A group of brain-derived small molecule RNAs that can be measured in the blood may serve as biomarkers to aid in the diagnosis of Parkinson’s disease, a recent study suggests.
The processes by which these molecules influence brain functions also were uncovered, providing additional information about the molecular players and pathways involved in Parkinson’s.
Typically, diseases such as Parkinson’s are defined largely on the basis of patients’ symptoms. But scales rating motor and non-motor symptoms are generally subjective, and influenced by symptom fluctuation.
Biomarkers that complement current diagnostic tools are urgently needed for these patients, but most protein biomarkers investigated to date have failed to provide reproducible results, do not accurately reflect disease progression, or require invasive lumbar punctures.
MicroRNAs, or miRNAs, are tissue-specific small molecule RNAs that regulate gene expression within cells. They bind to a particular gene’s messenger RNA (mRNA) — the molecule generated from DNA and used as the template for protein production — to prevent generation of that protein.
A single miRNA can regulate several mRNAs, and a single mRNA can be regulated by multiple miRNAs. miRNAs are known to play important roles in many important cellular processes, including maintaining nerve cell survival and function.
Using miRNAs as biomarkers has several advantages over other molecules. They are secreted from cells, meaning that even brain-derived miRNAs can be found in blood and urine, are stable in bodily fluids, and can be measured with fast methods available in most laboratories.
Researchers at the Academy of Athens and National and Kapodistrian University of Athens Medical School, in Greece, previously identified a set of brain-enriched miRNAs with the potential for aiding in Parkinson’s diagnosis.
The same team now set out to validate those findings in an independent group of patients and controls. They also sought to establish the molecular pathways that are affected by the abnormally expressed miRNAs.
The study included 108 patients with idiopathic (of unknown cause) Parkinson’s disease and 92 healthy controls, including spouses or unrelated companions of patients with no known disease or Parkinson’s family history. Both patients and controls were recruited from the National and Kapodistrian University of Athens between 2018 and 2019.
Honing in on their prior results, researchers examined blood samples for 12 potential miRNA biomarkers, eight of which had shown significantly different levels in patients and controls. The remaining four approached statistical significance.
In this group of patients, four of the 12 biomarkers had significantly different levels in patients compared to controls. These were miR‐22‐3p, miR‐154‐5p, and miR‐330‐5p, which were significantly higher in patients, and miR‐139‐5p, which was lower in patients than in controls.
Since most (10 out of 12) miRNAs showed a similar expression pattern in both studies, researchers pooled the data to increase accuracy and statistical power. Here, five biomarkers were differentially expressed in patients and controls: miR‐22‐3p, miR‐124‐3p, miR‐136‐3p, miR‐154‐5p, and miR‐323a‐3p.
“The fact that most of these miRNAs appear to have strong neuroprotective properties at multiple settings may suggest that they are regulated as a compensatory response to brain impairment,” the team wrote.
Overall, these biomarkers were not associated with any clinical feature, and while three biomarkers were associated with age, this was not enough to explain the differences in miRNA expression between patients and controls.
Notably, researchers found three miRNAs — miR‐330‐5p, miR‐433‐3p, and miR‐495‐3p — whose levels were significantly higher in males than females. This may help explain why the incidence of Parkinson’s is almost 50% higher in males.
“These three miRNAs have a rather negative impact on neuronal processes affected in PD [Parkinson’s disease], however, further work is required to better delineate their roles, and if/how their higher expression in males affects vulnerability to PD,” the researchers wrote.
When sex and age were taken into account, the team found that a set of three biomarkers — miR‐7‐5p, miR‐136‐3p, miR‐409‐3p — could distinguish patients from controls with an accuracy of 73%. With this panel, the amount of patients who were correctly identified as such was 72%, and the proportion of controls correctly identified was 67%.
Most of the genes (five of eight) that were different in patients compared to controls, and in men compared to women, were found to cluster in a single region of chromosome 14 called 14q32. This suggested that their production is controlled by the same regulatory factors, which was confirmed by additional analyses.
Researchers then conducted several computer analyses to explore which genes are targeted by differentially expressed miRNA, and the biological pathways in which they participate.
Results showed that “long‐term depression,” “TGF‐beta signaling,” and “FoxO signaling” pathways were significantly affected. As for cellular functions, the mostly affected were “protein modification,” “transcription factor activity,” and “cell death.”
“Importantly, existing information on their neurological functions provides a clue of the processes they regulate during PD. In silico analysis provided a comprehensive guide of the pathways and processes they control, improving current understanding of their biological role,” the researchers wrote.
Researchers believe “the identified miRNAs form a robust set of deregulated brain‐associated miRNAs in PD, that can now be further evaluated, along with other measures, as diagnostic and therapeutic tools for PD.”
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