Oxidative Stress Seen Promote Spread of Toxic Alpha-Synuclein Across Cells, Possibly Trigger Disease

oxidated stress study

Oxidative stress may be a trigger for Parkinson’s and can promote its progression by facilitating the spread of toxic alpha-synuclein protein across cells, researchers report.

Their study, “Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular α-synuclein transfer,” was published in the Journal of Clinical Investigation.

Parkinson’s is characterized by a buildup of the protein alpha-synuclein in the brain, which forms clumps known as Lewy bodies that damage and kill nerve cells.

Although Parkinson’s trigger remains to be identified, research indicates its causative mechanism involves genetics, problems in mitochondria (energy “powerhouses” of cells), and oxidative stress — an imbalance between the production of harmful free radicals and the ability of cells to detoxify, resulting in cellular damage. Taken together, these molecular and cellular changes eventually kill dopamine-producing neurons, the nerve cell type gradually lost in Parkinson’s disease.

Scientists at the German Center for Neurodegenerative Diseases (DZNE) investigated the relationship between oxidative stress, neurodegeneration, and alpha-synuclein pathology.

A single injection of adeno-associated viral vectors (AAVs) carrying human alpha-synuclein DNA was administered into the dorsal motor nucleus of the vagus nerve of mice, leading to protein aggregation and neuron-to-neuron transmission of alpha-synuclein. Mice also showed selective degeneration in cells that received the human alpha-synuclein DNA. (The vagus nerve is a brain region involved in movement control, and a primary site of Lewy body accumulation.)

The animals were then given paraquat, a toxic and fast-acting herbicide that’s capable of producing great amounts of free radicals, replicating oxidative stress in a laboratory setting.

Results showed that acetylcholine-producing neurons — which, along with dopaminergic neurons, are affected in Parkinson’s — of the dorsal motor nucleus of the vagus nerve were particularly susceptible to oxidative stress. The AAV injection alone induced oxidative stress, and those levels significantly increased with paraquat. These molecular changes led to the production of modified forms of alpha-synuclein, increased clump formation, and neuronal degeneration within the dorsal motor nucleus of the vagus nerve.

Higher levels of oxidative stress influenced neuron-to-neuron alpha-synuclein transfer and greater protein spread from the dorsal motor nucleus of the vagus nerve toward rostal brain regions (more frontal regions).

To further investigate alpha-synuclein’s spreading behavior, human neurons with alpha-synuclein were grown in the lab in different concentrations of paraquat. Pro-oxidant conditions were found to increase alpha-synuclein’s propensity to move from cell to cell.

Importantly, scientists identified nitrated forms of the protein as highly transferable molecules, supporting the hypothesis that oxidized or nitrated forms of alpha-synuclein have pronounced cell-to-cell mobility.

Like oxidative stress (involving reactive oxygen species), nitrative stress (involving nitrogen molecules) has been implicated in Parkinson’s. This oxidative/nitrative stress is known to provoke harmful changes in alpha-synuclein’s structure, and nitrated forms of the protein have been found in the brain, gastrointestinal tract, and blood cells of Parkinson’s patients.

“Oxidative stress has long been considered to be involved in the pathogenesis of Parkinson’s disease. Our work, however, reveals a new intriguing mechanism that may link oxidative stress to disease development,” Donato Di Monte, MD, a senior DZNE scientist and the study’s main researcher, said in a press release.

“We show that under oxidative stress the propensity of alpha-synuclein to ‘travel’ from one neuron to the other is significantly enhanced, thus facilitating the exchange of harmful protein species, occurrence of pathology and the spreading of this pathology throughout the brain,” Di Monte added.

Overall, this work suggests that cell-to-cell spread of alpha-synuclein is enhanced by oxidative stress and, as such, this stress could trigger and promote Parkinson’s disease.

“These findings substantiate the relevance of oxidative injury in PD [Parkinson’s disease] pathogenetic processes, establish a relationship between oxidative stress and vulnerability to α-synuclein pathology and define a new mechanism, enhanced cell-to-cell α-synuclein transmission, by which oxidative stress could promote PD development and progression,” the study concluded.

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Specific Form of Alpha-Synuclein Linked to More Severe Parkinson’s Symptoms in Early Study

alpha-synuclein study

Small amounts of a particular form of alpha-synuclein, known as beta-sheet, may cause a significant loss of dopamine-releasing neurons by recruiting more alpha-synuclein molecules, leading to Parkinson’s-like symptoms and disease progression, according to a recent lab study.

The study, “Defining α-synuclein species responsible for Parkinson disease phenotypes in mice,” was published in the Journal of Biological Chemistry.

In Parkinson’s, a particular form of the protein alpha-synuclein originates in insoluble fibrils (i.e. “small fibers”) that clump together, and those fibers accumulate inside nerve cells (neurons). These aggregates, also known as Lewy bodies, are harmful to cells and eventually kill them, which, in turn, contributes to the onset of disease-related symptoms.

Besides fibrils, alpha-synuclein exists in other structural forms, including an orderly stacked form called beta-sheet. To date, not much is known about which of alpha-synuclein’s structural arrangements contribute more strongly to disease mechanisms and Parkinson’s manifestations.

Researchers at the University of Alabama at Birmingham (UAB) studied three distinct structural forms of alpha-synuclein (long fibrils, a mix of fragmented fibrils, and short fragmented fibrils; all with beta-sheet in them) to determine which was most responsible for Parkinson’s-related damage.

Investigators injected one of the three alpha-synuclein forms, as well as small (insoluble) alpha-synuclein fibers, into the striatum — a crucial brain region involved in motor control that’s extensively damaged in Parkinson’s — of healthy mice to establish the ability of each protein arrangement to induce Parkinson’s-like symptoms.

Three months after injection of small alpha-synuclein molecules (that have a lesser amount of beta-sheet in them) there was a slight but significant loss of dopamine-producing neurons in the substantia nigra – a brain area deeply connected with the striatum. But it did not induce Lewy body formation or lead to evidence of motor impairment.

In contrast, those animals injected with short beta-sheet fibril fragments showed fewer striatal dopamine terminals (meaning “neuronal sites where dopamine is released to communicate with nearby neurons”), a loss of dopaminergic neurons within the substantia nigra, and Parkinson’s-like motor behavior defects.

“Our findings indicate that the form most toxic to neurons was a structure referred to as beta-sheet fibrillar fragments,” Laura Volpicelli-Daley, PhD, assistant professor at UAB’s Department of Neurology, and the study’s lead author, said in a press release.

“This is a form of alpha-synuclein that makes overlapping sheets of the protein, which subsequently develop into long filaments. The filaments can then break into smaller fragmented pieces. We hypothesize that the smaller fibrillar fragments are the most toxic to neurons because they are able to attract and corrupt normal alpha-synuclein, causing it to form aggregates that spread throughout the neuron, causing damage to the brain,” Volpicelli-Daley added.

“Our results suggest that inhibiting the accumulation of small fibrillar [alpha]-synuclein fragments generated either during the process of protein aggregation or by the fragmentation or disaggregation of longer fibrils, have the potential to be a therapeutic strategy against [Parkinson’s disease] progression,” the researchers concluded.

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Protein-linked Sugars Regulate the Spread of Alpha-synuclein, Study Suggests

neurexin 1-beta protein

A protein that has sugar molecules attached to it, called neurexin 1-beta, helps alpha-synuclein enter and accumulate within neurons contributing to the progression of Parkinson’s disease, a study has found.

The study, “Identification of N-linked glycans as specific mediators of neuronal uptake of acetylated α-Synuclein,” was published in PLOS Biology.

Parkinson’s is characterized by a build-up in the brain of the alpha-synuclein protein, which forms clumps known as Lewy bodies that damage and kill nerve cells, or neurons.

Cell-to-cell transmission of harmful alpha-synuclein protein appears to underly Parkinson’s propagation, and studies indicate there are components or properties of cellular membranes that are crucial for alpha-synuclein to get into cells.

“Indeed, specific components of the extracellular membrane, including proteins and proteoglycans [proteins with sugar molecules within them], have been identified as having roles in the uptake of pathogenic [alpha-synuclein] species,” the researchers wrote.

Changes in alpha-synuclein’s molecular structure — namely the addition of an acetyl group — have been found to alter its binding properties and rates of aggregation. But how these changes affect the protein’s binding to the cellular membrane remains unclear.

University of Pennsylvania researchers studied how these biochemical alterations changed alpha-synuclein “cellular behavior.” To do so, they used bacterial cultures, human-derived cellular cultures, and several biophysical methodologies.

Acetylated (with an added acetyl group) alpha-synuclein formed intracellular clusters in nerve cells more efficiently compared to an unchanged form of alpha-synuclein. No relevant studies have focused on acetylated alpha-synuclein molecular behavior, as this protein form is found in both normal and diseased neurons.

Removal of specific sugar molecules (glycans) found in the cellular membrane decreased the amount of alpha-synuclein that entered the cells. Of note, and among other things, the membrane surrounding cells is made of lipids (i.e., fat-like molecules) and proteins, predominantly those with added sugar.

Further biochemical analysis revealed that acetylated alpha-synuclein is structurally compatible to the same sugar molecules, and it is that proper molecular fitting that enables the protein to interact with the cell membrane.

Importantly, a neuronal glycoprotein — a protein with added sugar molecules — called neurexin 1-beta helped acetylated alpha-synuclein to get into cells.

Unchanged (not acetylated) alpha-synuclein’s behavior was not at all related to the sugar molecules, emphasizing the specific and important role of the latter in acetylated alpha-synuclein’s conduct.

“Some cells spontaneously internalize these [alpha-synuclein] proteins and some do not. It has generally been assumed that there are alpha-synuclein specific receptors on the cells that do internalize aggregates. That may or may not be true, but [our study] suggests that it’s not just the protein receptors but the glycans that are also important,” Elizabeth Rhoades, PhD, said in a press release. Rhodes is an associate professor of chemistry at the University of Pennsylvania, and the study’s lead author.

Having established that acetylated alpha-synuclein is a sugar-binding protein, scientists now have a new avenue to explore for the development of treatments for Parkinson’s disease.

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Key Protein in Parkinson’s – Alpha-synuclein – Travels from Gut to Clump in Brain, Study Reports

gut and alpha-synuclein

Altered forms of the alpha-synuclein protein travel along the vagus nerve from the gut to the brain where they accumulate, according to a study in mice. It also suggests that blocking this transport could prevent the progression of Parkinson’s disease.

The work lends support to theories that Parkinson’s begins in the gastrointestinal tract.

“This is an exciting discovery for the field and presents a target for early intervention in the disease,” Ted Dawson, MD, PhD, one of the study’s senior authors, said in a press release.

Transneuronal Propagation of Pathologic a-Synuclein from the Gut to the Brain Models Parkinson’s Disease” was published in the journal Neuron.

Parkinson’s is characterized by the buildup of alpha-synuclein in protein inclusions in the brain called Lewy bodies. Prior work in postmortem human brains has shown that misfolded alpha-synuclein accumulates in brain areas controlling the gut. This led researchers to hypothesize that Parkinson’s progression requires communication between the gut and the brain.

Aiming to test whether misfolded alpha-synuclein travels along the vagus nerve — the longest nerve in the autonomic nervous system that connects the stomach and small intestine to the brain — researchers at Johns Hopkins University School of Medicine injected 25 micrograms of synthetic misfolded alpha-synuclein fibrils into the muscle layers of the duodenum (the first part of the small intestine) and the pylorus (the opening from the stomach into the duodenum) of healthy mice.

Over the course of 10 months, the scientists then found that alpha-synuclein began to accumulate in the vagus nerve to subsequently spread throughout the brain, seen by the detection of the altered form of this protein there.

One of the brain areas with misfolded alpha-synuclein was the substantia nigra pars compacta (SNpC), where the scientists found a gradual loss of dopamine-producing nerve cells, as typically seen in people with Parkinson’s. The levels of dopamine and its by-products were also lower in the striatum, a brain area connected to the SNpC and a key component of the motor system.

Surgically cutting the vagus nerve before injecting mice with misfolded alpha-synuclein led to none of the signs observed in animals with an intact vagus nerve, namely alpha-synuclein transport, loss of dopaminergic neurons, and lower dopamine levels.

Mice genetically engineered to lack the alpha-synuclein protein also showed no evidence of transmission to the brain after being injected with the protein’s misfolded form.

Subsequent experiments assessed whether transmission of pathological (disease-causing) forms of alpha-synuclein from the the gut to the brain caused behavioral changes.

Seven months after modified alpha-synuclein injections, the animals’ ability to build nests was analyzed as a way to assess their motor skills. Mice injected with misfolded alpha-synuclein that had an intact vagus nerve had lower scores than those with cut nerves: their nests were smaller and messier. These animals also used less than half a gram of nesting material, in contrast to the 2.5 grams used by the animals with severed nerves.

These mice also had higher anxiety levels than those with a damaged vagus nerve or genetically modified to lack alpha-synuclein, as observed in a test of how long the animals would spend exploring a large open box.

Other tests indicated that injecting modified alpha-synuclein and having intact nerves led to motor dysfunction, reduced grip strength, impaired learning, and caused olfactory problems and depression-like symptoms.

“Our results support the theory that [Parkinson’s] could begin in the gastrointestinal tract and spread through the vagus nerve to the brain,” the researchers wrote.

“These findings provide further proof of the gut’s role in Parkinson’s disease, and give us a model to study the disease’s progression from the start,” Dawson, who also the director of the Johns Hopkins Institute for Cell Engineering, added.

The team is now planning to study which parts of the vagus nerve are key for the travel of the misfolded protein, as a way to find how to stop this process.

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Lewy Bodies Are Made of Much More than Alpha-Synuclein, Study Finds

Lewy bodies

Insoluble alpha-synuclein protein has long been thought to be the main component of Parkinson’s hallmark Lewy bodies, but researchers have now reported these abnormal aggregates are also made of cell membrane fragments, fat-like substances, and other cellular components.

This finding was reported in a study, “Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes,” that was published in the journal Nature Neuroscience.

Parkinson’s disease is a neurodegenerative disorder characterized by selective death of midbrain dopamine-producing neurons due to clustering of a protein called alpha-synuclein in structures commonly known as Lewy bodies.

For decades, scientists have believed that alpha-synuclein fibrils (meaning “small fibers”) were the main component of and at Lewy bodies’ core. However, investigators have now contested such belief after studying postmortem human brain tissue from patients with Parkinson’s disease.

Combining imaging techniques, the researchers were able to re-create the 3D structures of these disease-associated clusters. They found that besides alpha-synuclein, Lewy bodies also have membrane fragments, vesicular structures, and abnormal organelles (organ-like structures found inside cells) such as mitochondria — cells’ powerhouses.

Many, but not all, Lewy bodies with alpha-synuclein within them had protein fibers scattered between membrane fragments and organelles. Importantly, a non-fibrillar form of alpha-synuclein was also found to be intermingled with the other contents of the Lewy bodies.

“We used correlative light and electron microscopy and other advanced light microscopy methods to take a closer look at the brain of deceased Parkinson’s patients and discovered that the Lewy bodies consist mainly of membrane fragments from mitochondria and other organelles, but have in most cases no or only negligible quantities of protein fibrils,” Henning Stahlberg, PhD, professor and researcher at the University of Basel in Switzerland, and one of the study’s senior authors, said in a press release.

“The discovery that alpha-synuclein did not present in the form of fibrils was unexpected for us and the entire research field,” Stahlberg said.

The researchers also found that the bodies carried fat-like substances similar to those found in healthy brain cells, like myelin (nerve cells’ protective fatty layer) or fatty components of cell membranes.

“We present here a new theoretical model in which lipid membrane fragments and distorted organelles together with a non-fibrillar form of [alpha-synuclein] are the main structural building blocks for the formation of Lewy pathology,” the researchers stated.

Several studies have linked disturbances in intracellular movement of molecules and organelles with Parkinson’s disease. In addition, alpha-synuclein has been shown to be capable of disrupting the integrity of mitochondrial membranes, manipulating and reorganizing membrane components, and leading membranes to form vesicles under specific biochemical conditions.

Collectively, the study’s findings support the hypothesis of abnormal movement of organelles as a potential driver of Parkinson’s disease mechanism. Also, they “emphasize the need to consider population heterogeneity of Lewy pathology” and show that lipids (cells’ fatty molecules) could play an important role, the researchers said.

“The questions why it has taken so long to better characterize Lewy bodies can perhaps be answered with the previous sample preparation and electron microscopy methods. Today’s technologies enable us to have a much more detailed look into the morphology of [the] human brain,” Stahlberg said. “The big question for us now is: How does alpha-synuclein contribute to the formation of Lewy bodies, if not present in [the] form of fibrils?”

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Participants Sought for Clinical Trial Testing ENT-01 for Parkinson’s Dementia


Enterin Inc has enrolled the first patient in its Phase 1b DEMET clinical trial investigating the effectiveness, safety and tolerability of small molecule ENT-01 to treat Parkinson’s disease dementia.

Contacts and locations of participating sites can be found here.

Many neurodegenerative disorders involve aggregation of misfolded (harmful) proteins in the brain. Parkinson’s is characterized by a buildup of the protein alpha-synuclein in the brain, which forms clumps known as Lewy bodies that damage and kill nerve cells.

In order to form aggregates, these clumps need to stick to the membranes that line the inside of neurons. It is the sticky form of alpha-synuclein protein that causes most of the damage seen in Parkinson’s, more so than if this protein was freely floating within a neuron.

ENT-01 (kenterin) enters neurons from the enteric nervous system (ENS), attaches itself to the nerve cells’ membrane and dislodges Parkinson’s-related alpha-synuclein clumps. By unsticking harmful alpha-synuclein, the investigational treatment reduces the amount of alpha-synuclein aggregates within neurons and, in theory, cellular death.

The enteric nervous system is a network of neurons that independently governs the function of the gastrointestinal tract. Previous studies claim that alpha-synuclein begins accumulating in the ENS and then travels from the gut to the brain, where it is linked to the development and progression of Parkinson’s.

The multicenter, randomized, double-blind DEMET study (NCT03938922) will assess ENT-01’s effectiveness, safety and tolerability in patients diagnosed with Parkinson’s disease dementia. It expects to enroll 40 participants (aged 30 to 90 years), who will be assigned randomly to receive ENT-01 or a placebo tablet. Both will be taken once a day.

By being taken orally, and because ENT-01 is not absorbed into the bloodstream, the molecule will solely act on the gut’s neurons, changing the communication between the gut and brain.

The trial will be conducted on an outpatient basis and each patient will have to visit the clinic five times. The study’s primary goal is to evaluate if the experimental therapy improves cognition in people with Parkinson’s  dementia. Investigators also will assess ENT-01’s effects on attention, social function and frequency and/or severity of hallucinations/delusions.

In two separate Phase 2 clinical trials, NCT03047629 and NCT03781791, ENT-01 has been shown to ease both motor and non-motor symptoms of Parkinson’s, indicating its potential to change disease progression.

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Man-made DNA Molecules May Help Prevent Parkinson’s, Study Finds

man made DNA molecules

Osaka University scientists have built short fragments of DNA that can stop the production of abnormal alpha-synuclein protein in the brain — which may advance the development of new therapies for the control and prevention of Parkinson’s disease.

The study, “Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson’s disease,” was published in Scientific Reports.

“Although there are drugs that treat the symptoms associated with PD [Parkinson’s disease], there is no fundamental treatment to control the onset and progression of the disease,” Takuya Uehara, PhD, the study’s lead author, said in a press release.

It is believed that gene therapy could someday be used to treat or halt Parkinson’s. Potential therapeutic targets include genes associated with the disorder, such as the SNCA gene — the gene that codes for the alpha-synuclein protein. Mutations in SNCA lead to the production and accumulation of an abnormal, and harmful, form of the alpha-synuclein protein within brain cells of people with Parkinson’s. As the disease progresses, neuronal toxic protein buildup increases, eventually leading to cellular death. That, in turn, leads to the onset of disease-related motor and non-motor symptoms.

“The antisense oligonucleotide (ASO) is a potential gene therapy for targeting the SNCA gene. ASO-based therapies have already been approved for neuromuscular diseases including spinal muscular atrophy (SMA) [Spinraza] and Duchenne muscular dystrophy [Exondys 51],” the researchers said.

Japanese researchers now looked for ways to prevent the production of toxic alpha-synuclein, hoping to eliminate Parkinson’s molecular trigger. To do so, they designed 50 small fragments of DNA that mirrored parts of  the coding sequence of the SNCA gene messenger RNA (mRNA).

All genetic information contained within genes (DNA) is ultimately translated into proteins. However, several complex steps exist before a protein can be produced: DNA is first transformed into mRNA, and eventually, into a protein.

The man-made DNA fragments, also known as amido-bridged nucleic acid-modified antisense oligonucleotides (AmNA-ASO), were stabilized with resilient cyclic amide structures (hence the term “amido-bridged”). Amide are compounds that confer structural rigidity.

In total, these 50 molecules covered around 80.7% of SNCA’s mRNA. In doing so, engineered molecules were able to bind to their matching natural mRNA sequence, disabling it from being translated into a protein.

Using human embryonic kidney cells that naturally produce alpha-synuclein, scientists observed that several of these engineered molecules reduced SNCA mRNA levels. One of the constructs, specifically number 19, significantly decreased SNCA mRNA levels to 24.5% of the normal alpha-synuclein levels, “suggesting that AmNA-ASO [number] 19 is highly potent for targeting SNCA mRNA in human cultured cells,” the researchers said.

Importantly, this particular ASO was efficiently delivered into the brains of mice using an intracerebroventricular (a fluid-filled interconnected brain cavity) injection, without the aid of additional chemical carriers. The ASO was then mainly taken up by neurons and neuronal support cells.

Further testing, using a Parkinson’s mouse model that had disease-characteristic motor impairment, revealed AmNA-ASO number 19 successfully reduced alpha-synuclein protein levels, and significantly eased symptom severity 27 days after administration.

The researchers concluded that reducing alpha-synuclein mRNA and corresponding protein levels via gene therapy seems to enhance Parkinson’s-related motor manifestations in mice. This highlighted AmNA-ASO’s potential as a novel therapy for this neurodegenerative disorder.

The ASO Spinraza (nusinersen) was approved by the U.S. Food and Drug Administration (FDA) in December 2016 for treating spinal muscular atrophy. The FDA granted accelerated approval to Exondys 51 (eteplirsen) in September 2016, making it the first drug approved to treat Duchenne muscular dystrophy.

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Molecule May Halt Parkinson’s Progression, Study Using New Mouse Model Finds

anle138b molecule

A molecule called anle138b was able to reduce toxic alpha-synuclein aggregates, or clumps, in the brain — a key event linked to Parkinson’s — and reverse motor symptoms associated with the disease in a novel Parkinson’s mouse model.

The study, “Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model,” was published in Acta Neuropathologica. The work was funded by the charity Parkinson’s UK.

Many neurodegenerative disorders involve aggregation of misfolded (harmful) proteins in the brain. Parkinson’s is characterized by a buildup of the protein alpha-synuclein in the brain, which forms clumps known as Lewy bodies that damage and kill nerve cells, or neurons.

Anle138b has been shown to reduce toxic protein accumulation and delay disease progression in models of multiple system atrophy, Alzheimer’s disease and Parkinson’s.

Investigators from the University of Cambridge now evaluated the effects of anle138b in a new mouse model of Parkinson’s disease.

Although this molecule had previously been shown to reduce the clumping of proteins in other Parkinson’s models, the team wanted to understand its potential to treat the condition during its natural progression. To that end, they created a new mouse model that mimics the way alpha-synuclein gradually accumulates in specific areas of the brain, impairing neuronal communication and resulting in motor alterations.

The animals were nine months old before treatment initiation — around 46 human years. At the start of the treatment, the mice already showed low levels of dopamine in their striatum, a brain region involved in voluntary movement control that is severely affected in Parkinson’s. This reduction was associated with the onset of motor symptoms, including changes in gait that resembled some of the early motor symptoms seen in individuals with the disease.

However, the animals’ substantia nigra, another brain region involved in motor function that is also affected by the disease, had not yet been significantly damaged. Mice striatal (meaning “of the striatum”) and nigral (meaning “of the substantia nigra“) dopamine-producing neurons also exhibited alpha-synuclein aggregation.

Starting at nine months of age, mice were treated with anle138b for three months. Treatment reduced alpha-synuclein clumps, restored dopamine levels in the brain, and prevented dopaminergic nerve cell death. This was accompanied by gait improvements, suggesting that anle138b can effectively reverse, or at least halt, Parkinson’s progression.

These results indicated that “there is a window of time when it is possible to prevent [dopaminergic] neuronal death, even when striatal [dopaminergic] release is already impaired,” the researchers said. This means that if anle138b is given early on — before advanced nerve cell death — it may reduce  alpha-synuclein aggregates, potentially halting Parkinson’s progression.

“Our study demonstrates that by affecting early alpha-synuclein aggregation with the molecule anle138b in a novel transgenic mouse model, one can rescue the dopaminergic dysfunction and motor features that are typical of Parkinson’s,” Maria Grazia Spillantini, professor in the department of clinical neurosciences at the University of Cambridge, and the study’s lead researcher, said in a press release.

“The evidence from this early stage study builds on our understanding of how alpha-synuclein is involved in Parkinson’s and provides a new model that could unlock future treatments,” added Beckie Port, research manager at Parkinson’s UK.

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HYPE Protein Shows Promise in Treating Parkinson’s Disease, Research Shows

HYPE protein

The formation of alpha-synuclein aggregates in brain nerve cells (neurons) is thought to be one of the hallmarks of Parkinson disease. Researchers now have found that the activity of a single protein, called HYPE, may help halt alpha-synuclein accumulation and reduce its toxic outcomes, including neuronal death.

These findings, “Alpha-Synuclein Is a Target of Fic-Mediated Adenylylation/AMPylation: Possible Implications for Parkinson’s Disease,” were published recently in the Journal of Molecular Biology.

How Parkinson’s disease develops is still not well understood. However, evidence suggests that abnormal protein aggregates of alpha-synuclein, the main component of Parkinson’s disease hallmark Lewy bodies, are toxic and lead to neuronal death.

Clusters of misfolded (meaning altered structure) alpha-synuclein proteins also have been associated with disease severity. These aggregates lead to the formation of holes in the membranes of neurons, which affects their function and ability to communicate with other cells.

Previously, researchers had found that the HYPE protein can help cells cope with stress from misfolded proteins by promoting the addition of a chemical modification — called adenosine monophosphate (AMP), in a process known as AMPylation. They now asked whether HYPE also could play a role in Parkinson’s, specifically by modifying alpha-synuclein.

“Since HYPE plays such an important role in how cells deal with stress from misfolded proteins, we wondered whether diseases that result from protein misfolding were likely to need HYPE,” Seema Mattoo, PhD, an assistant professor of biological sciences at Purdue University and the study’s lead author, said in a press release.

“We know that in Parkinson’s disease, often the misfolded protein is [alpha-synuclein]. So we asked if HYPE could modify [alpha-synuclein], and if so, what are the consequences?,” Mattoo said.

Indeed, they found that HYPE is present in dopamine-producing neurons of the substantia nigra — a brain region involved in the control of voluntary movements, and one of the most affected in Parkinson’s disease – of rats.

Moreover, HYPE promoted the AMPylation of alpha-synuclein and this chemical modification decreased alpha-synuclein’s potential to aggregate.

When researchers looked at the protein under a microscope they found that HYPE changed its structure. While alpha-synuclein tends to twist, which may help promote aggregation, the new AMPylated protein did not twist as much, which may be why it aggregates less, Mattoo explained.

Importantly, AMPylation of alpha-synuclein also lessened the protein’s ability to make holes in neuronal membranes. “That means HYPE could possibly have a therapeutic effect on Parkinson’s disease,” Mattoo said.

Because alpha-synuclein is necessary for normal neuronal function, it has not been considered as a fit target for Parkinson’s therapy. However, these results open new possibilities.

“We’re all trying to apply a Band-Aid at the end of disease progression because we know aggregation causes the cells to become toxic, but how can we prevent that?” asked Mattoo. “There is still much to be understood mechanistically about it in the context of disease.”

Researchers now expect to expand their work to brain cells and animal models of Parkinson’s disease to validate their results.

“We’re in the early stages, but these results are giving us a new angle to look at potential therapeutics,” Mattoo said. “We’re trying to come up with drugs that could be used to manipulate HYPE’s activity. You could give them to patients who are starting to show signs of Parkinson’s or who are prone to having aggregated [alpha-synuclein]. That’s the direction we want to go.”

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Protein Works to Spread Toxic Clumps in Brain and Promote Parkinson’s, Study Finds


Connexin-32 — a protein found in small channels between nerve cells and involved in cell-to-cell communication — works to progress Parkinson’s disease by binding to alpha-synuclein and spreading toxic protein clumps throughout the brain, research suggests.

The study, “Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes,” was published in Acta Neuropathologica. It suggested that treatments targeting connexin-32 might help to prevent or slow disease progression.

Connexins are transmembrane proteins that form tiny channels (also known as gap junction channels), enabling communication between adjacent cells. Because connexins are expressed throughout the body and play various roles, their dysfunction is often associated with disease, including Parkinson’s, epilepsy, and Alzheimer’s.

Parkinson’s is characterized by a buildup in the brain of the protein alpha-synuclein, which forms clumps known as Lewy bodies that damage and kill nerve cells, or neurons.

“During the past few decades, we have realized that the protein deposits in the brain can spread between cells, acting as seeds that start a new aggregation cycle in the next cell. The disease in this way spreads in the brain in a manner similar to an infection,” study leader Martin Hallbeck, an associate professor in the Department of Clinical and Experimental Medicine at Linköping University in Sweden, said in a press release.

Hallbeck’s team set out to determine and better understand mechanisms that might promote the spread of alpha-synuclein.

The researchers observed that connexin-32 selectively binds to abnormally clumped alpha-synuclein and transfers it to neighboring neurons, a possible explanation for how Parkinson’s progresses within the brain. Connexin-32 also helped propagate toxic forms of alpha-synuclein between oligodendrocytes — cells that play a key role in the production of myelin that insulates nerve cells.

Neurons and oligodendrocytes, respectively, are “the primary cell types highly vulnerable to α-syn [alpha-synuclein] accumulation” in Parkinson’s and a neurological disease called multiple system atrophy (MSA), the study noted.

Using pharmacological and genetic techniques, researchers found that connexin-32 overexpression (higher-than-normal levels) was associated with the transport of alpha-synuclein clumps. When scientists blocked connexin-32 activity, the spread of abnormal alpha-synuclein lowered in a concentration-dependent manner.

Rare mutations of multiplications in the alpha-synuclein (SNCA) gene have been associated with early onset forms of Parkinson’s disease. Researchers observed that high levels of connexin-32 were present in cells that either overexpressed SNCA or were exposed to alpha-synuclein aggregates.

High levels of connexin-32 that correlated with alpha-synuclein accumulation were also observed in nerve cells in a mouse model of Parkinson’s disease.

Working with brain tissue taken from four deceased Parkinson’s patients, researchers again saw a direct binding between alpha-synuclein and connexin-32 in samples from two patients but not in four age-matched healthy controls. This finding suggests that these two proteins interact in Parkinson’s but not in a healthy brain.

“Collectively, our results provide strong evidence for [connexin-32] centrally involved in the preferential uptake and propagation of [alpha-synuclein clump] assemblies, pinpointing [connexin-32] as a novel therapeutic target to impede the uptake and spread of [alpha-synuclein] pathology in [Parkinson’s disease] and related α-synucleinopathies,” investigators concluded.

“We hope that connexin-32 can be used in the future as a target for drug treatment,” Hallbeck added.

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