The research also suggests that a translational approach — one that moves from cell lab work to patients — which also incorporates relevant protein biological functions may be a more efficient way of identifying disease biomarkers circulating in the blood, for Parkinson’s and other disorders.
The study, “A different vision of translational research in biomarker discovery: a pilot study on circulatory mitochondrial proteins as Parkinson’s disease potential biomarkers,” was published in the journal Translational Neurodegeneration.
Disease biomarkers are fundamental in medicine, helping to diagnose people with a given condition earlier, determine the severity of disease, predict responses to treatments, and have a sense of a person’s prognosis.
But most studies aiming at discovering circulating, or blood, biomarkers of Parkinson’s disease have failed to have reproducible results. This is likely because biomarker studies require large patient samples due to the high variability of each sample, and very complex analysis.
Researchers at the University of Coimbra, in Portugal, proposed a translational method to identify disease biomarkers, which first uses cells under well-defined circumstances that make sense in the context of disease, then selects proteins based on the function that is most important for the disease, and only then incorporates these findings with those of patient samples.
They demonstrated the potential of this approach in identifying circulating biomarker candidates of neurodegenerative diseases, particularly Parkinson’s.
The researchers started out by comparing proteins that are secreted by cells cultured in normal conditions, and in a setting of oxidative stress — an imbalance between the production and clearance of toxic reactive species that are harmful to cells, and which plays a key role in neurodegenerative diseases like Parkinson’s.
To narrow down biomarker candidates, they then selected only mitochondrial-related proteins, which are central in the modulation of oxidative stress and also participate in Parkinson’s and other neurodegenerative conditions. (Mitochondria are small organelles inside cells that function as a cell’s energy source or “powerhouse.”)
In total, their analysis retrieved 23 mitochondrial-related proteins that were differentially secreted by cells under these two conditions, including 19 proteins whose levels were significantly increased in the presence of oxidative stress, and four proteins with significantly decreased levels in this setting.
Next, a similar analysis was conducted to identify proteins whose levels were higher than normal in the blood of Parkinson’s patients. That is, higher compared to healthy people serving as a control group.
For that purpose, they examined blood plasma samples from 31 Parkinson’s patients, ages 65 to 86 and being followed at the Centro Hospitalar Cova da Beira in Portugal. They then compared these sample with 28 from matched controls, whose ages ranged from 55 to 83.
In addition to a conventional analysis in which data is extracted from a list of sample-specific identified proteins, researchers considered the list of proteins identified in their previous experiment with cells exposed (or not) to oxidative stress.
This combined approached yielded a total of 98 proteins that were significantly different between patients and controls. But a review of mitochondrial-related proteins retrieved only two candidates — clusterin and the vacuolar protein sorting-associated protein 35 (VPS35).
These two proteins were previously associated with Parkinson’s, but while clusterin was seen as a potential blood biomarker of this disease, VSP35 had never been identified in blood samples. VSP35 was only identified here because researchers also included the 23 proteins from the cellular experiment in this analysis.
Levels of these two mitochondrial-related proteins combined were better than each single protein at discriminating patients from controls, showing an accuracy of 82.1%. The rate of incorrectly classified patients also dropped significantly when people with more advanced disease were examined, the researchers reported.
In a final analysis, the team examined these two biomarkers in another group of patients and controls. While clusterin, but not VPS35, was significantly increased in plasma samples of patients compared to controls, a combined score of both proteins still provided a good way of distinguishing patients from controls.
The research suggests that studies looking for circulating disease biomarkers may benefit from complementary information of secreted proteins from cells cultured under well-defined, disease-associated conditions, and from selecting candidates based on relevant biological functions.
“From the application of this adapted pipeline, two mitochondrial-related proteins were identified as potential candidates for Parkinson’s disease diagnosis,” the researchers concluded.
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