occurring early in the course of the disease (at pre-motor stages). SvtRNA2-1a biogenesis was dependent on Dicer activity on its precursor (vtRNA2-1) but independent of Drosha endonuclease, unlike the canonical miRNAs. Although endogenous svtRNA2-1a was enriched in Ago-2 immunoprecipitates in differentiated SH-SY5Y neuronal cells, overexpression of svtRNA2-1a induced subtle transcriptomic changes, suggesting that gene expression regulation may involve other mechanisms than mRNA decay only. Function enrichment analysis of the genes deregulated by svtRNA2-1a overexpression or svtRNA2-1a predicted targets identified pathways related to nervous system development and cell type specification. The expression pattern of svtRNA2-1a during development and aging of the human brain and the detrimental consequences of a svtRNA2-1a mimic overexpression in neuronal cells further indicate that low svtRNA2-1a levels may be important for the maintenance of neurons. Our results suggest that early svtRNA2-1a upregulation in PD may contribute to perturbations of gene expression networks, underlying metabolic impairment and cell dysfunction. A better understanding of the pathways regulated by svtRNA2-a, and also the mechanisms regulating its expression should facilitate the identification of new targets for therapeutic approaches in PD.
authors.affiliation: Genetic Causes of Disease Group; Centre for Genomic Regulation (CRG); Barcelona, Spain; Universitat Pompeu Fabra (UPF); Barcelona, Spain; Universitat de Barcelona; Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Miñones-Moyano
authors.forename: Marc R
authors.initials: MR
authors.lastname: Friedländer
authors.forename: Joan
authors.initials: J
authors.lastname: Pallares
authors.forename: Birgit
authors.initials: B
authors.lastname: Kagerbauer
authors.forename: Sílvia
authors.initials: S
authors.lastname: Porta
authors.forename: Georgia
authors.initials: G
authors.lastname: Escaramís
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Eulàlia
authors.initials: E
authors.lastname: Martí
mesh_terms: D060565:Argonaute Proteins / Q000378:metabolism; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D016366:Open Reading Frames; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D058727:RNA, Small Untranslated / Q000737:chemistry / Q000235:genetics*; D015203:Reproducibility of Results; D043244:Ribonuclease III / Q000378:metabolism; D016415:Sequence Alignment; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D058727:RNA, Small Untranslated; D043244:Ribonuclease III
keywords: lincRNAs; microarrays; neuronal dysfunction; parkinson disease; sncRNA