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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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Mutations in Alpha-Synuclein Speed Protein Clumping in Familial Parkinson’s and Affect Severity, Study Finds

alpha-synuclein and A53T

A detailed analysis of alpha-synuclein — a key protein involved in Parkinson’s — revealed how variants of this protein change over time, allowing researchers to identify the initial stages of protein aggregation involved in early onset disease.

These findings provide new insights into how genetic mutations — especially the point mutation A53T — can contribute to familial Parkinson’s, and into understanding why this disease form manifests earlier and is often more severe than sporadic (of unknown cause) Parkinson’s.

The study, “Alpha-synuclein stepwise aggregation reveals features of an early onset mutation in Parkinson’s disease,” was published in the journal Communications Biology.

Parkinson’s is largely a sporadic disease, with 15% to 25% of all cases linked to inherited genetic mutations. One of the first genes identified as directly associated with Parkinson’s, leading to early onset disease, was the alpha-synuclein coding gene SNCA.

It is widely accepted that alpha-synuclein is an important element that drives nerve cell death across several human neurodegenerative disorders, including Parkinson’s and dementia with Lewy bodies. Its toxic effect is, at least in part, tied to the formation of abnormal protein aggregates or clumps.

Despite available knowledge of the damaging impact alpha-synuclein clumps have on nerve cells, the process by which alpha-synuclein changes from a single protein structure into an aggregate form remains poorly understood.

Researchers at the Federal University of Rio de Janeiro (UFRJ) in Brazil conducted a series of biochemical, kinetic, and structural studies to address this gap.

They evaluated in detail the behavior of alpha-synuclein — both its normal form as well as mutated versions found in people with familial Parkinson’s — and its ability to form toxic clumps.

“The conversion from one protein stage to the other takes place slowly. The intermediate structures and the amyloid aggregates accumulate over time in the brain. So far, we don’t know which species cause the symptoms and toxicity to cells,” Guilherme A. P. de Oliveira, a professor at UFRJ and the study’s lead author, said in a press release.

“If we understand the protein species forming during the early stages of disease conversion, we can propose new therapies for disease detection before the symptoms appear.”

Results showed that the versions of alpha-synuclein carrying A53T, A30P, or E46K point mutations were able to from small aggregates (known as oligomers) at a much faster rate than a normal version of the protein.

Of note, point mutations are genetic alterations where a single nucleotide — the building blocks of DNA — is changed, inserted, or deleted from a sequence of DNA. If you think of DNA as a Lego train, a point mutation would be the same as changing, adding, or taking out a single piece. 

Next, the researchers used cutting-edge imaging techniques to visualize for the first time, in detail and over time, all the elements involved in the expansion of alpha-synuclein aggregates — their transition from early oligomers to intermediate fibrils to late filaments.

“By (…) acquiring advanced electron microscope images, we are able to better understand these wrong protein associations in their native environment and [potentially find] ways to avoid their formation,” Oliveira said.

This approach showed that the different protein versions give rise to structurally different fibrils.

The expansion of fibrils into long filaments was found to be dependent on the ability of alpha-synuclein to continue to recruit available oligomers.

Interestingly, the A53T point mutated version was able to overcome some of the limits on protein clumping imposed by the surrounding environment, and for which normal alpha-synuclein showed a sensitivity. This suggests that A53T mutations give alpha-synuclein a greater potential to promote aggregation and induce faster spreading of its toxic clumps.

“Our findings place A53T with features that may explain the early onset of familial Parkinson’s disease cases bearing this mutation,” the researchers concluded.

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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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MJFF Announces $10M Challenge to Develop Critical Research Tool for Parkinson’s

MJFF challenge

With the aim of opening entirely new avenues in Parkinson’s disease research and care, The Michael J. Fox Foundation (MJFF) has announced a $10 million contest to drive development of an imaging tracer that would be used to see alpha-synuclein protein in the living brain.

Called the “Ken Griffin Alpha-synuclein Imaging Competition,” the project will award $8.5 million to up to three investigative teams. After two years, the team that makes the most progress will receive an additional $1.5 million to continue. The application deadline is Jan. 17, 2020.

Development of such a critical and, so far, elusive research tool would be a game changer for Parkinson’s. Of the roughly 10 million patients globally, nearly all have accumulations of the protein in their brains. Investigators believe these alpha-synuclein masses negatively affect cells and cause disease symptoms. The problem is the clumps are visible only after patients die, through post-mortem studies.

The competition to produce technology for the living brain is largely funded by a $7.5 million gift from Ken Griffin, founder and CEO of the investment company Citadel.

“Providing researchers and clinicians with the ability to detect and monitor disease would be revolutionary for the field and, most importantly, for patients,” said Todd Sherer, PhD, MJFF CEO, in a press release. “Ken Griffin’s gift invigorates research toward this important tool, which will make a meaningful impact in the lives of everyone touched by Parkinson’s.”

The MJFF has been at the fore of efforts to develop a positron-emission tomography (PET) tracer. It has sponsored independent research and organized a consortium around it. Three years ago, the MJFF announced it would award $2 million to the first team to reveal clinical proof of a tracer and share it with researchers at large. That challenge continues.

Meanwhile, at the organization’s 2019 PD Therapeutics Conference on Oct. 15, biotechnology company AC Immune will present  findings from its MJFF-supported tracer study.

The Ken Griffin award announcement is expected by April. The MJFF is encouraging applications from multidisciplinary teams, and is particularly interested in collaborations between academic and industry groups that have access to diverse compound libraries.

“The Michael J. Fox Foundation has led the charge in advancing ground-breaking research in this field over the past 20 years,” Griffin said. “I hope this partnership with the Foundation will bring us closer to a cure for the millions of people living with Parkinson’s disease.”

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Lewy Bodies Diverse in Structure and Some Fibrils Can Migrate, Study Reports

alpha-synuclein study

A detailed analysis of the structure of alpha-synuclein clumps suggests that Parkinson’s is a systemic disease, whose characteristic protein aggregates can move about inside the brain and migrate beyond the central nervous system, according to a new research.

This finding may help in better understanding why Parkinson’s patients experience symptoms other than the disease’s characteristic motor problems.

The study, “Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein,” was published in the journal Proceedings of the National Academy of Sciences.

A hallmark feature of Parkinson’s is the accumulation of small and complex structures called Lewy bodies, which are mainly composed of the alpha-synuclein protein in nerve cells of the brain. Recent work has shown these aggregates can travel across cells of connected brain regions. But little is known about how this migration is regulated, and scientists are still working to more fully understand the structure of proteins in Lewy bodies.

A team from Osaka University, in Japan, used a technique called microbeam X-ray diffraction to gather information in greater detail about the structure of alpha-synuclein clumps.

Using this technique, researchers can detail the complex 3D structure of protein aggregates based on the diffraction pattern they produce when crossing a beam of X-rays. (Diffraction patterns here refer to the bending of X-ray waves as they pass an object.)

The team first tested the sensitivity of their approach using senile plaques from mice in a model of Alzheimer’s disease. These plaques are also composed of complex protein clump, but consist of the beta-amyloid protein.  The researchers then used the same method to analyze thin brain sections taken from three Parkinson’s patients who died between the ages of 75 and 83.

Tests confirmed that protein clumps from patients mainly consisted of alpha-synuclein, by using an antibody specific for detecting this protein. Next, the researchers saw different X-ray scattering patterns in mice and patient tissue samples, confirming they consisted of different proteins.

They also found that different patient samples had slightly different scattering patterns, suggesting diverse clump structures. Importantly, some structures seen in patients’ alpha-synuclein aggregates were similar to structures previously reported in mice studies, which found fragments of these protein fibrils (called cross-beta, or cross-β, structures) could propagate — migrate — throughout the body.

“Our study is the first to find that aggregates in Parkinson’s disease brains also have this cross-β structure,” Hideki Mochizuki, MD, PhD, the study’s senior author, said in a news release.

Inconsistent findings across patient samples might indicate “the different maturity stages of Lewy bodies,” said Katsuya Araki, MD, PhD, and the study’s first author.

Importantly, rather than supporting Parkinson’s as a disease localized in the brain, “our finding supports the concept that [Parkinson’s] is a type of amyloidosis, a disease featuring the accumulation and propagation of amyloid fibrils” of alpha-synuclein, they wrote.

This appears to be in line with both the non-motor symptoms experienced by Parkinson’s patients before difficulties with movement are manifest, and with the presence of alpha-synuclein deposits found in peripheral nerves of the heart and the gut.

“This has obvious implications in the diagnosis of Parkinson’s disease, and could also have therapeutic implications in the long run,” Araki said.

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Urine Levels of Compound Rise Quickly After Brain Injuries Linked to Parkinson’s, Study Finds

brain injury and disease

Explosions that cause even mild traumatic brain injury can trigger molecular changes that, later in life, lead to neuroinflammation and degeneration, and a greater risk of Parkinson’s disease.

But work by researchers at Purdue University also found that analyzing urine levels of a compound called acrolein may help within days of such injury to identify people — like military veterans — at risk of developing Parkinson’s or other neurodegenerative disorders.

The study, “Acrolein-mediated alpha-synuclein pathology involvement in the early postinjury pathogenesis of mild blast-induced Parkinsonian neurodegeneration,” was published in Molecular and Cellular Neuroscience.

Parkinson’s is characterized by the build-up of damaging alpha-synuclein clumps inside nerve cells. These aggregates, also known as Lewy bodies, can become toxic to cells, triggering neuroniflammation and eventually killing nerve cells.

Blast-induced brain injury is a leading cause of injuries in veterans, as are traumatic brain injuries to athletes like football players and boxers. They associate with a greater susceptibility to Parkinson’s disease compared to the general population. However, information is limited on the underlying mechanisms linking such injury to the disease.

Earlier studies demonstrated that hours and days after even a mild blast-induced brain injury, microvascular and nerve cell damage and neuroinflammation are evident, as are increased levels of harmful oxidative stress.

To better understand these processes, the Purdue researchers evaluated rats exposed to mild, blast-induced traumatic brain injury. They focused on analyzing changes in the alpha-synuclein protein and in acrolein, a marker of oxidative stress.

“Most people have heard that traumatic brain injuries are linked to Parkinson’s, Alzheimer’s and other neurodegenerative diseases, dating back as far as to Muhammad Ali and even earlier. The seriousness of this relationship is readily apparent,” Riyi Shi, PhD, professor at Purdue University’s department of basic medical sciences, said in a university news release by Cynthia Sequin.

“[W]e want to, for the first time, implement a mechanism or protocol capable of connecting brain injuries to these diseases,” Shi added.

The team found that within seven days of their blast-induced brain injury, the animals showed significantly higher levels of acrolein in the urine and the brain, specifically in the substantia nigra and striatum — two brain areas crucial for motor control and both greatly affected by Parkinson’s disease.

“Even at one day post injury, a simple urine analysis can reveal elevations in the neurotoxin acrolein. The presence of this ‘biomarker’ alerts us to the injury, creating an opportunity for intervention,” Shi said.

In addition to higher acrolein levels, increases in the levels of alpha-synuclein variants that are prone to form aggregates were also evident.

Further experiments revealed that acrolein and alpha-synuclein are co-localized in the same brain areas, and can interact in brain injury. In particular, acrolein was found to directly contribute to the clumping of alpha-synuclein and Lewy body formation.

“Taken together, our data suggests acrolein likely plays an important role in inducing [Parkinson’s disease] following [blast-induced traumatic brain injury] by encouraging alpha-synuclein aggregation,” the researchers wrote.

“This study establishes a solid link between the two and opens the door for faster treatments utilizing acrolein urine tests during the days following a traumatic episode,” Shi said. “This early detection and subsequent treatment window could offer tremendous benefits for long-term patient neurological health.”

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Parkinson’s May Originate From Alpha-Synuclein Migrating From the Gut, Rat Study Shows

gut Parkinson's alpha-synuclein

New experimental evidence collected from rats shows that alpha-synuclein — the protein that causes Parkinson’s disease — can travel from the intestines to other organs, such as the heart and brain.

These findings, reported in the study “Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats,” provide further support to the hypothesis that the development of Parkinson’s disease is directly linked to the intestinal system.

The study was published in Acta Neuropathologica.

A hallmark feature of Parkinson’s is the progressive degeneration of brain cells due to the accumulation of toxic clumps of alpha-synuclein, called Lewy bodies.

Prior work in postmortem human brains has shown that the misfolded protein primarily accumulates in brain areas controlling movement, which explains the characteristic motor symptoms associated with the disease. But that work also revealed the protein’s accumulation in the vagus nerve – which connects the brain to the gut.

This led to the theory that Parkinson’s progression could require communication between the gut and the brain.

To further explore this association, researchers from Aarhus University and its clinical center, in Denmark, conducted a new study in rats. The team used rats that were genetically modified to produce excessive amounts of alpha-synuclein, and which were susceptible to accumulating harmful versions of the protein in nerve cells. Human alpha-synuclein or an inactive placebo was injected into the small intestines of these rats.

With this approach, the investigators found that both groups of rats — those injected with alpha-synuclein or placebo — had high levels of the protein in the brain. However, only those injected with alpha synuclein showed Parkinson’s characteristic clump build-up patterns, which affected the motor nucleus and substantia nigra in the brain.

“After two months, we saw that the alpha-synuclein had travelled to the brain via the peripheral nerves with involvement of precisely those structures known to be affected in connection with Parkinson’s disease in humans,” Per Borghammer, an Aarhus University professor and the study’s senior author, said in a press release written by Mette Louise Ohana.

“After four months, the magnitude of the pathology was even greater. It was actually pretty striking to see how quickly it happened,” Borghammer said.

Alpha-synuclein also was found to accumulate in the heart and stomach, which suggests a secondary propagation pathway. That pathway likely is mediated by the celiac ganglia, which are abdominal nerve bundles that innervate the gastrointestinal tract.

A recent study conducted by researchers at Johns Hopkins University School of Medicine revealed similar data, but in mice. The Hopkins team also found that, when they injected an altered form of alpha-synuclein in the intestine of mice, it would first accumulate in the vagus nerve and subsequently spread throughout the brain.

With the findings from the new study, researchers now have more detailed evidence on how the disease most likely spreads.

This may put the scientific community one step closer toward developing more effective medical strategies to halt the disease, Borghammer said.

“For many years, we have known that Parkinson patients have extensive damage to the nervous system of the heart, and that the damage occurs early on. We’ve just never been able to understand why. The present study shows that the heart is damaged very fast, even though the pathology started in the intestine, and we can continue to build on this knowledge in our coming research,” he said.

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Fox Foundation Awards AC Immune New Grant to Advance Alpha-Synuclein Imaging Agent

Grant award

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has awarded AC Immune a new grant to further the development of tracer compounds for Parkinson’s disease (PD).

Specifically, this award continues MJFF support for AC Immune’s alpha-synuclein positron-emission tomography (PET) tracer program, aiming for an accurate imaging agent of the alpha-synuclein protein clumps in nerve cells of the brain that are thought to underlie Parkinson’s development and progression.

Positron-emission tomography (PET) is a non-invasive imaging technique that enables the visualization of the metabolic processes in the body. A PET tracer that is alpha-synuclein specific would allow scientists to study the distribution and alterations of these toxic clumps as the disease progresses.

AC Immune researchers has identified several PET tracer compounds with high affinity and selectivity to alpha-synuclein deposits. They did so by screening the company’s library of small molecules for suitable alpha-synuclein PET tracer candidates.

This “molecular collection,” also known as the Morphomer platform, enables the identification of a new class of low molecular weight compounds. This platform, in turn, allows for the generation of small molecules — called morphomers — that specifically bind to misfolded proteins, working to break up the neurotoxic clusters and prevent protein aggregation.

Importantly, these molecules can reach the brains of non-human primates, adding to their potential as a central nervous system tracer.

A lead alpha-synuclein PET tracer candidate, ACI-3024, entered a Phase 1 clinical trial of its ability to capture pathological alpha-synuclein in neurodegenerative diseases like Parkinson’s. The study is assessing the safety, tolerability, and interactions between the body and ACI-3024 (pharmacokinetics and pharmacodynamics) in healthy volunteers.

Jan Stöhr, PhD, head of Non-Alzheimer’s Disease Proteinopathies at AC Immune, will give an oral presentation about this alpha-synuclein PET tracer program at the Fox Foundation’s 13th Annual PD Therapeutics Conference set for Oct. 15 in New York City.

“We are very proud to be working together with MJFF on our a-syn [alpha-synuclein] PET tracer program, which offers patients the potential for earlier diagnosis of PD and facilitates the development … of imaging agents capable of earlier detection and disease monitoring, as well as the development of a broad pipeline of effective therapeutic candidates focused on the prevention and treatment,” Andrea Pfeifer, PhD, CEO of AC Immune, said in a news release.

The Fox Foundation first began supporting AC Immune’s program for alpha-synuclein-specific tracer compounds in 2015. If the program is successful, it could offer a first imaging agent capable of accurately identifying and monitoring Parkinson’s progression.

AC Immune is also working to develop oral small molecule alpha-synuclein inhibitors, and anti-alpha-synuclein antibodies to treat Parkinson’s and related diseases.

The grant amount was not released.

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Engineered Protein Binds to Alpha-synuclein to Prevent Toxic Clumping, Study Reports

alpha-synuclein, AS69

An engineered protein known as AS69 is able to bind to individual units of alpha-synuclein to prevent them from clumping, and — in a fly model of Parkinson’s disease — its use led to preserved motor function, a study reports.

The study, “An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils,” appeared in the journal eLIFE.

Cellular aggregates, or clumps, of the protein alpha-synuclein are an established hallmark of Parkinson’s and focus of research into treatments. “The link between [alpha]-synuclein aggregation and PD [Parkinson’s] has been known for two decades … however, translation of this scientific discovery into a therapy has proven challenging,” the scientists wrote.

A team of international researchers now engineered a binding protein, known as beta-wrapin AS69, that can bind with high affinity to monomers (single units) of alpha-synuclein and induce a specific conformational or structural change called a beta hairpin.

The alpha-synuclein region that adopts this structure is essential for its clumping, as indicated by the presence of a cluster of disease-related mutation sites. Upon binding to this region, AS69 stops alpha-synuclein from aggregating into amyloid fibrils.

To better determine the potential of AS69 as a therapy, the scientists also tested it in cellular and animal models.

In vitro, the team confirmed that AS69 specifically worked to lower alpha-synuclein aggregation and not its amount, testing both with wild-type (normal) protein and a variant (A53T) previously linked to familial Parkinson’s and to quicker protein clumping. (In vitro refers to experiments in lab dishes; in vivo experiments are those within a living organism, including animal models.)

In fruit flies with A53T alpha-synuclein in their brain nerve cells, AS69 was then seen to preserve the flies’ ability to climb (reflecting motor function), which was associated with fewer alpha-synuclein aggregates. This climbing ability progressively declined in the absence of AS69.

Protein aggregation is a complex process involving multiple microscopic steps. It starts with an event called primary nucleation, in which misfolded (altered shape) proteins clump together to form fibrils, which then elongate. This first step proceeds slowly, potentially taking up to several decades.

A later event is called secondary nucleation. Here, aggregation speeds up and exponential growth occurs, with existing clumps promoting the formation of new ones. This faster phase is associated with evident disease, and a potential for rapid progression.

When the team investigated specific steps of alpha-synuclein protein clumping, it found that fibril elongation was suppressed by AS69 in a concentration-dependent manner. Both fibrils and AS69 competed for the single units of alpha-synuclein, but while the interaction with AS69 occurred within seconds, binding to fibrils took minutes to hours.

In contrast, the interaction of free AS69 with fibrils was weak, if it existed at all.

AS69 was also found to interfere with lipid (fat)-induce alpha-synuclein aggregation, and was a more efficient inhibitor of the amplification of alpha-synuclein amyloid fibrils than beta-synuclein — a protein known to suppress alpha-synuclein clumping.  Importantly, by binding to alpha-synuclein, AS69 also prevented secondary nucleation.

Based on these results, the team proposed that the complex of AS69 with alpha-synuclein incorporates into a fibril precursor, and prevents this precursor from undergoing the structural changes needed for further aggregation.

“An inhibitor functioning according to this dual mode, that is being active both as a free molecule and as a complex with (…) [alpha]-synuclein, is expected to efficiently reduce [alpha]-synuclein aggregation in vivo,” the researchers concluded.

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