Abstract
MicroRNAs (miRNAs) are key post transcriptional regulators of their multiple target genes. However, the detailed profile of miRNA expression in Parkinson's disease, the second most common neurodegenerative disease worldwide and the first motor disorder has not been charted yet. Here, we report comprehensive miRNA profiling by next-generation small-RNA sequencing, combined with targets inspection by splice-junction and exon arrays interrogating leukocyte RNA in Parkinson's disease patients before and after deep brain stimulation (DBS) treatment and of matched healthy control volunteers (HC). RNA-Seq analysis identified 254 miRNAs and 79 passenger strand forms as expressed in blood leukocytes, 16 of which were modified in patients pre-treatment as compared to HC. 11 miRNAs were modified following brain stimulation 5 of which were changed inversely to the disease induced changes. Stimulation cessation further induced changes in 11 miRNAs. Transcript isoform abundance analysis yielded 332 changed isoforms in patients compared to HC, which classified brain transcriptomes of 47 PD and control independent microarrays. Functional enrichment analysis highlighted mitochondrion organization. DBS induced 155 splice changes, enriched in ubiquitin homeostasis. Cellular composition analysis revealed immune cell activity pre and post treatment. Overall, 217 disease and 74 treatment alternative isoforms were predictably targeted by modified miRNAs within both 3′ and 5′ untranslated ends and coding sequence sites. The stimulation-induced network sustained 4 miRNAs and 7 transcripts of the disease network. We believe that the presented dynamic networks provide a novel avenue for identifying disease and treatment-related therapeutic targets. Furthermore, the identification of these networks is a major step forward in the road for understanding the molecular basis for neurological and neurodegenerative diseases and assessment of the impact of brain stimulation on human diseases.
Highlights
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease worldwide and the first movement disorder
We found significant differences in miRNA expression levels in PD, partially reversed by deep brain stimulation (DBS), which co-occurred with high confidence changes in gene isoform expression levels and cell lineage composition
We found three target genes (HBG2, RARRES3, and VASP) common to both networks to be regulated by the same miRNAs predicted to target the same junction probe-set pairs (Figure 7A), and in opposite directions from healthy controls to PD patients as compared with pre- to post-DBS
Summary
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease worldwide and the first movement disorder. We performed a comparative miRNA, splicing and gene expression analysis of PD patients’ blood leukocytes pre- and post-DBS with the electrical stimulus being on and following 1 h of stimulation cessation using high throughput RNA sequencing in conjunction with exon and splice junction microarrays of the same cells. Along with these samples, mRNA samples from matched healthy control volunteers were analysed. We provide these data sets and analyses as a resource for understanding miRNA expression and splicing in Parkinson’s patient’s leukocytes pre- and post-treatment
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