Summary: Changes in nascent intronic transcription may serve as indicators of risk and progression in Parkinson’s disease.
Source: Murdoch University
New research into Parkinson’s disease reveals promising molecular signals that could guide future diagnostics and treatments for this common neurodegenerative movement disorder.
A feature article published in Experimental Biology and Medicine presents findings that broaden our understanding of genetic processes associated with the degeneration of nerve cells in Parkinson’s disease.
The study was led by Professor Sulev Koks at the Perron Institute for Neurological and Translational Science and Murdoch University in Western Australia. The team reports that alterations in nascent transcription within introns — regions of DNA typically not translated into protein — may indicate both risk for and progression of Parkinson’s disease.
“Better understanding of the mechanisms underlying the degeneration of nerve cells can help in developing targeted therapies for people with Parkinson’s,” Professor Koks said. He noted that much of genetic risk is located outside the protein-coding exons.
Historically, genetic investigations have concentrated on exons, the roughly two percent of the genome that encodes proteins. This work emphasizes that the remaining 98 percent — regulatory regions and non-coding sequences including introns — play a central role in determining when, where and for how long exons are expressed, and therefore influence protein production and cellular function.
Previous transcriptomic studies often measure exon abundance in specific cell types and largely overlook intronic reads. The current study focuses on introns to capture nascent transcription — a snapshot of genes actively being transcribed that is not confounded by steady-state RNA levels.
Professor Koks led the work together with Dr. Abigail Pfaff (Perron Institute and Murdoch University) and Dr. Vivien Bubb and John Quinn from the University of Liverpool. Their analysis examined intronic transcriptional changes and how those correlate with Parkinson’s disease over time.
The research demonstrates that introns can act as significant modulators of cellular behavior by influencing exon usage and the pattern of gene expression. These intronic changes appear to be selectively altered in people with Parkinson’s disease compared with healthy controls.
“Our study highlights the importance of introns as potential modulators that regulate cell function by manipulating how exons are used in the cell,” Professor Koks said. “This work opens a new avenue of genomic research towards developing novel approaches for improved diagnosis and more targeted therapeutic intervention in Parkinson’s disease progression.”
The published paper is titled “Longitudinal intronic RNA-Seq analysis of Parkinson’s disease patients reveals disease-specific nascent transcription.” Dr. Steven Goodman, Editor-in-Chief of Experimental Biology and Medicine, commented that these results point to additional blood-based biomarkers that could be predictive of risk and useful for tracking disease progression.
About this genetics and Parkinson’s disease research news
Author: Press Office
Source: Murdoch University
Contact: Press Office – Murdoch University
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Original Research: Open access. “Longitudinal intronic RNA-Seq analysis of Parkinson’s disease patients reveals disease-specific nascent transcription” by Sulev Koks et al., published in Experimental Biology and Medicine.
Abstract
Longitudinal intronic RNA-Seq analysis of Parkinson’s disease patients reveals disease-specific nascent transcription
Most transcriptomic investigations concentrate on exon- or gene-level annotations, with relatively few studies examining reads that map to intronic regions. Intronic reads provide a window into nascent transcription — the immediate transcriptional activity of genes — and are less affected by steady-state RNA abundance. That makes intronic analysis a useful approach to detect active transcriptional changes that may precede or accompany disease processes.
In this longitudinal study, the authors describe substantial changes in intronic transcription in people with Parkinson’s disease (PD) compared with healthy control subjects (CO) at two timepoints: at diagnosis (baseline, BL) and three years later (visit V08). Using blood RNA-Seq data drawn from the Parkinson’s Progression Markers Initiative (PPMI) cohort, the team identified widespread differential intronic expression specific to PD patients over the follow-up interval.
Control subjects exhibited minimal intronic change between visits, with only nine transcripts showing differential intronic expression. In contrast, PD patients displayed dramatic alterations: 4,873 transcripts had differentially expressed introns at V08 compared to baseline. Many of these affected genes are already linked to neurodegenerative disease biology, including LRRK2, C9orf72, LGALS3, KANSL1AS1 and ALS2.
At the time of diagnosis, 836 transcripts showed PD-specific differences in intronic expression, examples being SNCA, DNAJC19 and PRRG4. By the three-year follow-up visit V08, there were 2,184 transcripts with PD-specific intronic changes, including PINK1, GBA, ALS2 and PLEKHM1. Notably, reads that map to exonic regions showed little variation over the same period, emphasizing that the observed changes are specific to intronic, nascent transcription rather than reflecting broad shifts in steady-state RNA.
The findings indicate that Parkinson’s disease is marked by pronounced alterations in nascent transcription, detectable in peripheral blood. Describing these intronic transcriptional changes contributes to a deeper understanding of the molecular pathology of PD and suggests new avenues for developing blood-based biomarkers and targeted therapeutic strategies.