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Human Splice Junction Arrays of Parkinson's Patients Leukocytes mRNA Pre- and Post-Deep Brain Stimulation

ABSTRACT: Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide and the first involving motor symptoms. Deep brain stimulation (DBS) neurosurgery treatment through electrodes implanted to the subthalamic nucleus (STN) improves dramatically the debilitating motor symptoms of the disease due to yet unknown molecular mechanisms. Affymetrix human junction prototype microarrays (HJAY) of blood leukocytes mRNA from PD patients prior to, and following DBS neurosurgery treatment on electrical stimulation were compared to these of age- and gender-matched healthy control volunteers. About 95% of all human genes undergo alternative splicing, and alternative splicing is involved in human diseases and specifically in neurodegenerative diseases. Thus, the goal of this study was to detect alternatively spliced genes in PD patients prior to, and following DBS and to predict the effect of these on the functional level of change at the transcript level (such as exon inclusion, intron retention and nonsense-mediated decay events). Understanding the role of alternative splicing in neurodegenerative diseases will open new avenues to future novel approaches for early detection and neuroprotective treatment enabled by the development of future genetic therapeutics targeted at specific modified splice variants.

ORGANISM(S): Homo sapiens

PROVIDER: GSE37591 | GEO | 2015/05/22

SECONDARY ACCESSION(S): PRJNA161893

REPOSITORIES: GEO

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Project description:Sub-thalamic deep brain stimulation (DBS) reversibly modulates ParkinsonM-bM-^@M-^Ys disease (PD) motor symptoms, providing an unusual opportunity to compare leukocyte transcripts in the same subjects before and after neurosurgery and after disconnecting the stimulus (ON-and OFF-stimulus). Here, we report rapid stimulus-induced and largely reversible changes in PD leukocyte transcripts, which were larger in scope than the disease-induced changes. These transcript changes classified advanced pre- from post-surgery PD patients and discriminated patients from controls. Moreover, the extent of changes correlated with the neurological efficacy of the DBS neurosurgery, and covered both regulatory pathways and individual transcript changes, e.g. SNCA, PARK7 and the splicing factor SFRS1. Following 1 hour OFF-stimulus, these changes were largely reversed. We extracted from these differences a modified transcripts signature which discriminated controls from advanced PD patients, pre- from post-surgery and ON-from OFF-stimulus conditions. A further gene-list independent analysis detected reversed pathways. Our findings suggest future uses of this approach and the discovered molecular signature for early diagnostics of PD and for identifying novel targets for therapeutic intervention in this and other DBS-treatable neurological diseases. 27 Total samples were analyzed. Study design included four conditions. PD patients (n=7) leukocyte blood samples were examined at 3 time points, and healthy control subjects (n=6) were examined once each. Samples were taken 1 day prior to sub-thalamic nucleous (STN) DBS treatment, several months after STN-DBS treatment upon optimal stimulation and following one hour electrical stimulation cessation. The off stimulation caused recruitment of the disease symptoms as measured by the Unified Parkinson's Disease Rating Scale motor section (UPDRS-III). The different stages are designated: S1 (pre-treatment), S2 (post STN-DBS) and S3 (upon off stimulation). All patients were on dopamine replacement therapy (DRT) when examined pre- and post-DBS off stimulation (albeit with reduced therapy dose post-DBS). To reduce biological variability among the samples which is not related to the study, only male subjects were included in this study. Samples from six age- and gender- matched healthy control subjects served to detect disease modified transcripts and for pre- and post- treatment comparisons. The study was approved by the human review board at the Hadassah University Hospital, Ein-Kerem (no. 6-07.09.07) in accordance with the Declaration of Helsinki. All study participants signed informed consent.

Project description:Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder that is clinically defined in terms of motor symptoms. These are preceded by prodromal non-motor manifestations that prove the systemic nature of the disease. Identifying genes and pathways altered in living patients provide new information on the diagnosis and pathogenesis of sporadic PD. We study changes in gene expression in the blood of 40 sporadic PD patients and 20 healthy controls (Discovery set?) by taking advantage of the Affymetrix platform. Patients were at the onset of motor symptoms and before initiating any pharmacological treatment. By applying Ranking-Principal Component Analysis, PUMA and Significance Analysis of Microarrays, gene expression profiling discriminates patients from healthy controls and identifies differentially expressed genes in blood. The majority of these are also present in dopaminergic neurons of the Substantia Nigra, the key site of neurodegeneration. Together with neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, already found in previous analysis of PD blood and post-mortem brains, we unveiled transcriptome changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation. Candidate transcripts were validated by RT-qPCR in an independent cohort of 12 patients and controls (?Validation set). Our data support the use of blood transcriptomics to study neurodegenerative diseases. It identifies changes in crucial components of chromatin remodeling and methylation machineries as early events in sporadic PD suggesting epigenetics as target for therapeutic intervention. Analyzed samples include blood samples from 40 PD patients and 20 healthy controls. Of the original 60 samples, one (a control sample) did not pass the microarray hybridization quality controls and was excluded from further analyses. All results of bioinformatics analyses shown in this study refer to this set of 59 samples (reported here).

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Human Splice Junction Arrays of Parkinson's Patients Leukocytes mRNA Pre- and Post-Deep Brain Stimulation

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