Parkinson’s disease involves monocytic alterations in the blood


The behavior of immune cells in the blood is so different in patients with Parkinson’s disease that it advocates for a new type of supplementary medicine, which can regulate the immune system and thus inhibit the deterioration of the brain.

These are the perspectives in a new study which researchers from the Department of Biomedicine at Aarhus University, Denmark, are behind.

The article has just been published in the scientific journal Movement Disorders.

“The research project confirms a growing theory that Parkinson’s disease is not only a brain disease, but is also connected with the immune system.

Both in the brain and the rest of the body,” says Marina Romero-Ramos, associate professor of neuroscience, who leads the team behind the study.

PhD Sara Konstantin Nissen, who is the study’s first author adds:

“This knowledge may in the long term lead to the development of supplementary immune-regulating treatment being combined with the current medical treatment with the drug L-dopa, which only has an effect on the brain and the symptoms.

We believe such an additional drug might help to slow down the progression of the disease,” says PhD Sara Konstantin Nissen.

Parkinson’s disease is characterised by the slow degeneration of the neurons in brain due to the abnormal accumulation of a protein called alpha-synuclein.

This leads to the patients shaking and then to the slow, stiff movements which many people associate with the disease.

In the new study, researchers have subjected blood samples from 29 Parkinson’s patients and 20 control subjects to the protein alpha-synuclein and ascertained that the immune cells in the blood from Parkinson’s patients are significantly worse at regulating the immune markers on the cell surface and that they are also less efficient to secrete anti-inflammatory molecules than the controls’ cells.

“The immune system functions in a delicate balance. On the one hand, it cleans up invasive microorganisms and accumulations of unwanted proteins, such as alpha-synuclein, and does so by creating an inflammatory condition.

But on the other hand, the immune system must also avoid damaging the body’s own cells via too much inflammation, and apparently this balance goes awry in the case of Parkinson’s disease,” says Sara Konstantin Nissen.

She adds that in research circles it is believed that immune cells in the blood, which contain (or express) a certain receptor called CD163 on their surface, migrate into the brains of Parkinson’s patients.

It has been thought that the cells help to clean up the accumulations of the alpha-synuclein which damages the brain, but with the present study it is now suggested that the cells in question are already incorrectly regulated in the bloodstream – before they reach the brain.

“This leads us to believe that it might be possible to, at the very least, slow down the degeneration of the neurons in the brain of Parkinson’s patients by regulating the immune system with medicine,” says Sara Konstantin Nissen.

In the new study, researchers have subjected blood samples from 29 Parkinson’s patients and 20 control subjects to the protein alpha-synuclein and ascertained that the immune cells in the blood from Parkinson’s patients are significantly worse at regulating the immune markers on the cell surface and that they are also less efficient to secrete anti-inflammatory molecules than the controls’ cells.

In addition to paving the way for supplemental medication for patients who have already been diagnosed with Parkinson’s, Sara Konstantin Nissen also points out that the study suggests new ways of preventing or delaying the development of Parkinson’s disease.

This can be achieved by keeping a watchful eye on people who have an increased risk of developing Parkinson’s disease, for example those persons diagnosed with REM sleep behaviour disorder (RBD), a disease where patients act vividly their dreams .

“Screening everyone for changes in the blood’s immune cells would be pointless. However, we know that more than half of those who suffer from this sleep disorder, RBD, develop Parkinson’s disease years later, so this is an obvious place to start.

Other studies show that inflammation in the body can be reduced with exercise as a form of treatment, which can therefore reduce the risk of becoming ill at all.

However, this requires a change of views among medical doctors and neurologists, because they will have to treat Parkinson’s disease as more than just a brain disorder,” says Sara Konstantin Nissen.

Facts about the type of study:

A cross-sectional study of 29 Parkinson’s patients and 20 healthy control subjects of the same age and gender distribution.

Immune cells from the blood (PBMCs) were purified and stimulated in culture with fibrils of alpha-synuclein

. Markers were subsequently measured on the cell surface using flow cytometry and on secreted cytokines using ELISA and Mesoscale. The study cohort was collected by the Hertie Biobank in Germany.

Partners from Denmark and abroad include: Professor Daniel Otzen (Interdisciplinary Nanoscience Centre (iNANO)) and MD and Professor Holger Jon Møller (Aarhus University Hospital) together with a team of neurologists from the University of Tübingen in collaboration with Hertie Biobank.

Funding: Funding support for the research covered on this article was provided from the Michael J. Fox Foundation (MR‐R), the Bjarne Saxhof Fund administered through the Danish Parkinson’s Foundation (MR‐R), the Aarhus University Forskningsfond AU IDEAS center NEURODIN (MR‐R), and the Novo Nordisk Foundation (to D.E.O.; NNF17OC0028806).

Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article.

PD is a multisystem disease where both central and peripheral nervous systems are affected. This systemic involvement also includes the immune response in PD, which implicates not only microglia in the brain, but also peripheral immune cells, such as monocytes; however, this aspect has been understudied.


The purpose of this study was to investigate the PD‐related changes in peripheral immune cells, their responsiveness to stimulation, and their ability to release immunomodulatory molecules that might have consequences for the disease progression.


Using flow cytometry, we investigated the monocytic population in peripheral blood mononuclear cells from PD patients and healthy individuals. We also evaluated the in vitro response to inflammogen lipopolysaccharides and to fibrillar α‐synuclein by measuring the expression of CD14, CD163, and HLA‐DR and by analysis of soluble immune‐related molecules in the supernatant.


Peripheral blood immune cells from PD patients had lower survival in culture, but showed a higher monocytic proliferative ability than control cells, which was correlated with shorter disease duration and late disease onset. In addition, PD patients’ cells were less responsive to stimulation, as shown by the lack of changes in CD163 and CD14 expression, and by the absence of significant upregulation of anti‐inflammatory cytokines in culture. Moreover, PD peripheral immune cells shed lower in vitro levels of soluble CD163, which suggests a less responsive monocytic population and/or an activation status different from control cells. Interestingly, some of the results were sex associated, supporting a differential immune response in females versus males.


Our data suggest that PD involves monocytic changes in blood. These cells show reduced viability and are unresponsive to specific stimuli, which might have a relevant consequence for disease progression. © 2019 International Parkinson and Movement Disorder Society


Parkinson’s disease (PD) is a common movement disorder, with diagnostic symptoms of resting tremor, bradykinesia and muscle rigidity resulting from degeneration of dopamine producing neurons in the substantia nigra region of the midbrain. The underlying causes of PD remain unclear however, several genetic factors have been identified that associate with an increased risk of developing PD. The most common genetic risk factor for PD comprises heterozygous missense mutations in GBA1, the gene encoding the lysosomal enzyme beta-glucocerebrosidase (GCase). GBA1 mutations occur in as many as 5–15% of PD cases, depending on ethnicity13, and can increase the risk of developing PD by up to 20-fold4,5.

The finding that GBA1 mutations increase the risk of developing PD resulted from observation of a higher incidence of PD in patients with the lysosomal storage disorder, Gaucher’s disease, a recessive disorder also caused by GBA1 mutations6. Studies of Gaucher’s disease patients have identified almost 300, mostly missense, mutations for GBA1 that negatively impact on GCase stability and function7. As GCase catalyses the hydrolysis of glucosylceramide to ceramide and glucose, affected cells from Gaucher’s disease patients display lipid abnormalities8.

We have previously shown that GCase activity is also reduced in pathologically affected brain tissue from PD subjects without GBA1 mutations9. This decreased GCase activity was not due to changes in GBA1 mRNA expression, but was associated with impaired lysosomal function and decreased levels of ceramide. Importantly, these results suggest a broader role for GCase dysfunction in PD beyond just those carriers who have GBA1 mutations. Indeed, in both human PD post-mortem tissue and in GCase-deficient cell and animal models, reduced GCase is associated with an increase in the pathological PD protein, α-synuclein913. Clinically, PD associated with GBA1 mutations is also largely indistinguishable from the idiopathic form, although PD patients with GBA1 mutations appear at greater risk of cognitive decline1419, a finding consistent with a higher incidence of GBA1 mutations in patients with dementia with Lewy bodies20.

There is currently much interest in the development of small molecule chaperones that can stabilise and/or increase GCase activity. Such compounds could have utility for the treatment of Gaucher’s disease, but could potentially also be therapeutic options for PD2123. Consequently, a better understanding of GCase activity in PD is required. In particular, peripheral blood cells offer a convenient source of GCase for measurement and a recent study identified a significant decrease in GCase activity in whole blood samples from idiopathic PD patients24. However, other studies using peripheral mononuclear cells have not found a decrease in GCase activity in PD patients2528. Interpretation of these outcomes is complicated due to different methodologies employed and the heterogeneous nature of the sample material. Indeed, in peripheral immune cells, GCase is most highly expressed in monocytes29, which comprise only a small fraction of whole blood.

To try resolve these issues, we have used the cell permeable GCase substrate 5-Pentafluorobenzoylamino Fluorescein Di-β-D-Glucopyranoside (PFB-FDglu) combined with flow cytometry and immunoblotting to determine GCase activity in specific immune cell populations isolated from PD participants relatively early in their clinical disease duration. We found that in the absence of GBA1 missense mutations, GCase activity was significantly reduced specifically in monocytes from PD participants compared to matched controls. Further work is now required to determine the extent to which monocyte GCase activity associates with PD pathogenesis.

Aarhus University
Media Contacts:
Marina Romero-Ramos – Aarhus University
Image Source:
The image is in the public domain.

Original Research: Closed access
“Alterations in Blood Monocyte Functions in Parkinson’s Disease”. Marina Romero-Ramos et al.
Movement Disorders doi:10.1002/mds.27815.


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