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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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Mutations in Genes Other Than GBA May Collectively Raise Parkinson’s Risk and Severity, Study Suggests

risk and genetics

Mutations in the SNCA and CTSB genes — among the many known to increase the likelihood of Parkinson’s disease — also contribute to the risk associated with mutations in the GBA gene, one of this disease’s most common and significant genetic risk factors, a study shows.

Its results further suggest an interaction between the CTSB and GBA genes, and that raising the levels of the protein the CTSB gene is responsible for producing — cathepsin B — may be a way of treating Parkinson’s.

The study, “Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia,” is available on the bioRxiv pre-print server.

The GBA gene contains the instructions to produce the enzyme glucocerebrosidase (GCase) that is active in lysosomes, special compartments within cells that break down and recycle different types of molecules.

GBA mutations, which reduce GCase activity, are one of the most common genetic risk factors for Parkinson’s and dementia with Lewy bodies (LBD), found in 3%–20% of patients in different populations. GBA mutations confer a risk of these diseases that 1.4 times to more than 10 times higher.

Parkinson’s patients with GBA mutations also have earlier ages at onset and faster disease progression, previous studies found.

Researchers hypothesize that the loss of GCase activity leads to a reduced ability to degrade alpha-synuclein, the protein produced through instructions in the SNCA gene. Mutations in the SNCA gene are associated with a greater risk of Parkinson’s disease, likely due to increased alpha-synuclein levels.

A buildup of abnormal alpha-synuclein can result in toxic aggregates of insoluble small fibers that deposit in the form of Lewy bodies, hallmarks of Parkinson’s and LBD.

Despite the well-established link between GBA mutations and Parkinson’s, most people carrying these mutations will not develop the disease, implying the influence of other genetic and/or environmental factors on GBA-associated risk.

An international team of researchers set out to evaluate genetic factors weighing on GBA-associated risk, including those that influence the age at which the disease develops.

They analyzed genetic data covering 217,165 people, stored in several large databases using genome wide association studies (GWAS) and the most recent Parkinson’s-associated genetic risk score.

GWAS scan complete sets of DNA, or genomes, of large numbers of people to identify all the genetic changes associated with a disease or trait of interest, and the various weights in terms of disease or trait risk they are assigned. This data is then used to generate genetic risk scores to determine someone’s predisposition to a given disease or trait.

Out of a genetic analysis of 22,757 Parkinson’s patients, 13,431 people whose parents have Parkinson’s, 622 LBD patients, and 180,355 unaffected individuals, the team identified 1,772 Parkinson’s patients, 711 Parkinson’s relatives, and 7,624 unaffected people with GBA mutations.

Results also showed that the GBA-associated risk of developing Parkinson’s disease was significantly influenced by the presence of mutations in the SNCA and CTSB genes. CTSB contains the instructions to produce cathepsin B, an enzyme suggested to be involved in the degradation of alpha-synuclein in lysosomes.

Nerve cells derived from people with GBA mutations had significantly lower cathepsin B levels than those derived from people without such mutations, suggesting a link between GBA and cathepsin B.

In other words, the combination of GBA mutations and mutations in the SNCA and/or CTSB genes may result in greater lysosomal function impairment and a greater buildup of protein aggregates in nerve cells, resulting in an increased risk of Parkinson’s disease.

Age at Parkinson’s onset in patients with GBA mutations was significantly lower than in patients without them, with an average onset at almost 56.81 vs. 60.54 years old.  Mutations in SNCA and TMEM175 — a gene involved in lysosomal processes and associated with increased risk of Parkinson’s and lower age of onset — were also found to potentially affect the age of onset of GBA-associated Parkinson’s.

“These data provide a genetic basis for modification of GBA-associated [Parkinson’s disease] risk and age at onset and demonstrate that variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease,” the researchers wrote.

These results “have important implications for selection of GBA carriers for therapeutic interventions,” and suggest that “cathepsin B might play a larger role in [Parkinson’s disease] than previously thought and that increasing CTSB/cathepsin B levels could be a potential therapeutic strategy,” they added.

The team emphasized, however, that larger GWAS (studies with greater numbers of people carrying GBA mutations) and more extensive studies into genetic factors are needed to confirm these results.

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High Corticosterone Levels a Risk Factor for Parkinson’s, Mouse Study Finds

corticosterone mouse study

High levels of corticosterone — a hormone that regulates energy, immune, and stress responses — is a risk factor for the development and progression of Parkinson’s disease, according to a mouse study.

The study, “Chronic corticosterone aggravates behavioural and neuronal symptomatology in a mouse model of alpha-synuclein pathology,” was published in the journal Neurobiology of Aging.

Parkinson’s disease is a neurodegenerative disorder mainly resulting from the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for controlling body movements.

This is a consequence of overproduction and misfolding of the protein alpha-synuclein in neurons, which leads to the formation of small toxic deposits called Lewy bodies that gradually damage and kill nerve cells. Growing evidence has demonstrated that these alpha-synuclein aggregates are associated with Parkinson’s onset and progression.

“Injection of alpha-synuclein preformed fibrils (PFFs) in different brain regions … induces pronounced alpha-synuclein pathology [aggregate] propagation. Interestingly, in these [mouse] models the amygdala is among the brain regions most severely affected by alpha-synuclein pathology [disease],” the researchers wrote.

The amygdala is an area of the brain involved in memory, decision-making, and emotional responses. Several non-motor symptoms in Parkinson’s, including anxiety and depression, have been linked to structural alterations and functional impairments of the amygdala.

“Similarly, chronic stress and glucocorticoid [imbalance] change amygdala physiology [function], and indeed are involved in the development of anxiety and depression,” they wrote.

The group of researchers from the Brain Mind Institute at the École Polytechnique Fédérale de Lausanne in Switzerland set out to investigate if mood/emotional alterations linked to amygdala dysfunction might accelerate the formation and propagation of alpha-synuclein aggregates associated with Parkinson’s in a mouse model of the disease.

To test their hypothesis, they first treated mice with corticosterone, a glucocorticoid that is normally produced in response to stress, to mimic the effects of depression and chronic stress in the amygdala.

Animals were then injected on one side of the brain’s striatum — a region involved in motor and cognitive control — with either alpha-synuclein preformed fibrils to trigger the formation and propagation of alpha-synuclein aggregates across the whole brain, or with a saline solution (vehicle control).

Chronic treatment with corticosterone triggered depression in animals and had a strong effect on their body shape, fat deposition, body weight, and drinking and eating habits. Injection of alpha-synuclein preformed fibrils had no effects on any of these parameters.

Behavioral tests performed one to two months after the injection of alpha-synuclein showed that animals that had been injected with these fibrils displayed mild anxiety, which was reversed by corticosterone treatment.

However, they found that chronic treatment with corticosterone in animals that had been injected with preformed fibrils led to the accumulation of phosphorylated alpha-synuclein in specific regions of the brain, including the entorhinal cortex, a region involved in memory, spatial navigation, and time perception.

Alpha-synuclein phosphorylation is a chemical modification in which a phosphate group is added to the protein. It is known to occur in Parkinson’s disease, and is thought to be a critical step in disease progression, as it enhances alpha-synuclein’s toxicity, possibly by increasing the formation of aggregates.

They also discovered that treatment with corticosterone in mice that had been injected with alpha-synuclein fibrils increased the loss of dopaminergic neurons.

“We report aggravated alpha-synuclein pathology [disease] and neurodegeneration in mice injected with alpha-synuclein [preformed fibrils] in a condition of heightened corticosterone, suggesting heightened glucocorticoid levels as a risk factor for the development of the neuropathological hallmarks of Parkinson’s disease and potential target for treatment,” the researchers wrote.

“Further studies aimed at elucidating the vulnerability factors of specific brain regions to alpha-synuclein pathology, and why at some point resilience fails and neurodegeneration (such as in the substantia nigra) occurs, are needed and will greatly enhance our understanding of the role of alpha-synuclein pathology in the [development] of Parkinson’s disease and synucleinopathies,” they added.

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Researchers Contemplate Salivary Alpha-Synuclein as Parkinson’s Biomarker

biomarker

Alpha-synuclein in saliva may be a potential biomarker for Parkinson’s disease, according to a recent review article, but more research is necessary to determine its reliability as a possible screening approach.

The study with that finding, “Salivary alpha‑synuclein as a biomarker for Parkinson’s disease: a systematic review,” was published in the Journal of Neural Transmission.

In Parkinson’s, a protein called alpha-synuclein clumps together, creating insoluble fibrils (small fibers) that accumulate inside nerve cells. These aggregates, known as Lewy bodies, are harmful to cells, eventually leading to cellular death, which then contributes to the onset of disease-related symptoms.

Unfortunately, alpha-synuclein aggregates can be confirmed only during an autopsy examination, so current diagnosis relies on Parkinson’s-related clinical symptoms instead of objective tissue changes.

That is why researchers are seeking reliable molecular biomarkers that can distinguish Parkinson’s from other conditions, monitor disease progression, or provide insight about a patient’s response to a given therapeutic intervention.

Lewy bodies have been found in the salivary glands of early-stage Parkinson’s patients. “Salivary alpha-synuclein is an easily accessible biomarker for PD [Parkinson’s disease] with promising results,” the researchers wrote.

The team decided to summarize the current knowledge of salivary alpha-synuclein as a potential biomarker for Parkinson’s. They searched the U.S. National Library of Medicine’s MEDLINE database from 1970 to April 2019 for several keywords related to Parkinson’s diseasem including “alpha synuclein,” “Lewy body pathology,” “saliva,” and “biomarker.”

Based on all their established criteria, researchers identified 476 studies, of which only eight had data on salivary alpha-synuclein, totaling 1,240 participants.

Of the eight studies, three reported total salivary alpha-synuclein levels (i.e., including all forms of the protein) were significantly lower in Parkinson’s patients, compared to healthy individuals, but the remaining five indicated no association between total alpha-synuclein concentration in saliva and the neurodegenerative disorder.

“In some studies, total salivary [alpha-synuclein] was associated with demographic and clinical features; however, no consistent pattern emerged. In one study, total [alpha-synuclein] levels were associated with poor cognitive performance in [Parkinson’s disease] patients,” the investigators noted.

Alpha-synuclein can be found in various molecular and structural forms. Half of the studies analyzed showed that people with Parkinson’s had higher levels of salivary oligomeric (aggregated) alpha-synuclein and a higher oligomeric alpha-synuclein/total alpha-synuclein ratio, than controls.

Additionally, one study indicated multiple genetic variants could alter total salivary alpha-synuclein concentrations in Parkinson’s. Nonetheless, in all studies there were important limitations to the scientific protocol and the corresponding results that may have influenced its conclusions. Some of those confounding factors included problems with sample collection, sample contamination, inadequate sample storage, or difficulties performing the tests.

“Utilization of saliva in biomarker discovery has several advantages over other biofluids. For instance, in comparison to CSF [cerebrospinal fluid, the liquid surrounding the brain and spinal cord] or serum/plasma, human saliva is readily accessible and is easier and less invasive to collect in adequate quantities,” the researchers explained.

Because of the minimal risk the approach imposes on the patient, salivary biomarkers may enable monitoring how the disease progresses and the effects of treatments.

Although studies suggest a decrease in total, and an increase in oligomeric,  salivary alpha-synuclein levels, results lack consistency. For now, salivary alpha-synuclein tests have yet to be adopted in clinical practice.

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Alpha-Synuclein Protein Works to Repair Damage to Cell’s DNA, Study Suggests

alpha-synuclein and DNA repair

Contrary to current knowledge, alpha-synuclein protein — whose toxic form is responsible for the formation of Lewy bodies — may play a crucial role in preventing cell death by repairing damaged DNA, a study has found.

This critical function of the protein may also be lost in Parkinson’s patients, its researchers said.

The study, “Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders,” was published in Scientific Reports.

Parkinson’s is marked by a buildup in the brain of the alpha-synuclein protein, which forms clumps known as Lewy bodies that damage and kill neurons (nerve cells). These protein inclusions are found in the cell’s cytoplasm — the jelly-like fluid that fills a cell.

Although it remains unclear how cytoplasmic aggregation of alpha-synuclein into Lewy bodies contributes to neuronal death, alpha-synuclein has also been found in the cell’s nucleus, where DNA is located and where important DNA repair mechanisms take place.

Researchers at the Oregon Health & Science University had previously shown that the formation of Lewy bodies coincided with the loss of soluble alpha-synuclein from both the cytoplasm and nucleus of mouse neurons with aggregates (clumps) in them.

“This suggests that cytoplasmic alpha-synuclein aggregation may decrease the amount of protein available for any nuclear or cytoplasmic role it may play,” the researchers wrote.

The same team now investigated whether alpha-synuclein could be involved in the DNA damage response.

Alpha-synuclein was found in the same cellular sites as DNA damage response components in both human and mouse brain cells.

DNA damage was then chemically induced in human cells that lacked alpha-synuclein. Researchers reported finding higher rates of DNA damage (what they called “double-strand breaks”) compared to alpha-synuclein-bearing cells. Likewise, mice without alpha-synuclein had increased neuronal DNA damage, which was rescued by reintroducing the human form of alpha-synuclein.

Importantly, mouse and human neurons with Lewy bodies had increased levels of DNA damage.

Scientists also observed that normal (i.e., non-toxic) alpha-synuclein is rapidly recruited to DNA damage sites and helps to repair harm by binding to the DNA molecule and facilitating a repairing reaction; more specifically, this process is called the non-homologous end-joining reaction.

Besides its known toxic role in Parkinson’s, findings suggest alpha-synuclein may have an important function in the cell nucleus, that of regulating DNA repair. They also suggest that such function is compromised in Lewy inclusion-bearing neurons, which, in turn, contributes to cell death.

“This is the first time that anyone has discovered one of its [alpha-synuclein’s] functions is DNA repair,” Vivek Unni, MD, PhD, an associate professor of neurology in the OHSU School of Medicine and senior author of the study, said in a news release.

“That’s critical for cell survival, and it appears to be a function that’s lost in Parkinson’s disease,” Unni added.

“Based on these data, we propose a model whereby cytoplasmic aggregation of alpha-synuclein reduces its nuclear levels, increases DSBs [double-strand breaks], and may contribute to programmed cell death via nuclear loss-of-function. This model could inform development of new treatments for Lewy body disorders by targeting alpha-synuclein-mediated DNA repair mechanisms,” the team concluded.

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Boosting Levels of Molecule in Brain Slows Parkinson’s Progression and Eases Symptoms, Animal Study Finds

animal model study

A molecule called GM1 ganglioside may protect the brain against the molecular changes associated with Parkinson’s disease progression, and may one day directly treat its neurodegenerative processes, according to an early study.

The study, “GM1 Ganglioside Modifies α-Synuclein Toxicity and is Neuroprotective in a Rat α-Synuclein Model of Parkinson’s Disease,” was published in Scientific Reports.

GM1 ganglioside is a component of the cell membrane and has long been considered a master modulator of the nervous system because of the many functions it regulates.

Parkinson’s patients have lower-than-usual levels of GM1 ganglioside within the substantia nigra, a brain region that’s severely damaged in Parkinson’s.

In lab experiments, GM1 ganglioside was found to protect against the aggregation of alpha-synuclein protein, the main component of Parkinson’s hallmark Lewy bodies. Specifically, GM1 ganglioside did not allow acetylated alpha-synuclein to form harmful clumps or aggregates within the cells. Acetylated (with an added acetyl group) alpha-synuclein has been shown to more effectively induce intracellular clustering in nerve cells, compared to the unchanged form of alpha-synuclein.

This suggests that problems with GM1 may somehow contribute to the vulnerability and degeneration of dopamine-producing neurons seen in Parkinson’s disease.

Using a rat model of Parkinson’s, researchers for this study investigated the extent to which GM1 ganglioside could protect against alpha-synuclein toxicity and the development of Parkinson’s-related molecular and behavioral changes.

A single injection of an adeno-associated viral vector (AAV) carrying a copy of human mutant alpha-synuclein was administered into the substantia nigra of rats, leading to protein aggregation and the degeneration of dopaminergic neurons, a decrease in dopamine levels within the striatum (another motor control brain center that’s affected by Parkinson’s), and behavioral problems.

Some rats were then randomly assigned to daily GM1 ganglioside injections (30 mg/kg) beginning 24 hours after AAV-alpha-synuclein administration and lasting for six weeks (early start group). Others were given the daily GM1 ganglioside injections (30 mg/kg) three weeks after the AAV-alpha-synuclein, and lasting for five weeks (delayed start group).

Results showed that GM1 ganglioside protected against loss of substantia nigra dopamine-releasing neurons and striatal dopamine levels, and reduced alpha-synuclein clumping. Importantly, the delayed start of GM1 ganglioside reversed motor deficits that had appeared in this animal group, suggesting the therapy was able to restore their motor function.

“When we looked in the brains of these animals, not only did we find we could partially protect their dopamine neurons from the toxic effects of alpha synuclein accumulation, we had some evidence that these animals had smaller and fewer aggregates of alpha-synuclein than animals that received saline injection instead of GM1,” Jay Schneider, PhD, a professor in the department of pathology, anatomy and cell biology at Thomas Jefferson University and first author of the study, said in a press release.

Scientists believe the low brain levels of GM1 ganglioside seen in Parkinson’s may facilitate the formation of harmful alpha-synuclein clumps.

“By increasing GM1 levels in the brains of these patients, it would make sense that we could potentially provide a slowing of that pathological process and a slowing of the disease progression, which is what we found previously in a clinical trial of GM1 in Parkinson’s disease patients,” Schneider said. Results of that university-sponsored trial (NCT00037830) in 77 patients, concluded in 2010, supported its potential as a disease-modifying treatment.

Schneider’s team is now focused on finding out what other effects GM1 ganglioside might have on alpha-synuclein.

“It’s important to understand how GM1 is working because there might be other ways we could manipulate GM1 levels in the brain to have a beneficial effect,” he added.

According to the researchers, GM1 has the potential to be a treatment that directly impacts “the underlying disease processes in [Parkinson’s disease] and that can slow neuronal cell death and symptom progression,” protecting dopamine neurons from dying “as well as rescue and restore function to damaged but viable neurons.”

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