Deep brain stimulation modulates nonsense-mediated RNA decay in Parkinson’s patients leukocytes

Abstract

BackgroundNonsense-Mediated decay (NMD) selectively degrades mRNA transcripts that carry premature stop codons. NMD is often triggered by alternative splicing (AS) modifications introducing such codons. NMD plays an important regulatory role in brain neurons, but the in vivo dynamics of AS and NMD changes in neurological diseases and under treatment were scarcely explored.ResultsHere, we report exon arrays analysis of leukocyte mRNA AS events prior to and following Deep Brain Stimulation (DBS) neurosurgery, which efficiently improves the motor symptoms of Parkinson’s disease (PD), the leading movement disorder, and is increasingly applied to treat other diseases. We also analyzed publicly available exon array dataset of whole blood cells from mixed early and advanced PD patients. Our in-house exon array dataset of leukocyte transcripts was derived from advanced PD patients’ pre- and post-DBS stimulation and matched healthy control volunteers. The mixed cohort exhibited 146 AS changes in 136 transcripts compared to controls, including 9 NMD protein-level assessed events. In comparison, PD patients from our advanced cohort differed from healthy controls by 319 AS events in 280 transcripts, assessed as inducing 27 protein-level NMD events. DBS stimulation induced 254 AS events in 229 genes as compared to the pre-DBS state including 44 NMD inductions. A short, one hour electrical stimulus cessation caused 234 AS changes in 125 genes compared to ON-stimulus state, 22 of these were assessed for NMD. Functional analysis highlighted disease-induced DNA damage and inflammatory control and its reversal under ON and OFF stimulus as well as alternative splicing in all the tested states.ConclusionsThe study findings indicate a potential role for NMD both in PD and following electrical brain stimulation. Furthermore, our current observations entail future implications for developing therapies for PD, and for interfering with the impaired molecular mechanisms that underlie PD and other neurodegenerative and neurological disorders, as well as DBS-treatable conditions in general.

Long Non-Coding RNA and Alternative Splicing Modulations in Parkinson's Leukocytes Identified by RNA Sequencing

“…The resolution of RNA-Seq is higher compared to microarrays, and the technology enables detection of novel gene structural elements and events. Nevertheless, changes in 20 of the RNA-Seq disease detected leukocyte genes were also detected as altered under PD in our previous exon array analysis of a larger cohort of PD patients pre- and post-DBS [47], [48]. These included the motor movement disorder dystonia related LRRC16A gene [81].…”

Cellular, molecular, and clinical mechanisms of action of deep brain stimulation—a systematic review on established indications and outlook on future developments

“…A distinct pattern of microRNAs between healthy subjects, PD patients under medical treatment, and PD patients with DBS was observed (Soreq et al , ). Changes in the methylation pattern were even observed after 1 h without stimulation, suggesting rapid miRNA responses (Soreq et al , ) related to inflammatory control and protection against DNA damage. The authors suggest that leukocyte methylation patterns could be used as biomarkers for effective DBS treatment of PD.…”

“…Epigenetic effects DNA-methylation status in brain and blood samples from PD patients show high levels of congruence (Consales et al, 2018). Thus, a transcription fingerprint of leukocytes from PD patients was proposed, as these have been shown to respond to different brain pathologies such as stroke (Soreq et al, 2013). A distinct pattern of microRNAs between healthy subjects, PD patients under medical treatment, and PD patients with DBS was observed (Soreq et al, 2013).…”

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

“…For the 26 original studies on blood, the majority (10 studies) were performed on venous whole blood (Scherzer et al., ; Aguiar & Severino, ; Shehadeh et al., ; Potashkin et al., ; Karlsson et al., ; Alieva et al., ; Calligaris et al., ; Infante et al., , ; Pinho et al., ). In the remaining studies, five studies were on peripheral blood mononuclear cells (Kedmi et al., ; Martins et al., ; Mutez et al., , ; Nkiliza et al., ), five studies on white blood cells (Soreq et al., , ,b; Soreq et al., ; Kobo et al., ), four on serum (Botta‐Orfila et al., ; Vallelunga et al., ; Ding et al., ; Dong et al., ) and two on plasma (Table ; Table S1; Khoo et al., ; Cardo et al., ).…”