Parkinson’s Disease Blood Test Detects Mitochondrial DNA Damage

Researchers headed by a team at Duke University School of Medicine have developed a blood test that detects Parkinson’s disease, potentially establishing a way to help diagnose the condition before nervous system damage worsens. Assessed on blood samples from patients with Parkinson’s disease, the PCR-based assay (Mito DNA_DX) identifies mitochondrial DNA (mtDNA) damage and could feasibly be used to help measure response to new treatments.

“Currently, Parkinson’s disease is diagnosed largely based on clinical symptoms after significant neurological damage has already occurred,” said Laurie Sanders, PhD, an associate professor in Duke School of Medicine’s departments of neurology and pathology and member of the Duke Center for Neurodegeneration and Neurotherapeutics. “A simple blood test would allow us to diagnose the disease earlier and start therapies sooner. Additionally, a clear-cut diagnosis would accurately identify patients who could participate in drug studies, leading to the development of better treatments and potentially even cures.”

Sanders is senior author of the team’s published paper in Science Translational Medicine, which is titled “A blood-based marker of mitochondrial DNA damage in Parkinson’s disease,” in which they stated “Our data provide evidence to support inclusion of mtDNA damage as a blood-based candidate marker for PD in future clinical trials.”

Parkinson’s disease (PD) affects some 10 million people worldwide, and represents the second most common neurodegenerative disease after Alzheimer’s disease, and the most common neurodegenerative movement disorder. Parkinson’s disease is characterized by  progressive loss of dopaminergic neurons in the substantia nigra region of the brain by the time a clinical diagnosis a significant proportion of dopaminergic neurons will already have degenerated, they continued. “… neuroprotective or disease-modifying interventions remain elusive.” A new blood-based diagnostic test would be a major advance. “The development of blood-based molecular markers for early detection and to define PD subtypes most likely to benefit from a particular intervention could transform the way clinical trials are conducted and enhance the success of disease-modifying therapies,” the team continued.

As a potential biomarker for their diagnostic tool, Sanders and colleagues focused on mitochondrial DNA damage. Mitochondria are factories within cells that convert raw energy into a form that powers cells. They contain their own DNA, which can undergo damage separately from the nuclear DNA that encodes most of an organism’s genome. Earlier studies have associated mitochondrial DNA damage with an increased risk of Parkinson’s disease, and the Duke-led team had previously reported an accumulation of mitochondrial DNA damage specifically in the brain tissue of deceased Parkinson’s patients. “Mitochondrial dysfunction is a well-established underlying mechanism contributing to the pathogenesis of PD,” they commented. “Mitochondrial dysfunction is a well-established underlying mechanism contributing to the pathogenesis.”

To see whether mitochondrial DNA could be a marker of disease, the researchers developed a PCR-based test called Mito DNA_DX,  that could quantify mitochondrial DNA damage in blood samples, in scalable manner. Using the new assay, the scientists could successfully quantify higher levels of mitochondrial DNA damage in blood cells collected from patients with Parkinson’s disease, compared to people without the disease.

The new test identified high levels of the damaged DNA in the blood samples of people with idiopathic PD, and those who harbor a mutation in LRRK2 kinase enzyme gene. “Pathogenic mutations in LRRK2 are one of the most common known causes for PD,” they explained. “We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls.” Interestingly, the investigators found that mtDNA damage was higher also in individuals without diagnosed Parkinson’s disease who carried the LRRK2 mutation,“… demonstrating that mtDNA damage can occur irrespective of a PD diagnosis,” they pointed out. The assay also showed that mice with the same mutation displayed more mitochondrial DNA damage than wild-type rodents.

The test showed that inhibiting LRRK2 using the experimental small molecule MLi-2 reduced DNA damage in a rat model of Parkinson’s disease and also in patient-derived cells. LRRK2 inhibition was associated with reduced mtDNA damage also in cells derived from PD patients without the LRRK2 mutation. “LRRK2 kinase activity may be elevated in idiopathic PD, even in the absence of a genetic mutation,” they wrote. “These results suggest a role for increased LRRK2 kinase activity in driving mtDNA damage in both LRRK2 and idiopathic PD.”

The findings indicate that the assay could help pinpoint Parkinson’s disease patients who might benefit from LRRK2 kinase inhibitor treatments, even if they do not have a LRRK2 mutation. “… LRRK2 represents a promising therapeutic target for disease modification, and small-molecule kinase inhibitors are currently being evaluated in clinical trials,” the researchers pointed out.

“Our hope is that this assay could not only diagnose Parkinson’s disease, but also identify drugs that reverse or halt mitochondrial DNA damage and the disease process,” Sanders added. “This disease takes a terrible toll on people, and we are still just treating the symptoms. It’s important to get new, effective treatments over the finish line.” Sanders said the research team’s future work will include further testing of the assay in samples from patients with the earliest stages of disease, before symptoms develop.