Introns in DNA, Largely Ignored, May Be Parkinson Determinants
Researchers have identified distinct changes to introns — a historically understudied component of genes — associated with the presence and progression of Parkinson’s disease.
Learning more about these changes and the signaling pathways they impact may help in identifying biomarkers and treatment targets for the neurodegenerative disease, the researchers 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,” Sulev Koks, MD, PhD, a professor at the Perron Institute for Neurological and Translational Science and Murdoch University, both in Australia, and the study’s first author, said in a press release.
The study, “Longitudinal intronic RNA-Seq analysis of Parkinson’s disease patients reveals disease-specific nascent transcription,” was published in Experimental Biology and Medicine.
Genes are composed of alternating stretches of two types of material: exons and introns. Exons contain DNA that directly encodes information needed by intermediate molecules, called RNA, to produce proteins. Introns serve a regulatory role that dictates how exons are used in cells, but they are removed, or spliced out, from RNA before a protein is produced.
Although exons make up about 2% of our DNA, most studies of genetic risk factors for Parkinson’s have focused on exons, given their role in protein production.
“The bulk of the DNA risk resides in the other 98 per cent of the genome that determines where, when and for how long exons are produced to generate these proteins,” Koks said. “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.”
Koks and his team focused on introns to identify “substantial intronic transcriptional changes in Parkinson’s disease (PD) patients.”
Using data from the Parkinson’s Progression Markers Initiative (PPMI), the researchers compared the genetic sequences of introns in the blood of 390 Parkinson’s patients at the time of diagnosis with those from 189 healthy adults (control group), and then monitored whether they had changed with Parkinson’s progression after three years.
At diagnosis, 836 intronic differences were observed in Parkinson’s patients compared with controls. Several of these changes occurred in genes involved in signaling pathways predicted to impact Parkinson’s progression, the researchers said.
Three years later, a “highly significant” 4,873 intronic changes were evident in patients, whereas healthy people had experienced nine. Several genes in patients showing intronic changes have been previously linked to neurodegenerative diseases, the researchers noted, including LRRK2, a gene associated with Parkinson’s risk.
The number of intronic differences between patients and controls at the end of the three-year period was 2,184.
A pathway analysis showed that, broadly, the activation of pathways involved in nervous system and muscle function, many of which have been implicated in Parkinson’s, were affected by these intron changes in patients.
Few exon changes were observed in either Parkinson’s patients or healthy controls over the study’s course.
Taken together, the findings show marked differences in intron expression between Parkinson’s patients and healthy people, the researchers noted, adding, “these differences were evident at the time of diagnosis and escalated during the three-year progression of the disease.”
The genes and pathways affected by intronic changes have potential to be used as biomarkers of Parkinson’s and its progression, but “their functional significance awaits further analysis,” the researchers wrote.
“Our study highlights the importance of introns as potential modulators that regulate cell function by manipulating how exons are used in the cell,” Koks said.
“Better understanding of the mechanisms underlying the degeneration of nerve cells can help in developing targeted therapies for people with Parkinson’s,” he added.
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