Devastating neurological diseases leave behind biological clues in the body.
Like Sherlock Holmes, scientists identify and trace these clues back to the disorder in order to paint a more complete pathological picture. Sometimes these clues are misfolded proteins, dead cells or damaged DNA. If they are specific enough to one disease, they can be considered a unique fingerprint for the disorder, known as a biomarker. Researchers are forever on the hunt for biomarkers as they enable early diagnosis and clinical intervention, which could ultimately curb disease severity.
In a study published last month in the journal Science Translational Medicine, a Duke University-led research team found that damaged DNA in the blood may be used as a biomarker for Parkinson’s disease. The scientists think that this biomarker may be used in the future to diagnose Parkinson’s before the nervous system fully deteriorates.
Neurodegenerative diseases like Parkinson’s and Alzheimer’s are typically diagnosed based on clinical symptoms, which only emerge after significant neurological damage. However, these diseases can only be definitively diagnosed after death through autopsy.
What if early detection of Parkinson's disease was possible?
“Optimistically, we will be able to measure Parkinson’s disease before there are symptoms,” says Laurie Sanders, an associate professor of neurology at Duke and the study’s senior author. “If we can identify people even earlier, we have a chance to be able to intervene even earlier.”
All roads lead to the ‘powerhouse of the cell’
Parkinson’s disease is the result of massive cell death in an area of the brain known as the substantia nigra. Located just above the brainstem, the substantia nigra receives its names from the darkly pigmented cells that make up the tissue. This cluster of dark cells pump out the neurotransmitter dopamine. When dopamine cells die, the brain experiences a widespread loss of the molecule, which is necessary for voluntary body movements. Overtime, dopamine cell death manifests in hallmark Parkinsonian symptoms, including muscle stiffness, balance problems, speech impairments, and cognitive deficits.
Dopamine powers the neurons that provide movement, but what fuels the cells themselves? The mighty mitochondria.
Furthermore, mitochondrial dysfunction has been previously implicated in Parkinson’s disease. The mitochondria, as the popular expression goes, "is the powerhouse of the cell." They extract energy from food to fuel the body’s many processes. Mitochondria contain their own DNA and it is believed that damage to this genetic code in dopamine cells contributes to Parkinson’s. Additionally, two of the main risk factors associated with Parkinson's, environmental toxins and genetic mutations, are also connected to damaged mitochondrial DNA.
Sabine Hilfiker, an associate professor of anesthesiology at Rutgers and co-author on the paper says that mitochondrial damage can both “give you Parkinson's disease… and is also a risk factor for the disease.”
Given these strong pathological connections, the scientists concluded that malfunctioning mitochondria would be a viable contender as a biomarker for Parkinson’s.
Sifting for mito-DNA in blood
In order to measure mitochondrial DNA disruption, scientists needed a way to detect damage in the brain indirectly and noninvasively. According to Sanders, previous studies performed in animal models demonstrated that the bloodstream could reflect abnormalities occurring in the brain. She hypothesized that if the same principle held true in the human system, then damaged mitochondria DNA could be detected via a human blood sample.
IV blood draws were collected from Parkinson’s disease patients and healthy control participants. The blood samples were then run through a test that quantified the amount of mitochondrial DNA present in each sample. If more mitochondrial DNA was read on the test, that indicated that there was healthy mito-DNA present, while less DNA indicated dysfunction. Ultimately, patients with Parkinson’s disease had less mitochondrial DNA readouts compared to healthy controls.
The researchers had uncovered a biomarker clue for Parkinson’s disease. Levels of mitochondrial DNA damage in the blood could distinguish between individuals who have Parkinson's disease and those who do not. Scientists were able to predict whether a patient had Parkinson’s disease based solely upon their mitochondrial DNA assay results.
Strikingly, younger asymptomatic study participants who possessed a genetic mutation associated with Parkinson’s disease, still had high levels of mitochondrial DNA damage in their blood. This suggests that mitochondrial dysfunction could be a harbinger of the disorder.
“We think that [mitochondrial DNA damage] is likely something that's happening very, very early,” says Sanders.
As for next steps Sanders adds, “We really need to follow those [participants] and see who goes on to develop Parkinson’s disease.”
Pairing patients with prescriptions
The mito-DNA biomarker and test may open up new avenues for matching patients to the right drug to treat their Parkinson’s. The researchers are hopeful that the mito-DNA test could be used as a readout to measure drug efficacy.
“We may be able to identify or stratify those patients that might best respond to certain types of therapeutics,” Sanders said. “So now, we're really really eager to take sort of a precision medicine approach.”
Both Hilfiker and Sanders are careful to note that more research is necessary before these tests are widely available for use in a clinical setting. One area of further research is the specificity of the mitochondrial biomarker to Parkinson’s disease. It is possible that mitochondrial DNA damage may not occur exclusively in Parkinson’s, but could be a feature of other disease states. To test the specificity, scientists ran the mito-DNA test on patients with Alzheimer’s disease and found no change in mitochondrial DNA damage compared to controls. Mitochondrial DNA damage is not a biomarker for Alzheimer’s and this result provides assurance that it does not seem to be a general marker for neurodegenerative disease.
Sanders and her team are motivated to follow their scientific clues until they reach their goal of clinical adoption. She believes that together they have the passion and commitment to do so.
“I want to see this in my lifetime,” Sanders said. “Because, unfortunately, I think we're all going to be touched by some of these neurodegenerative diseases, one way or another.”
