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Deleting Specific Region of Alpha-Synuclein Protein May Prevent Parkinson’s Symptoms, Fly Study Suggests

alpha-synuclein study

By deleting a section of alpha-synuclein, a protein that forms damaging clumps in the brains of Parkinson’s disease patients, researchers were able to prevent Parkinson’s-like symptoms in fruit flies, a study reports.

The study, “The Non-amyloidal Component Region of α-Synuclein Is Important for α-Synuclein Transport Within Axons,” was published in the journal Frontiers in Cellular Neuroscience.

Parkinson’s disease is characterized by the buildup of toxic forms of the alpha-synuclein protein within nerve cells, or neurons, causing clumps and blockages that stop these cells from functioning correctly.

Proper transport of alpha-synuclein is thought to be crucial for its localization and function at the synapse — the junction between two nerve cells that allows them to communicate.

A particular section of the alpha-synuclein protein called the non-amyloidal component (NAC) has been linked to the formation of these clumps.

“Previous work has shown that defects in long distance transport within [neurons] occur early in PD [Parkinson’s disease], but how such defects contribute to PD is unknown,” the researchers wrote.

To understand whether the NAC region is involved in alpha-synuclein’s motility, researchers used fruit fly larvae genetically engineered to express higher levels of the human form of alpha-synuclein protein. They then deleted the NAC region in these flies’ alpha-synuclein and studied the resulting animals for signs of Parkinson’s disease.

They observed that excess alpha-synuclein accumulated in clumps and disrupted the normal transport of other proteins along neuronal axons — long projections that conduct electrical impulses away from the neuron’s cell body toward another nerve cell.

To understand how deleting the NAC region affected motor symptoms, the scientists measured how fast the flies were able to crawl. Flies with too much alpha-synuclein crawled at a significantly slower speed than normal flies. This was likely due to the blockages that occur in the neurons. The higher the levels of alpha-synuclein aggregation within neurons, the more aggravated these symptoms became.

Flies that produced too much alpha-synuclein typically showed Parkinson’s-like symptoms, but if the NAC section of alpha-synuclein was deleted, the protein no longer formed clumps within neurons and crawling speeds returned to normal.

“Our work highlights a potential early treatment strategy for Parkinson’s disease that would leverage the use of deletion of the NAC region,” lead investigator Shermali Gunawardena, PhD, associate professor of biological sciences from the University at Buffalo, said in a press release.

Gunawardena and her team were also interested in how alpha-synuclein gets transported along neuron cells. The researchers thought the movement of alpha-synuclein could be linked to how it interacts with neuronal cell membranes.

They found that when they deleted the NAC region, less alpha-synuclein was able to bind to neuronal membranes, preventing it from being transported along axons. Instead, the alpha-synuclein stayed in the wider sections of neurons and did not cause aggregates.

“While further study is needed to isolate the structural details of how the NAC region facilitates [alpha]-syn protein–protein interactions on membranes, taken together our observations indicate that the NAC region plays an essential role in [alpha]-syn associations on axonal membranes and its transport within axons under physiological conditions,” the researchers wrote.

Overall, the work identifies a pathway that can be targeted in early-stage Parkinson’s disease before symptoms such as neuron loss and behavior changes occur.

“One reason this study is important is because it shows rescue of [alpha]-synuclein aggregates, synaptic morphological defects and locomotion defects seen in Parkinson’s disease in the context of a whole organism,” Gunawardena said.

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Gut Bacteria Protects Against Alpha-Synuclein Buildup in Nerve Cells in Worm Model, Study Shows

alpha-synuclein

A common gut bacteria called Bacilus subtilis (B. subtilis), which aids in digestion, shows the potential to counteract the misfolded alpha-synuclein protein central to Parkinson’s disease, according to a new study.

B. subtilis, a so-called “good” bacteria, slowed the buildup of this protein in the nerve cells of worms engineered to produce human alpha-synuclein, and was found to clear some of its harmful clumps.

The study, Probiotic Bacilus subtilis Protects against α-Synuclein Aggregation in C. elegans,”was published in Cell Reports.

In order to function correctly in the body, proteins are folded into specific shapes, like making biological origami cranes. In Parkinson’s, the alpha-synuclein in nerve cells misfolds and then clumps together into structures that are toxic to these neurons.

Several recent studies have drawn links between what happens in the gut and in the brain. That led researchers at the University of Edinburgh and the University of Dundee, both in the U.K., to ask whether changes in the gut could affect alpha-synuclein aggregation, or buildup.

As a proof-of-principle — a study designed to evaluate whether further research should take place — the team fed various over-the-counter probiotics, or so-called “healthy bacteria,” to a roundworm model of synucleinopathy. Synucleinopathy are neurodegenerative diseases such as Parkinson’s that are characterized by the abnormal buildup of alpha-synuclein protein in nerve cells.

The goal was to see which, if any, of the pribiotics could alter the formation of these toxic alpha-synuclein clumps in the roundworm model, known as C. elegans.

Worms raised on a specific strain of B. subtilis, called PXN21, showed a near-total absence of these clumps, compared with worms on other diets. B. subtilis also managed to clear away clumps that had already formed in older worms, which were later switched to the B. subtilis diet. The probiotic’s protective effects lasted over the worms’ lifespan and improved locomotion defects associated with the toxic clumps.

Importantly, the observed anti-aggregation effect was found to be a general property of the B. subtilis species, and not only of the particular strain used.

B. subtilis’s capacity to protect against alpha-synuclein aggregation later in adulthood was partly mediated by the action of the DAF-16 gene, the worm equivalent of the human FOXO1 gene, and also by the bacteria’s capacity to produce a biofilm matrix — a three-dimensional bacterial community embedded in a self-produced matrix.

However, this mechanism was not the same one responsible for the strong protection observed in early adults. The team found that protection was partially mediated by the action of an active and stable bacterial metabolite.

Importantly, in both early and older adults, B. subtilis changed how the worms processed fats called sphingolipids. More specifically, B. subtilis produced chemicals that changed how certain enzymes — ceramide synthase, acid sphingomyelinase and serine palmitoyltransferase — processed sphingolipids.

Previous studies have suggested that sphingolipid metabolism modifies alpha-synuclein pathology, or disease manifestation, in Parkinson’s.

While encouraging, these findings are quite early and must be corroborated in other settings. Mice, a model organism much more closely related to humans than worms, will be a logical next step. If all goes well and a probiotic-based Parkinson’s therapy makes it to clinical trials, these could be fast-tracked, as probiotic B. subtilis is already commercially available.

“The results from this study are exciting as they show a link between bacteria in the gut and the protein at the heart of Parkinson’s, alpha-synuclein,” Beckie Port, research manager at Parkinson’s UK, one of the study’s funders, said in a press release.

“Studies that identify bacteria that are beneficial in Parkinson’s have the potential to not only improve symptoms but could even protect people from developing the condition in the first place,” Port said.

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What I Learned from Attending a Parkinson’s Symposium

symposium

I recently attended a symposium titled “Shaping the Future” at the University of Delaware. The event, organized by the Johns Hopkins Udall Center, was patient-oriented, so rather than their peers, the expert speakers were addressing people with Parkinson’s.

Looking around the room, I noticed that the audience included people of various ages and degrees of progression. However, we all had one thing in common: hope for a brighter future. I came prepared with my iPad, ready to learn and take notes for this column.

Presentations covered a wide range of subjects, including gut models, cognitive and psychiatric aspects, disease-modifying versus symptomatic therapy, nutrition, pathophysiology, biomarkers, and genetic mutations.

The highlights

  • Biomarkers are like dominoes — a “cascade” leads to cell death. Remove a domino and stop the process. This video explains the concept.
  • You may have heard of alpha-synuclein. I learned that it’s a “bad protein” and potential biomarker when “misfolded” in the development of Parkinson’s.
  • The impact of depression on quality of life in those with Parkinson’s is almost twice the impact of motor impairments.
  • Protein and L-dopa compete for the same receptor in the digestive tract to get into the blood and the brain.
  • Exercise can be a disease-modifying therapy. This presentation looked at a 2017 study that used the Unified Parkinson’s Disease Rating Scale. It found that Parkinson’s patients who exercised at high intensity three times a week for six months had no progression compared with a moderate exercise group whose disease worsened by 1.5 points and a no-exercise group who had a three-point decline.

These are my takeaways from the symposium. If you’d like to explore further, the slide presentations are available here.

Symposiums may not be for everyone; the content can be clinical and hard to understand. However, we should be encouraged by and grateful for the fantastic researchers who are working on finding new treatments and a cure for this disease.

Above all, we should be hopeful that their collective efforts may identify the “dominoes.”

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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Phase 1 Trial Opens into Potential Parkinson’s Therapy, Anle138b

Phase 1 trial opens

A Phase 1 clinical trial of MODAG Neuroscience Solutions’ lead candidate anle138b is now underway and recruiting healthy participants at its one site in Nottingham, England, to study the compound’s safety.

The small molecule is being developed to treat multiple system atrophy (MSA), but holds the potential to be used in other diseases caused by clumping of the protein alpha-synuclein, such as Parkinson’s disease.

“With the start of this trial, we are on track to run the tests necessary to bring anle138b one step closer to patients,” Torsten Matthias, PhD, chief executive officer of MODAG, said in a press release.

Many neurodegenerative disorders involve the aggregation of misfolded (harmful) proteins in the brain. Anle138b works by binding to harmful forms of alpha-synuclein — a key protein involved in Parkinson’s disease — to clear the brain of existing clumps and to prevent new clumps, also known as Lewy bodies, from forming.

The compound has been shown to reduce the buildup of these toxic clumps and delay disease progression in models of MSA, Parkinson’s, and Alzheimer’s disease. Moreover, anle138b was found to reverse Parkinson’s-related motor symptoms in mice models of the neurodegenerative disorder.

This Phase 1 study’s primary goal is to evaluate the safety and tolerability of oral anle138b in healthy volunteers. Secondary objectives include dose-finding evaluations and assessments of its pharmacokinetics  — essentially how a compound is absorbed, distributed, metabolized, and excreted by the body.

Recruitment is ongoing and being overseen by Quotient Sciences in Nottingham.

“Anle138b has the potential to become a tangible treatment option to stop MSA, a highly underserved indication, in its tracks. MSA patients are severely impacted by progressing movement, balance and autonomic function impairments and as with many neurodegenerative diseases, there are no disease-halting treatment options available,” said Johannes Levin, MD, chief medical officer of MODAG.

“If successful, the Phase 1 trial also opens the opportunity for MODAG to investigate anle138b in other Parkinsonian disorders and Parkinson’s itself,” Levin added.

The biotech company has already secured a worldwide patent for anle138b.

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Immunotherapy Reduced Alpha-synuclein Clumps, Improved Dopamine Levels in Parkinson’s Mouse Model

antibodies and alpha-synuclein

Antibodies that selectively target the misfolded form of the alpha-synuclein protein — that which underlies the development of Parkinson’s disease — reduced the formation of alpha-synuclein clumps and improved dopamine levels in a mouse model. 

The study with that finding also provided a framework for screening  antibodies (immunotherapies) that target alpha-synuclein to identify those with the best therapeutic properties.

The study, “Characterization of novel conformation-selective α-synuclein antibodies as potential immunotherapeutic agents for Parkinson’s disease,” was published in the journal Neurobiology of Disease.

Nerve cell damage in Parkinson’s disease is caused by the build-up of toxic forms of the protein alpha-synuclein that forms clumps of misfolded proteins known as Lewy bodies.

Studies have found that reducing misfolded alpha-synuclein may be an effective therapeutic strategy for treating the disease. 

One idea is to create antibodies that specifically target misfolded alpha-synuclein, avoiding the problems associated with reducing the levels of properly folded, fully functioning alpha-synuclein.

This was the approach taken by a group of researchers at the University of Pennsylvania in Philadelphia. Their first step was to create and isolate antibodies that were highly selective for misfolded alpha-synuclein, then test the best candidate in a Parkinson’s mouse model to find out if the antibody had therapeutic potential. 

To create these antibodies, mice were injected with misfolded alpha-synuclein and the antibodies generated during the immune response were isolated and screened to find the best candidate. 

Brain sections from Parkinson’s patients with high numbers of Lewy bodies first were used to identify antibodies that selected pathological (disease-associated) alpha-synuclein.

The team hoped these antibodies may be used in humans, so those that bound to both mouse and human alpha-synuclein were preferred. 

Further testing found antibodies that bound to only the misfolded form of alpha-synuclein, but not the normal form. 

The final screen was to identify a candidate that prevented the development of alpha-synuclein pathology in neurons. Mouse neurons were treated with the previously selected antibodies and were exposed to toxic forms of human alpha-synuclein protein. The highest performing antibody, named Syn9048, reduced pathology [disease manifestation] by 97%.

As antibody treatments for Parkinson’s are likely to be given after symptoms emerge (when brain disease is already established), a mouse model was chosen to test the effectiveness of Syn9048 to reduce disease and rescue nerve cell function. 

Mice were injected with misfolded alpha-synuclein, which triggered nerve cell loss in the same areas of the brain as seen in Parkinson’s patients. Then they were given Syn9048 or a control antibody every week for six months.  

All mice gained weight in a similar manner, showing that the therapy was well-tolerated.

Examination of the mouse brains showed that Syn9048 reduced the aggregation of alpha-synuclein in areas related to Parkinson’s disease. 

Although Syn9048 was not successful in rescuing cells responsible for producing dopamine (dopaminergic), it increased dopamine levels in the brain, which suggested that the reduction of alpha-synuclein pathology may improve the function of remaining dopamine-producing neurons.

“Our study suggests that immunotherapy will not likely reverse existing pathology, but may halt the spread of pathology through the brain, preventing further motor and cognitive decline,” the researchers wrote.

“Future studies assessing brain-wide spread patterns could help predict the maximal possible benefit of immunotherapy and could be used to determine when during disease progression immunotherapy would need to be administered to be most efficacious,” they added. 

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3D Structure of Brain Alpha-Synuclein More Heterogeneous Than Previously Thought, New Study Reports

Alpha-synuclein aggregates

Clumps, or aggregates of alpha-synuclein protein in the brain, a hallmark of Parkinon’s disease, are more heterogeneous than previously thought, according to a new study. Moreover, the protein’s 3D-structure is different in Parkinson’s patients as compared with lab-made versions.

These findings may hold implications for the development of treatments targeting alpha-synuclein, as new therapies need to take into account what kind of shape the protein adopts within nerve cell aggregates.

The study, “Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts,” was published in the journal Nature Communications.

Parkinson’s disease and multisystem atrophy (MSA) belong to a class of neurodegenerative disorders called synucleinopathies that are characterized by the accumulation of misfolded alpha-synuclein proteins.

These abnormal protein aggregates are toxic, and mainly accumulate in Parkinson’s disease in dopamine-producing nerve cells — those responsible for releasing the neurotransmitter dopamine. Dopamine is a chemical messenger that allows nerve cells to communicate and, among other functions, helps regulate movement.

“These deposits successively appear in various areas of the brain. They are a disease hallmark,” Markus Zweckstetter, a professor and research leader at the German Center for Neurodegenerative Diseases (DZNE) and the Max Planck Institute for Biophysical Chemistry (MPI-BPC), said in a press release.

“There is evidence that these aggregates are harmful to neurons and promote disease progression,” he added.

Given the key role of alpha-synuclein aggregates in the development and progression of Parkinson’s disease and other neurodegenerative disorders, these protein clumps represent potential therapeutic targets. Treatments could either prevent the aggregates from forming or eventually clear them from within the brain.

To identify which specific sites on alpha-synuclein can be targeted by potential therapies, researchers need to have an understanding of the complex structure these proteins acquire once they form aggregates. However, current knowledge is limited to aggregates that are established in the lab, in a test tube, which may be different from what actually happens in patient’s brains.

“Previous studies investigated the molecular structure of aggregates that were synthesized in a test tube. We asked ourselves how well such artificially produced specimens reflect the patient’s situation. That is why we studied aggregates generated from tissue samples from patients,” Zweckstetter said.

Zweckstetter and his team collaborated with researchers in Australia and South Korea to analyze the structure of alpha-synuclein aggregates derived from brain samples of individuals with Parkinson’s disease (five patients) and MSA (five patients). They then compared them to those artificially produced in the lab.

The brain samples were taken from a region of the brain called the amygdala, which plays a key role in regulating emotions and memory, and is known to be affected in Parkinson’s.

The brain-derived alpha-synuclein aggregates were structurally different to those generated in the lab, the researchers found.

Alpha-synuclein proteins found within aggregates contained a structure known as “beta sheets”— whose orientation was of relevance — and their molecular backbone was twisted in a way that the protein was mainly two-dimensional. That is in contrast with a three-dimensional structure.

Within aggregates, alpha-synuclein proteins stick together in layers. However, this folding was not seen across the whole protein, with certain areas remaining unstructured.

The scientists also found that alpha-synuclein aggregates from Parkinson’s patients showed more diverse structures than those from people with MSA. That may reflect “the greater variability of disease phenotypes [manifestations] evident in PD [Parkinson’s disease]”, the researchers said.

“Proteins of MSA [multisystem atrophy] patients differed from those of Parkinson’s patients. If one looks at the data more closely, you notice that the proteins of the MSA patients all had a largely similar shape. The proteins of the patients with Parkinson’s were more heterogeneous. When comparing the proteins of individual Parkinson’s patients, there is a certain structural diversity,” said Timo Strohäker, first author of the study.

The researchers noted that “although larger patient numbers are required to link [alpha-synuclein] aggregate structure with symptomatic heterogeneity of the disease, our data point to the possibility that [alpha-synuclein] aggregate structure could be specific for individual patients or certain subtypes of [Parkinson’s disease].”

The findings of differently structured alpha-synuclein proteins among different Parkinson’s patients contrasts with current hypotheses theorizing that each neurodegenerative disease is associated with a single, defined structure of alpha-synuclein protein.

“The variability of Parkinson’s disease could be related to differences in the folding of aggregated alpha-synuclein,” Zweckstetter said. “This would be in contrast to the ‘one disease-one strain’ hypothesis, that is to say that Parkinson’s disease is associated with one, clearly defined aggregate form.”

“However, in view of our relatively small sample of five patients, this is just a guess,” he added. “Yet, our results certainly prove that studies with tissue samples from patients are necessary to complement lab experiments in a sensible way.”

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Defects in Molecular Chaperones May Help Drive Lewy Body Formation in Parkinson’s, Study Finds

Lewy bodies, Parkinson's

Defects in chaperone proteins that interact with alpha-synuclein and work as a type of “molecular bodyguard” may help drive the formation of Lewy bodies, which are a hallmark of Parkinson’s disease.

The findings were published in the journal Nature, in a study titled “Regulation of α-synuclein by chaperones in mammalian cells.”

Lewy bodies are protein aggregates — basically clumps of improperly folded protein — that are often found in the brains of people with Parkinson’s disease. The main protein that forms Lewy bodies is alpha-synuclein. However, what drives alpha-synuclein to form Lewy bodies is an area of ongoing investigation, which may open avenues for the development of treatments.

In this new study, researchers investigated not alpha-synuclein itself but its so-called chaperones. Traditionally, “chaperone” proteins are thought of as proteins that temporarily bind to other proteins to help them fold properly.

The researchers screened dozens of known chaperones in detail to see whether they could interact with alpha-synuclein.

“[W]e have discovered a specific pattern that determines the exact interaction site of [alpha]-synuclein with chaperones,” study co-author Sebastian Hiller, a professor at the University of Basel, said in a press release.

Hiller and colleagues identified six that can interact with alpha-synuclein. Many of these were heat shock proteins, a well-established family of chaperones.

The researchers then set about inhibiting the interaction between alpha-synuclein and its chaperones. They found that, upon blocking this interaction, chaperones could no longer act as “molecular bodyguards” and protect alpha-synuclein, which tended to accumulate in the mitochondria — cells’ powerhouses — where it aggregated, forming clumps of protein that bear a striking resemblance to Lewy bodies.

“Our results establish a master regulatory mechanism of [alpha]-synuclein function and aggregation in mammalian cells,” the researchers said.

While this study doesn’t definitively prove that abnormally functioning chaperones are responsible for Parkinson’s, it suggests that the chaperone system plays a role in the progression of the disease — and, as such, it could be a target for future therapies.

These findings also have implications for the broader biological understanding of what chaperone proteins do.

“With our work, we are questioning the paradigm that the function of chaperones is solely to help proteins to fold into their proper shape,” Hiller said. “Chaperones do far more than just assist in protein folding. They control cellular processes by flexibly interacting with a variety of proteins and accompanying them like a shadow.”

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Alpha-synuclein Blood Levels May Be Biomarker for Parkinson’s with Motor Symptoms

blood biomarkers of disease

Measuring the levels of alpha-synuclein in red blood cells can reliably distinguish people with Parkinson’s disease and evident motor symptoms from healthy individuals, and could serve as a diagnostic biomarker, a study reports.

These levels in Parkinson’s patients with symptoms of dementia, however, did not measurably differ from healthy people serving as a control group.

The study, “α‐Synuclein in blood cells differentiates Parkinson’s disease from healthy controls,” was published in the journal Annals of Clinical and Translational Neurology.

The hallmark of Parkinson’s disease is the build-up of the protein alpha-synuclein in the brain, which goes on to form clumps of misfolded proteins known as Lewy bodies that damage nerve cells. 

Alpha-synuclein levels in the blood have been evaluated as a biomarker for Parkinson’s, as the ease and accessibility of a blood test would help with treatment during the course of the disease.

Low levels of misfolded alpha-synuclein — originating in neurons — have been found in the blood of Parkinson’s patients and are associated with disease progression.  

However, the primary source of alpha-synuclein in the blood comes from red blood cells, and little is known about the relevance of this source of alpha-synuclein and disease pathology.

To determine if alpha-synuclein levels in blood cells could be a biomarker for Parkinson’s, researchers at The Hebrew University‐Hadassah Medical School in Jerusalem tested the levels of alpha-synuclein in red blood cells isolated from 46 people with Parkinson’s. They compared them to those from 45 healthy controls. 

These blood samples were obtained from The BioFIND Study, an observational clinical study designed to discover and confirm Parkinson’s biomarkers. 

The overall levels of blood cells’ alpha-synuclein and misfolded alpha-synuclein were determined, as were known markers of Parkinson’s: phosphorylated and oxidized forms of alpha-synuclein. 

Alpha-synuclein phosphorylation — a chemical modification in which a phosphate group is added to the protein — and oxidation — which modifies the protein’s side chains —  are known to occur in Parkinson’s disease, and are thought to be critical steps in disease progression. They enhance alpha-synuclein’s toxicity, possibly by increasing the formation of alpha-synuclein aggregates (clumps).

Parkinson’s patients were divided into two groups: 32 people with motor symptoms and 14 with symptoms of dementia as determined by the Montreal Cognitive Assessment. Blood cell alpha-synuclein levels of these two groups were then compared to healthy controls. 

While the average levels of blood cell alpha-synuclein from both Parkinson’s groups combined were slightly lower than those of controls, alpha-synuclein levels in patients with motor symptoms were significantly higher than both controls and patients with dementia symptoms.

The levels of misfolded alpha-synuclein, in addition to its phosphorylated form, followed the same pattern — both were significantly higher in motor symptom patients and were found to correlate with disease severity. 

The test for oxidized alpha-synuclein found no differences between groups.

To validate these three tests as potential Parkinson’s biomarkers, the team collected a second set of blood samples from the Hadassah hospital, comprising 35 Parkinson’s patients with motor symptoms and 28 healthy controls. The levels of total, misfolded, and phosphorylated alpha-synuclein were measured.

This analysis confirmed that these three markers were able to reliably distinguish between Parkinson’s patients with motor symptoms and those without the disease. 

“We conclude that blood cells expressed [alpha-synuclein] can differentiate [Parkinson’s with motor symptoms] and [healthy controls] with a high degree of accuracy. It provides a reliable classification rate, correlates with the severity of disease and is reproducible,” the researchers wrote.

“A longitudinal study that will determine whether alterations in blood cell-expressed [alpha-synuclein] forms are associated with disease progression is required,” they added.

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Early Parkinson’s Detection Technique Validated in Prion Animal Models, Study Shows

Parkinson's and IL-17A

The early detection of diseases characterized by protein misfolding and aggregation, such as Parkinson’s disease, moved one step closer by the validation in animal models of a sensitive technique to capture and analyze misfolded and aggregated proteins in the blood quickly and efficiently.

The technique was validated by showing that prions — a misfolded protein that causes prion disease — can be captured, isolated, analyzed, and transferred between species, a study has shown. 

The study, “Enhanced detection of prion infectivity from blood by preanalytical enrichment with peptoid-conjugated beads,” was published in the journal PLOS ONE

Parkinson’s disease is caused by the damage or death of dopamine-producing nerve cells (neurons) in a region of the brain that controls balance and movement. 

A hallmark of the disease is the accumulation of a misfolded form of a protein called alpha-synuclein, a protein typically located near the tips of nerve cells and associated with the regulation of dopamine release.

To function properly, a protein must fold into a specific shape. However, when alpha-synuclein does not fold properly or misfolds, it clumps together to form plaques in the brain, causing cell damage and death. 

A misfolded protein is also the causative agent in transmissible spongiform encephalopathies or prion diseases. The most famous prion disease is bovine spongiform encephalopathy (BSE) — otherwise known as “mad cow disease” — where misfolded proteins, called prions, from cows in the food chain or infected people trigger other proteins in the brain to misfold and aggregate. 

The outbreak of BSE in European cattle and several hundred associated cases in humans in the late 1980s has spawned efforts to find methods to detect the very low levels of prions in the blood of infected people.

One method that has been successful, called the misfolded protein assay (MPA), involved selectively capturing prions using molecules that mimic the parts of the prion that bind together to form aggregates.

These mimicking molecules — known as peptoids — are composed of modified versions of the naturally occurring amino acids (building blocks) of prion proteins.

The peptoids are fixed to magnetic beads (PSR1) which can be mixed, then easily isolated from blood and tested for prions. One of the advantages of MPA over other tests is that it can analyze large numbers of samples quickly and for less cost.

The MPA technique was used to successfully identify prions in a patient with prion disease when other tests failed. In addition, the utility to capture and analyze prions extends beyond prion diseases to other conditions characterized by protein misfolding, such as Parkinson’s, and may provide a means to diagnose the disease years before symptoms arise.

Before MPA can be used in humans, efficacy must be determined in animal models, so researchers designed a study to test the reliability and sensitively of MPA to detect prions using mouse and hamster models of prion disease.

Brain tissue from hamsters bred to develop prion disease was injected into 40 healthy hamsters, and five control hamsters were inoculated with brain tissue from non-infectious hamsters. 

Blood was withdrawn from the hamsters before and after the appearance of prion disease symptoms, namely ataxia (lack of muscle control), loss of appetite, and poor grooming. 

The PSR1 magnetic beads were mixed with these blood samples and were washed to remove extra proteins. The washed beads were then injected into a special breed of mice — Tg(SHaPrP) — that expressed the normal form of hamster prion protein. If infectious misfolded prions were captured by the beads, they would trigger the normal form of hamster prion protein to misfold in the mice and lead to prion disease. 

The results demonstrated that in mice that were inoculated with beads mixed with blood from hamsters with prion disease symptoms, nearly all of the mice (25 of 28 injected) developed prion disease. Prion disease was confirmed by examining mice brain tissue under a microscope. 

In contrast, mice injected with beads mixed with non-symptomatic hamster blood (or controls) did not develop signs of prion disease. 

“We therefore conclude that PSR1 beads highly efficiently capture prion infectivity from plasma from presymptomatic and symptomatic cases and are able to transmit infectivity to Tg(SHaPrP) mice,” the researchers wrote. “We found that the readout of the peptoid-based misfolded protein assay (MPA) correlates closely with prion infectivity in vivo, thereby validating the MPA as a simple, quantitative, and sensitive surrogate indicator of the presence of prions.” 

Ronald Zuckermann, PhD, study co-author and senior scientist at the Lawrence Berkeley National Laboratory Molecular Foundry, in Berkeley, California, noted in a news release, “Our peptoid beads have the ability to detect the misfolded proteins that act as infectious agents, so it could have a significant impact in the realm of prion diseases, but we have also shown that it can seek out the large aggregated proteins that are the disease agents in Alzheimer’s and Parkinson’s diseases, among others.” 

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Mouse-brain Computer Model Tracks Spread of Alpha-synuclein in Parkinson’s

alpha-synuclein protein

Researchers have developed a computer model of the mouse brain that integrates both Parkinson’s disease-related genetic risk factors and the animals’ brain networks to help them understand how abnormal alpha-synuclein protein spreads and how neurodegeneration progresses.

The study, “Spread of α-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis,” was published in Nature Neuroscience. The research was funded by the National Institute on Aging.

In recent years, mutations in the gene coding for the leucine-rich repeat kinase 2 (LRRK2) have been identified as the most common cause of genetic Parkinson’s, accounting for 1%–2% of all cases and up to 40% in some ethnic groups.

Mutations in this gene usually result in the malfunctioning of lysosomes (special compartments within cells that digest and recycle different types of molecules).

Lysosomal dysfunction is involved in the formation of Lewy body protein aggregates and, therefore, neurodegeneration. One of the most common mutations found in the LRRK2 gene is called G2019S and occurs when a glycine is substituted by a serine at amino acid 2019. (Amino acids are the proteins’ building blocks.)

Evidence indicates that in neurodegenerative diseases misfolded proteins, such as alpha-synuclein, spread through the brain along anatomically connected networks, inducing progressive decline. In the laboratory, scientists have been able to reproduce the cell-to-cell transmission of disease-related molecules and consequent neuronal death.

However, it is still unclear which factors make cells vulnerable to disease and regulate the spread of misfolded.

To better understand the spatiotemporal pattern of misfolded protein spreading, researchers at the University of Pennsylvania have combined quantitative mapping of disease with network modeling of the mouse brain.

Researchers injected a toxic form of the alpha-synuclein protein into the dorsal striatum, a brain area involved in motor control, of 3-month-old mice and evaluated the protein buildup at 1, 3, and 6 months post-injection.

Alpha-synuclein was found to distinctly accumulate in different brain regions, including the substantia nigra, which is severely affected in Parkinson’s disease, the hippocampus (involved in learning and memory), dorsal striatum (involved in voluntary movement), motor cortex and somatosensory cortex (processes sensations). Higher concentrations were discovered in the brain regions connected to the injection site.

Three months after injection, alpha-synuclein had produced Lewy body-like cellular inclusions.

To understand how this protein spread in a context of disease, scientists developed a computer-based model using a map of the mouse brain and its inner neuronal pathways.

When the team compared the protein accumulations from the mouse brains to the computational model, alpha-synuclein was found to spread primarily along specific brain pathways. Nonetheless, some areas with alpha-synuclein buildup were not associated with those pathways, but instead to higher levels of SNCA, the gene that provides instructions for alpha-synuclein.

That discovery led the team to incorporate genetic variables into the  computer model.

Although the LRRK2 G2019S mutation is a known risk factor for developing Parkinson’s, mutated animals showed similar alpha-synuclein spreading patterns as non-mutated mice. Still, there were large regional differences in the degree and rate of alpha-synuclein pathology accumulation, namely within the hippocampus, substantia nigra and primary somatosensory cortex.

Importantly, mutated mice had no accumulation of alpha-synuclein if they were not injected with abnormal alpha-synuclein first, suggesting LRRK2 G2019S may not initiate disease by itself, but rather alter neuronal vulnerability to the disorder.

This hypothesis was confirmed when scientists observed a greater buildup of alpha-synuclein in specific brains regions of LRRK2 G2019S mutated mice, while those same areas were less vulnerable to abnormal cellular changes in non-mutated animals.

In conclusion, a brain network computer-based model that visualizes alpha-synuclein spreading and takes into account both brain connectivity and genetic background may become a reliable way to test different protein spreading scenarios. In the long-run, that should help investigators to better understand the processes behind neurodegenerative diseases such as Parkinson’s.

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