Summary: Alterations in the nascent transcription of introns may indicate risk factors for, and the progression of Parkinson’s disease.
Source: Murdoch University
Findings of a new Parkinson’s disease study have opened an exciting avenue for developing therapeutics to intervene in the progression of this common movement disorder.
The feature article in Experimental Biology and Medicine contributes to understanding of genetic processes underlying nerve cell degeneration in people with Parkinson’s.
The study, led by Professor Sulev Koks at Western Australia’s Perron Institute for Neurological and Translational Science and Murdoch University, reports that alterations in the nascent transcription of introns (pertaining to DNA sequencing) may be indicators of risk and progression of Parkinson’s.
“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.
“For many years the search for DNA risk factors for specific diseases such as Parkinson’s has focused on exons, the two percent of our genome that encode the information for proteins.
“The bulk of the DNA risk resides in the other 98 percent of the genome that determines where, when and for how long exons are produced to generate these proteins.
“Similarly, previous research has focused on the measurement of exons in specific cells, ignoring the bulk of non-exon material that can affect their function.”
In this study, Professor Koks, Dr. Abigail Pfaff (Perron Institute and Murdoch University), and University of Liverpool’s Dr. Vivien Bubb and John Quinn analyzed introns and investigated changes correlating with Parkinson’s disease progression.
The study showed the importance of introns in regulating cell function and causing changes.
“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 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, said the research illustrates additional blood-based biomarkers with potential to be predictive of risk and diagnostic for progression of Parkinson’s disease.
About this genetics and Parkinson’s disease research news
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.