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Impaired Immune Cells May Contribute to Parkinson’s Progression, Study Suggests

monocytes Parkinson's

Reduced viability and impaired activity of monocytes — a subset of immune cells that circulate in the blood — may contribute to the progression of Parkinson’s disease.

That discovery, by researchers from Aarhus University in Denmark, may further understanding of the underlying mechanisms involved in the development and progression of this complex disease.

“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,” Marina Romero-Ramos, PhD, associate professor at Aarhus University and senior author of the study, said in a press release.

The study, “Alterations in Blood Monocyte Functions in Parkinson’s Disease,” was published in the journal Movement Disorders.

Parkinson’s disease is characterized by the accumulation of misfolded alpha-synuclein protein in the brain. This protein is toxic for brain cells, causing them to die and resulting in the characteristic motor symptoms associated with the disease.

However, the underlying mechanism that triggers this disease is not restricted to accumulation of alpha-synuclein. Indeed, growing evidence suggests that abnormal forms of the protein may originate in the gut, which then migrate to brain where it becomes toxic to brain cells.

These recent findings suggest that the immune system also may play a central role in this process, as circulating immune cells should be the first front to fight and destroy these potentially harmful abnormal proteins.

Researchers set up a new study to explore the role of circulating immune cells, in particular monocytes, in the development and progression of Parkinson’s disease.

Monocytes are a type of white blood cells that secrete several signaling molecules that are increased in Parkinson’s patients, and also are important mediators of the inflammatory response associated with diseases such as multiple sclerosis and stroke.

Researchers analyzed blood samples from 29 Parkinson’s patients and 20 age- and sex-matched volunteers without any sign of neurodegenerative disease.

Although at the time of sample collection no significant differences were observed between patients and controls, after culturing blood samples for two hours the team found that the count of viable cells was decreased significantly in female Parkinson’s patients compared to controls, with males showing a similar trend.

This reduction in viability also was observed in the number of monocytes, which were significantly lower in female patients than healthy female controls (5,780 vs. 12,813). This tendency also was observed in male patients (14,479 vs. 19,447).

In addition to the low viability of the cells, the team also found that monocytes of Parkinson’s patients were less responsive to stimuli. The cells showed less signs of activation when exposed to a pro-inflammatory chemical and to alpha-synuclein clumps.

“The lack of a response to stimulation suggests that the [Parkinson’s disease] patient cells are unresponsive and maybe even overstimulated, thus unable to respond to further stimulation,”  the researchers wrote.

Further experiments revealed that monocytes from healthy volunteers secreted the signaling molecule IL-10 when in the presence of alpha-synuclein fibrils, while monocytes from Parkinson’s patients did not. This difference suggested that patients’ monocytes were unable to respond to alpha-synuclein stimulation, suggesting a differential activation and functional status of these cells.

“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,” said Sara Konstantin Nissen, PhD, lead author of the study. “We believe such an additional drug might help to slow down the progression of the disease.”

These findings provide further support to the idea that Parkinson’s disease is more “than just a brain disorder,” which “requires a change of views among medical doctors and neurologists,” she said.

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Changes in Innate Immunity, Cell Waste Disposal Process Linked to Loss of Dopaminergic Neurons in Early Study

autophagy, immune response

Together with aging, the disruption of a cell’s waste disposal system and exaggerated immune responses can lead to the progressive loss of dopamine-producing neurons seen in diseases like Parkinson’s, according to new research in fruit flies.

The study, “Hyperactive Innate Immunity Causes Degeneration of Dopamine Neurons upon Altering Activity of Cdk5,” was published in the journal Cell Reports.

Immune responses in the brain may be triggered by pathogens (like microbes) and by its links to autophagy — a cellular process that uses organelles called lysosomes to clear waste products and toxic elements (like protein clumps), serving as the cell’s waste disposal system.

Autophagy is also an alternative route for cell death, and it is implicated in a variety of neurodegenerative diseases. However, whether autophagy favors cell survival or death — and whether it is an early triggering event in neurodegeneration or a “late-acting piece” of the mechanism — remains to be understood.

Aging, the greatest risk factor for most neurodegenerative diseases, impacts immunity and autophagy. But it is not yet known if changes in these processes due to aging have a direct role in neurodegeneration, or simply reflect “a correlation among the processes of normal aging,” the study notes.

Researchers at the National Institutes of Health (NIH) used fruit flies, whose autophagy and innate immunity have significant similarities to those of mammals, to study why immunity is altered during neurodegeneration and whether immune system changes are a cause or a consequence of neuronal dysfunction.

A hyperactive innate immune response has been suggested to impact neurodegeneration and aging in fruit flies. However, some studies found that anti-microbial peptides (AMPs) —  small molecules that are part of the innate immune response — may benefit the aging process. These small molecules also have potent antibiotic activity that can kill bacteria, virus, fungi, or cancer cells.

Altered activity of an enzyme called Cdk5 causes changes in fruit flies that highly resemble neurodegeneration in humans, including the loss of neurons linked to learning and memory, disrupted autophagy, sensitivity to oxidative stress, progressive motor dysfunction, and accelerated aging. Preclinical studies have suggested Cdk5 is important for early brain development and may be associated with diseases like Parkinson’s, amyotrophic lateral sclerosis, and Alzheimer’s.

In this study, researchers found that increasing or decreasing the expression of the activating subunit of Cdk5, called Cdk5-alpha, severely disrupted autophagy. Changes it effected were sufficient to trigger an immune system attack on dopamine-producing neurons — whose loss is a hallmark of Parkinson’s — in the animals. Neuronal death was particularly evident in older flies.

Subsequently, the team found that autophagy disruption caused a hyperactive innate immune response, as shown by increased expression of AMPs. This effect was independent of aging and suggested that “AMP overexpression likely plays a central role in the Cdk5α-associated loss of [dopamine-producing] neurons,” the researchers wrote.

Hyperactivation of the immune system was responsible for the age-dependent death of dopamine-producing neurons. Genetically blocking immune responses — either by reducing the expression of a transcription factor called Rel, or by restoring autophagy by increasing a transcription factor known as Mitf, a key regulator of lysosomal function — prevented the loss of these neurons. (Transcription factors are tiny proteins that regulate protein production.)

“These data reveal a simple, linear, dependent genetic pathway, encompassing both autophagy and innate immunity, which, while rigorously separable from aging, interacts with the effects of aging to lead to the degeneration of [dopamine-producing] neurons,” the scientists wrote.

The similarity of “genes, pathways, and cellular phenotypes” between flies and humans make it “very likely” that the processes revealed in this study “also play a central role in the development and progression of human [neurodegenerative disorders],” they concluded.

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LRRK2 Worthy Target of Research into Parkinson’s Therapies, Study Suggests

LRRK2 mutations

A perspective article summarizes what researchers have learned so far on the role of LRRK2 mutations in the development of Parkinson’s disease, and recommends the enzyme as a target for therapy development.

The report, “LRRK2 kinase in Parkinson’s disease,” was published in the journal Science.

Although the vast majority of Parkinson’s cases are idiopathic, or of unknown cause, LRRK2 mutations — the leading genetic cause of this disease — account for about 1 to 2 percent of all cases. Mutations in this gene increase the risk of developing Parkinson’s due to an LRRK2-increased risk of neuronal death.

About 20 LRRK2 mutations have been linked with the disease, and its incidence can be higher in some populations such as the Ashkenazi Jews and North African Berbers.

The LRRK2 gene codes for the enzyme leucine-rich repeat kinase 2 (LRKK2), a protein that modifies other proteins’ activities, including signaling, replication, and gene expression.

All LRRK2 disease-causing mutations lead to higher LRKK2 enzyme activity; as such, researchers believe that inhibiting or blocking its activity can be used as a potential therapeutic target.

In fact, two LRRK2 inhibitors are currently being evaluated to treat Parkinson’s in two Phase 1 trials. The experimental therapies, called DNL-201 and DNL-151, are being developed by Denali Therapeutics. So far, DNL201 has stopped an average 90 percent of LRRK2 kinase activity at its highest concentration. When the drug’s levels dropped to the lowest concentration, it still inhibited on average 50 percent of such activity.

Studying the effects of LRRK2 mutations also provides an opportunity to better understand how Parkinson’s disease unravels, the study notes.

Recent advances support that LRRK2 modifies a group of proteins, called Rab GTPases, that regulate diverse cellular processes.

These proteins play important roles in immune responses and vesicular trafficking — the transport and recycling of materials inside the cell through a system of vesicles.

Disruption of RAB-related transport may also promote accumulation of alpha-synuclein aggregates inside neurons, a hallmark of Parkinson’s disease.

LRRK2 is also thought to be linked to inflammation, a process that plays an important part in disease development. LRRK2  is highly expressed  in several immune system cells, including macrophages,  monocytes, and neutrophils. 

“Research indicates that, in early  life, increased LRRK2 activity may protect against opportunistic  pathogenic infection but then later increases the risk of developing Parkinson’s disease,” the researchers write.

LRRK2-associated Parkinson’s closely resembles idiopathic disease in terms of its late age of onset and  symptoms. But several factors seem to influence the ability of LRRK2 mutations to cause disease, including age and the type of mutation.

People carrying some types of mutations, such as G2019S, may never develop Parkinson’s, while nearly all of those bearing the R1441G mutation eventually will.

One case report in twins carrying the same LRRK2 mutation found only one developed Parkinson’s. This highlights the importance of environmental factors and lifestyle (smoking, exercise, diet), as well as the gut microbiome and infection in the development of LRRK2-dependent Parkinson’s.

“However, for now, the most exciting question will be whether LRRK2 inhibitors have disease-modifying effects in PD patients with LRRK2 mutations,” the researchers wrote.

The authors stress that preclinical studies in animal models indicate potential toxicity of LRRK2 inhibitors to the lungs and kidneys, and recommend special attention be taken to monitor toxicity in these organs in human clinical trials. 

Given the role of LRRK2 in fighting infections, it will also be important to establish whether blocking LRRK2 increases the risk of opportunistic infections. But, overall, the scientists believe that “LRRK2 is a possible therapeutic target for Parkinson’s disease.”

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Source: Parkinson's News Today