Longitudinal intronic RNA-Seq analysis of Parkinson’s disease patients reveals disease-specific nascent transcription

Abstract

Transcriptomic studies usually focus on either gene or exon-based annotations, and only limited experiments have reported changes in reads mapping to introns. The analysis of intronic reads allows the detection of nascent transcription that is not influenced by steady-state RNA levels and provides information on actively transcribed genes. Here, we describe substantial intronic transcriptional changes in Parkinson’s disease (PD) patients compared to healthy controls (CO) at two different timepoints; at the time of diagnosis (BL) and three years later (V08). We used blood RNA-Seq data from the Parkinson’s Progression Markers Initiative (PPMI) cohort and identified significantly changed transcription of intronic reads only in PD patients during this follow-up period. In CO subjects, only nine transcripts demonstrated differentially expressed introns between visits. However, in PD patients, 4873 transcripts had differentially expressed introns at visit V08 compared to BL, many of them in genes previously associated with neurodegenerative diseases, such as LRRK2, C9orf72, LGALS3, KANSL1AS1, and ALS2. In addition, at the time of diagnosis (BL visit), we identified 836 transcripts (e.g. SNCA, DNAJC19, PRRG4) and at visit V08, 2184 transcripts (e.g. PINK1, GBA, ALS2, PLEKHM1) with differential intronic expression specific to PD patients. In contrast, reads mapping to exonic regions demonstrated little variation indicating highly specific changes only in intronic transcription. Our study demonstrated that PD is characterized by substantial changes in the nascent transcription, and description of these changes could help to understand the molecular pathology underpinning this disease.

Longitudinal dysregulation of long non-coding RNAs in Parkinson’s disease

“…The PPMI data set used in this study included controls without PD, and cases with confirmed PD, prodromal PD and scan without evidence of dopaminergic deficit (SWEDD) PD. The RNA-sequencing of the PPMI data set has been outlined elsewhere, 8,9 and a summary of the individuals included in this study at each time point is given in Table 1. Consent from all the study participants was previously obtained by the PPMI and conformed with the ethical standards of the World Medical Association Declaration of Helsinki.…”

Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson’s Disease and Aging

“…Substantial intronic transcriptional changes in PD patients compared to healthy controls have been reported [70]. Although the exact cause of PD is unknown, several factors, such as genetic, environmental, and head trauma, are implicated in the disease process.…”

“…Although the exact cause of PD is unknown, several factors, such as genetic, environmental, and head trauma, are implicated in the disease process. Mutations in certain genes, such as SNCA, PARK2, PARK7, PINK1, and LRRK2, can lead to the development of PD [20,[70][71][72][73]. The onset of neurodegenerative diseases may be influenced by a combination of environmental and genetic factors, including interactions between genes.…”

Unraveling Psychiatric Disorders through Neural Single-Cell Transcriptomics Approaches

“…miRNA analysis from the blood and brains from PD subjects revealed known and novel biomarkers implicated in PD development and progression, such as axon guidance, TGF-β signaling pathway, ubiquitin-mediated proteolysis, and endocytosis [ 61 ]. Besides miRNA changes in PD-associated tissues, highly specific time-dependent intronic transcriptional changes were observed in blood RNA-seq but not yet tested in the brain [ 62 ].…”