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

ABSTRACT: BACKGROUND: Nonsense-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. RESULTS: Here, 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. CONCLUSIONS: The 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.

SUBMITTER: Soreq L

PROVIDER: S-EPMC3723527 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Soreq Lilach L Bergman Hagai H Israel Zvi Z Soreq Hermona H

BMC genomics 20130716

<h4>Background</h4>Nonsense-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.<h4>Results</h4>Here, we report exon arrays analysis of leukocyte mRNA AS events prior to and following Deep Brain S ...[more]

PMID: 23865419

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Project description:Nonsense-mediated decay (NMD) is a host RNA control pathway that removes aberrant transcripts with long 3' untranslated regions (UTRs) due to premature termination codons (PTCs) that arise through mutation or defective splicing. To maximize coding potential, RNA viruses often contain internally located stop codons that should also be prime targets for NMD. Using an agroinfiltration-based NMD assay in Nicotiana benthamiana, we identified two segments conferring NMD-resistance in the carmovirus Turnip crinkle virus (TCV) genome. The ribosome readthrough structure just downstream of the TCV p28 termination codon stabilized an NMD-sensitive reporter as did a frameshifting element from umbravirus Pea enation mosaic virus. In addition, a 51-nt unstructured region (USR) at the beginning of the TCV 3' UTR increased NMD-resistance 3-fold when inserted into an unrelated NMD-sensitive 3' UTR. Several additional carmovirus 3' UTRs also conferred varying levels of NMD resistance depending on the construct despite no sequence similarity in the analogous region. Instead, these regions displayed a marked lack of RNA structure immediately following the NMD-targeted stop codon. NMD-resistance was only slightly reduced by conversion of 19 pyrimidines in the USR to purines, but resistance was abolished when a 2-nt mutation was introduced downstream of the USR that substantially increased the secondary structure in the USR through formation of a stable hairpin. The same 2-nt mutation also enhanced the NMD susceptibility of a subgenomic RNA expressed independently of the genomic RNA. The conserved lack of RNA structure among most carmoviruses at the 5' end of their 3' UTR could serve to enhance subgenomic RNA stability, which would increase expression of the encoded capsid protein that also functions as the RNA silencing suppressor. These results demonstrate that the TCV genome has features that are inherently NMD-resistant and these strategies could be widespread among RNA viruses and NMD-resistant host mRNAs with long 3' UTRs.

Dataset Information

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

Publications

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

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