Researchers analyzed molecular modifications in the early stages of the disease
Parkinson's disease represents one of the greatest current challenges for neurology, as it is a neurodegenerative condition that is usually diagnosed when motor symptoms are already evident and brain damage is considerable.
The identification of biomarkers in early stages is one of the most intense areas of medical research, with the hope of developing tools that allow intervention before neuronal loss progresses.
A study published in the journal npj Parkinson’s Disease, the result of a collaboration between Chalmers University of Technology (Sweden) and Oslo University Hospital (Norway), investigated how the activity of genes responsible for repairing DNA and managing cellular stress changes over time.
The analysis compared healthy individuals with already diagnosed patients and, fundamentally, with individuals going through the "silent" (prodromal) stage of the disease, before motor symptoms appear.
Changes in genes before the onset of symptoms
Parkinson's affects motor control due to the progressive death of dopamine-producing neurons. However, these cells do not die suddenly; due to their very intense metabolic activity, they generate toxic byproducts that cause "oxidative stress," a chemical process that damages their own DNA.
The genes analyzed in the study are precisely those responsible for repairing these genetic lesions; when unusual activity is detected in them, it is a sign that the cells are struggling to correct this accumulated damage and survive before collapsing.
“By the time the motor symptoms of Parkinson's disease appear, between 50% and 80% of the relevant brain cells are usually already damaged or have disappeared. The study represents an important step in facilitating the early identification of the disease and counteracting its progression before it reaches this point,” emphasizes Danish Anwer, a doctoral student in the Department of Life Sciences at Chalmers and first author of the study, in an official statement. The research documented that individuals in the silent phase of the disease (when damage is progressing but there are no tremors or rigidity yet) exhibit distinctive alterations in how their genes repair DNA and respond to stress. According to the scientific article, the ability of genetic models to detect these signals peaked in the later stages of this silent phase.
These results suggest that failures in DNA repair and deregulation of cellular stress defenses play a much more critical role in the early stages of disease development than in later stages.
The study revealed a striking behavior: at the beginning of this silent phase, gene activity is extremely unstable, reflecting an intense and disordered effort by the body to repair the damage. However, as the disease progresses, this response stops fluctuating and becomes uniform. This indicates that the cellular defense mechanism, which initially acted strongly, becomes exhausted and loses its ability to react over time.
The article also reported that “50% of DNA repair genes and 74% of stress response genes exhibited non-linear patterns.” In simple terms, this suggests that the body activates a temporary defense mechanism to try to adapt to the damage, but this effort shuts down in later stages.
Among the genes identified as having the greatest weight in predicting this pre-symptomatic stage are ERCC6, PRIMPOL, NEIL2, and NTHL1. According to the article, these findings “indicate that problems in DNA repair and stress management are key pieces in prodromal Parkinson's and could serve as biomarkers for early detection.”
Strategies and tools to capture progression
To reach these conclusions, the scientific team used the database of the Parkinson's Progression Markers Initiative (PPMI), obtaining blood samples and genetic data from three groups: healthy individuals, people in the prodromal phase, and patients with a confirmed diagnosis. Samples were analyzed at four different time points over three years: at the beginning, and at 12, 24, and 36 months. The analysis focused on specific gene groups responsible for repairing DNA (both in the cell nucleus and in the mitochondria) and managing the stress response.
To differentiate between the groups, the researchers used artificial intelligence and statistical validation techniques. The article indicates that the accuracy in distinguishing between healthy individuals and those in the silent phase was very high, even exceeding 90% in some cases.
moments of evaluation thanks to stress response genes.
In contrast, the ability to differentiate between patients with established Parkinson's disease and healthy individuals was low, confirming that the clearest molecular "signatures" appear before clinical diagnosis.
Perspectives for diagnosis and potential interventions
Annikka Polster, associate professor in the Department of Life Sciences at Chalmers University of Technology, who led the study, commented: “This means that we have found an important window of opportunity that allows us to detect the disease before the motor symptoms caused by brain nerve damage appear. The fact that these patterns only manifest at an early stage and cease to be active when the disease has progressed further also makes it interesting to focus on these mechanisms to find future treatments.”
The scientific article emphasizes that finding these biomarkers in the blood opens the door to non-invasive diagnostic tests, such as a simple blood test, at very early stages of Parkinson's disease.
The researchers highlight that being able to detect the pathology before motor symptoms appear is crucial, as it would facilitate the use of neuroprotective treatments that would be more effective when applied before extensive brain damage occurs.
Despite the importance of the findings, the study warns of certain limitations. What is seen in the blood only partially reflects what happens inside the brain, the document clarifies. In addition, external factors such as the state of the immune system, the use of medications, or other diseases could influence the results.
Therefore, the authors recommend confirming these markers in larger and more diverse patient groups, and integrating other complementary analyses (such as the study of proteins or metabolism) to refine their medical utility.
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