Researchers from the Institute of Biomedicine of Seville (IBis) demonstrated in a new to study the existence of an important relationship between the inflammatory response, Parkinson’s disease and its genetic characteristics.
The peripheral inflammatory immune response is different depending on the presence of variants in genes associated with the disease, which implies that there are different pathophysiological mechanisms and, therefore, different potential forms of treatment and action against Parkinson’s.
For the authors, the results highlight the need to subclassify patients in research based on their genetic characteristics.
The origin of Parkinson’s disease lies in neurodegeneration, that is, in the chronic and progressive deterioration of the nervous system. Parkinson’s, however, has several variants that make this disease really many. Classic motor symptoms result from the degeneration of dopaminergic neurons in the substantia nigra of the midbrain.
However, the combination of mechanisms responsible for neuronal death is likely to be variable and different in each patient with the disease. Therefore, considering Parkinson’s disease as a single entity may be a limitation in advancing our knowledge of the disease.
“Parkinson’s is today the second most prevalent neurodegenerative disease, after Alzheimer’s, and belongs to the so-called movement disorders”, explains Laura Muñoz Delgado, a researcher in this specialty at IBiS.
This disease has a great personal and socioeconomic impact on a global scale.
Laura Muñoz Delgado, first signatory of the study
“This disease has a great personal and socioeconomic impact on a global scale, which makes it necessary to persevere in the study of its causes to identify disease-modifying treatments. It is known that the clinical characteristics and its evolution are highly variable between patients”, he continued .
The probable existence of several diseases depending on the mechanisms that lead to neuronal death, as indicated by the specialist, can lead to completely different needs and approaches in coping with the disease.
Along these lines, “the identification of associated genes represents an excellent opportunity to investigate the cellular mechanisms in which they are involved”, he continues. “Two well-established genes associated with Parkinson’s disease are the LRRK2 gene, the most common cause of familial Parkinson’s disease, and the GBA gene, which is the main genetic risk factor for Parkinson’s disease.”
Currently, the causes are not fully known, but evidence suggests that inflammation, both in the central and peripheral blood, is a key element in the initiation and progression of neurodegeneration.
Evidence points to inflammation as a key factor in the initiation and progression of neurodegeneration
“The research group led by Dr. Pablo Mir previously demonstrated the existence of peripheral inflammation and immune dysregulation in patients with Parkinson’s disease”, he specified.
Researchers have previously described that the ratio of neutrophils to lymphocytes is higher in patients with Parkinson’s disease compared to healthy subjects. This ratio is a well-established biomarker of the presence of inflammation in the body.
As detailed by the researcher, the increased proportion reflects greater systemic inflammation and dysregulation between two types of cells in our immune system, neutrophils and lymphocytes. In other words, the number of neutrophils, a type of white blood cell, is in an abnormal proportion to lymphocytes, another type of essential immune cell.
In the current work, the team found that this, and the associated inflammatory response, is directly related to the patients’ genetic characteristics.
The relationship with your genetic background
In this study published in the journal npj Parkinson’s disease, according to Muñoz Delgado, it is demonstrated that this peripheral inflammatory response differs in patients with Parkinson’s disease according to their genetic characteristics.
“In the study, we observed that patients with sporadic Parkinson’s disease, without identified genetic variants, and those with mutations in the GBA gene have a higher neutrophil-lymphocyte ratio and a lower number of lymphocytes in the peripheral blood”, he indicates. This, in the words of the scientist, corroborates the presence of greater peripheral inflammation in these patients.
This peripheral inflammatory response differs in patients with Parkinson’s disease based on their genetic characteristics.
Laura Munoz Delgado
“This ratio is a well-established marker of inflammation, reflecting the dysregulation between two populations of cells: neutrophils represent chronic inflammation, while lymphocytes show the regulatory pathway”, he explains.
“The decrease in the number of lymphocytes in the blood in patients with Parkinson’s disease is a constant finding in many published works and it is suggested that it could be due to a dysregulation in its subpopulations -the number of cells of this specific type- with an increase in lymphocytes pro-inflammatory drugs and a decrease in anti-inflammatory drugs”, he maintains.
On the other hand, as the specialist points out, “it should be noted that patients with severe variants in the GBA gene tend to have a more aggressive course in terms of dementia. Interestingly, the development of dementia in Parkinson’s disease has also been linked to increased peripheral inflammation.”
This relationship emphasizes the importance of the inflammatory response in some of the most aggressive manifestations of Parkinson’s, which may highlight new ways of studying the pathology.
The most relevant finding is that patients with mutations in the LRRK2 gene did not show differences either in the neutrophil-lymphocyte ratio or in the lymphocyte count.
The most relevant finding, however, is that patients with mutations in the LRRK2 gene did not show differences in the neutrophil-lymphocyte ratio or in the lymphocyte count compared to healthy individuals. “This may indicate that the inflammatory pathogenic mechanisms may be different in these patients”, clarifies Muñoz Delgado.
“This result is very much in line with other recent publications that suggest that inflammation associated with mutations in the LRRK2 gene would be associated with circulating inflammatory mediators rather than lymphocyte dysregulation”, which implies a different pathophysiological mechanism and therefore , suggests other avenues of investigation.
As the researcher emphasizes, “it is believed that, given the results of the study, there is a need to subclassify patients in studies based on their genetic characteristics, since they involve different cellular pathways that could facilitate the understanding of the pathophysiology of the disease and apply personalized medicine”.
In search of new therapeutic targets
The research projects developed within the research group will allow a better understanding of the causes involved in the pathology, looking for potential implications in the development of future individualized therapeutic targets.
Although it is a complex path and a great scientific challenge, studies such as the journal help to clarify the correct direction in which research efforts should be directed, laying the foundations for future new possibilities for treating the disease in search of new therapeutic targets .
Munoz-Delgado, et al. “The peripheral inflammatory immune response differs between sporadic and familial Parkinson’s disease.” npj parkinson Dis. (2023)