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Lack of Tissue Oxygenation from Sleep Apnea Linked to Parkinson’s, Study Suggests

obstructive sleep apnea

Lack of tissue oxygenation associated with episodes of upper airway obstruction in patients with obstructive sleep apnea syndrome (OSAS) may increase the levels of alpha-synuclein in the blood and may contribute to the development of Parkinson’s disease, a study says.

The study, “Plasma α‐synuclein levels are increased in patients with obstructive sleep apnea syndrome,” was published in the Annals of Clinical and Translational Neurology.

Parkinson’s disease mainly results from the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for controlling movement.

The disease also seems to be associated with overproduction of the protein alpha-synuclein in nerve cells of the brain. When this protein clumps together, it gives rise to small toxic deposits inside brain cells, called Lewy bodies, inflicting damage and eventually killing them.

Of note, alpha-synuclein phosphorylation — a chemical modification in which a phosphate group is added to the protein — 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 alpha synuclein aggregates.

“Recent studies found that [obstructive sleep apnea] was a risk factor for PD [Parkinson’s disease] onset, and hypoxia [lack of oxygen] may have contributed to it. [In addition,] previous studies both in vitro and in vivo revealed that hypoxia is able to induce overexpression of alpha‐synuclein (…). However, the detail mechanism remains to be further investigated,” the researchers wrote.

In this study, a group of Chinese scientists investigated the relationship between lack of tissue oxygenation caused by episodes of upper airway obstruction during sleep, and the levels of alpha-synuclein in patients with OSAS.

OSAS occurs when the throat muscles intermittently relax and block upper airways during sleep.

The study enrolled 42 patients who had been diagnosed with OSAS (eight with mild, 16 with moderate and 18 with severe OSAS) and 46 age- and sex-matched individuals with simple snoring (controls). The levels of total and phosphorylated alpha-synuclein in the patients’ blood plasma were measured by Enzyme-Linked Immunosorbent Assay (ELISA), a technique that allows researchers to measure the amount of a specific protein of interest using an enzymatic reaction).

Results showed that patients with OSAS had significantly higher levels of both total (37.68 ng/ml vs 21.08 ng/ml) and phosphorylated (26.87 ng/ml vs 14.61 ng/ml) alpha-synuclein in the plasma compared to controls.

Moreover, correlation analyses revealed the levels of both total and phosphorylated alpha-synuclein were positively correlated with the apnea–hypopnea index (an index that measures the severity of sleep apnea) and the oxygen desaturation index (an index that measures the number of times oxygen levels dip below a given threshold during sleep).

Conversely, the levels of both total and phosphorylated alpha-synuclein in the plasma were negatively correlated with the lowest and mean oxyhemoglobin saturations — the fraction of hemoglobin (red blood cells) bound to oxygen relative to the total hemoglobin found in the blood.

“In summary, the present study found that increased alpha-synuclein levels in the plasma are correlated with the degree of hypoxia in OSAS, indicating that chronic hypoxia caused by OSAS may be involved in the pathogenesis [disease manifestations]” of Parkinson’s, the scientists concluded.

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Salivary Gland Biopsy Detects Abnormal Alpha-Synuclein in Early Stages of Parkinson’s, Study Finds

salivary glands biomarker

A modified form of the alpha-synuclein protein can be found in the salivary gland tissue of Parkinson’s patients even in the early stages of the disease, suggesting the protein could be a potential biomarker for this neurodegenerative disorder, a study reports.

The study, “Nitrated alpha-synuclein in minor salivary gland biopsies in Parkinson’s disease,” was published in Neuroscience Letters.

Accumulation of alpha-synuclein, the main component of Parkinson’s disease hallmark Lewy bodies, is not limited to the brain but also occurs in the peripheral autonomic nervous system, which regulates (innervates) the viscera and gut, controlling breathing and digestion, for instance.

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

In Parkinson’s, there’s an imbalance between the production of free radicals (including oxygen and nitrogen molecules) and the ability of cells to detoxify them, which damages dopamine-producing neurons. This oxidative/nitrative stress is also known to provoke undesirable modifications 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.

Studies focusing on Parkinson’s biomarkers have suggested that patients’ salivary glands may contain a high concentration of alpha-synuclein; however, none of these studies investigated alpha-synuclein’s nitrated form.

In this study, researchers at the Beijing Tiantan Hospital in China decided to explore the presence of nitrated alpha-synuclein in minor salivary glands of Parkinson’s disease patients.

To do so, eight patients with idiopathic (of unknown cause) Parkinson’s disease in the early clinical stages, including four men and four women at a mean age of 50.75 years, and seven age-matched healthy individuals used as controls underwent a minor salivary gland biopsy. Peripheral tissue biopsy enables the assessment of tissue changes in Parkinson’s disease over a patient’s lifetime.

Results revealed that all patients had nitrated alpha-synuclein in their salivary gland tissue, while controls were all negative for the presence of the abnormal form of this protein. Alpha-synuclein positive structures were mainly located in the gland’s less irrigated connective tissue part.

Brain imaging showed patients had asymmetrical and reduced dopamine uptake in movement control brain centers, more specifically in the caudate nucleus and the putamen.

Because nitrated alpha-synuclein exists in the early stages of the disease, it could be a promising Parkinson’s biomarker. Easily accessible, minor salivary glands constitute an ideal site for abnormal protein detection.

Nonetheless, larger sample studies and those exploring nitrated alpha-synuclein in other tissues should be conducted, the researchers said.

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Alpha-Synuclein PET Tracers Identified with Potential to Track Parkinson’s Progression, AC Immune Says

alpha-synuclein PET tracers

Tracer compounds with high affinity and selectivity to alpha-synuclein deposits have been identified that could be used to detect and track Parkinson’s disease progression, AC Immune announced.

Findings were recently presented in the study, “Identification and Characterization of Selective and High Affinity Small Molecules for Positron Emission Tomography (PET) Imaging of Pathological Alpha-Synuclein,” during the 14th International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders (AD/PD 2019) in Lisbon, Portugal.

In the brains of Parkinson’s patients, there is a buildup of a protein called alpha-synuclein that forms clumps known as Lewy bodies, which are toxic and lead to neuronal death. Tau and beta-amyloid protein aggregates, commonly found in Alzheimer’s disease, are also known to play a role in Parkinson’s disease, but the exact mechanism remains elusive.

Clusters of misfolded alpha-synuclein proteins — meaning they are not in their correct structure — have been associated with disease severity.

There are noninvasive imaging techniques that allow researchers to visualize the metabolic processes in the body, such as the positron-emission tomography (PET) scan.

Developing new alpha-synuclein-specific PET tracers would allow scientists to study the distribution and the changes of the toxic clumps of alpha-synuclein protein as the disease progresses.

AC Immune screened its robust 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, which, 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 inhibit protein aggregation.

Researchers measured these molecules’ affinity to alpha-synuclein and selectivity over other protein aggregates (tau and beta-amyloid) in post-mortem samples from Parkinson’s and Alzheimer’s patients.

Several molecules exhibited high affinity, binding to alpha-synuclein present within neurons of Parkinson’s brain sections. These compounds were selective for alpha-synuclein aggregates over beta-amyloid and tau clusters.

Because a PET scan uses a small amount of a radioactive molecule, or tracer, to show differences between healthy tissue and diseased tissue, researchers radio-labeled these promising compounds with fluorine-18, a radioactive molecule.

They then evaluated these molecules’ ability to penetrate the brain as well their molecular fate within a living organism. Using non-human primates, they identified molecules with fast brain uptake and a rapid washout (meaning the biomolecule was rapidly eliminated from the body), which are the desired characteristics for a central nervous system PET tracer.

The identified alpha-synuclein PET tracer candidates will soon enter clinical trials for the imaging of pathological alpha-synuclein in Parkinson’s disease and other alpha-synuclein-related diseases.

“These data show the potential for what may be the first PET tracer for PD, which we are now moving into a Phase 1 trial,” Andrea Pfeifer, PhD, CEO of AC Immune SA, said in a press release.

“We believe that therapeutic developments coupled with the diagnostic tools needed to properly identify and select patients allow us to follow disease progression and confirm potential efficacy of therapeutic interventions. This will provide critical differentiation for our product-candidates and benefit patients with neurodegenerative diseases,” she added.

Besides these data on PET tracers, AC Immune and its partners presented six more studies on the potential role and discovery of other imaging tracers for Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), supranuclear palsy, and dementia.

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Delays in Parkinson’s Treatment Due to Fear of Side Effects a Serious Problem, Neurologist Says

delays in treatments

A fear of the potential side effects of Parkinson’s disease treatments, dubbed “levodopa phobia,” can cause patients and their doctors to delay the use of these therapies, a neurologist says.

However, evidence suggests that starting adequate levodopa therapy early is safe, particularly for patients with increased functional disability, according to a lecture by Joseph Jankovic, MD, a professor of neurology at Baylor College of Medicine, which was presented by the Parkinson Voice Project (PVP.)

Jankovic’s lecture, “New and Emerging Treatments for Parkinson’s Disease,” was presented to patients and caregivers via Skype as part of the PVP’s Parkinson’s Lecture Series, from the Clark and Brigid Lund Parkinson’s Education Center. A video of the presentation is available online.

Disease-modifying therapies

There are no therapies currently available that slow or prevent the progression of Parkinson’s, though several are in clinical trials. A Phase 3 trial (NCT00256204), called ADAGIO, completed in 2011, suggested that early Azilect (rasagiline) treatment might be able to delay the progression of the disease. However, the study included two dosages, 1 mg and 2 mg, and while the benefits were true for the the lowest dose, they didn’t hold up for the larger dose. Because the two doses were associated with different outcomes, the results needed careful interpretation, and the U.S. Food and Drug Administration (FDA) did not approve Azilect as a disease-modifying therapy. 

Researchers are exploring several treatments with the potential to modify the disease, including inosine (which elevates urate levels), and isradipine (a calcium channel inhibitor). Both are in Phase 3 trials (NCT02642393 and NCT02168842).

However, Jankovic said, the “most important strategy in development” is reducing alpha-synuclein, the protein that doesn’t work properly and accumulates in the brains of Parkinson’s patients, leading to neuronal death.

Jankovic and his colleagues last year published a study based on a Phase 2 trial  (NCT03100149) of an antibody — prasinezumab (PRX002/RG7935) — that’s designed to clear alpha-synuclein proteins. The 80-patient, ascending-dose study showed that the treatment was safe, and reduced alpha-synuclein concentrations in the blood over the course of 52 weeks, with no serious adverse events reported. The study supported the continuation of the Phase 2 trial.

Similar antibodies currently being tested in trials include Biogen’s BIIB054 (NCT03318523), AstraZeneca’s MEDI1341 (NCT03272165) — both currently recruiting — and AbbVie’s ABBV-951 (NCT03781167), which is not yet enrolling participants.

Early symptomatic therapies

When patients first start to experience symptoms severe enough to require treatment, they and their doctors may be reluctant to start levodopa or levodopa-carbidopa — the most commonly used treatment for Parkinson’s symptoms — for fear they will develop motor complications such as dyskinesias.

Some patients may turn to natural supplements, such as bacopa extract or mucuna pruriens. Jankovic “strongly discouraged” the use of these products for “many, many reasons,” chief among them that some supplements contain levodopa at inconsistent doses.

An alternative for patients and neurologists concerned about starting levodopa too early are dopamine agonists such as Mirapex (pramipexole), Requip (ropinirole), Dostinex (cabergoline), and Permax (pergolide). Instead of helping the brain produce more of the dopamine it lacks, these treatments directly stimulate the receptors that dopamine would normally act on.

A 2009 study, which compared pramipexole with levodopa in patients who had not yet been treated with levodopa, found that 50% of those on pramipexole experienced dyskinesia, compared with 68.4% of the levodopa patients.

“There is no doubt that delaying levodopa therapy by using dopamine agonists early may delay the onset of levodopa-related motor complications,” Jankovic said.

Although levodopa has some potential for side effects in vitro (or in the laboratory), Jankovic said there is no evidence that this translates to patients. Therefore, delaying the use of the therapy, particularly for patients with increased functional disability, is not backed by currently available scientific data, he said.

However, he believes that because every patient is different, the timing, choice, and dosage of therapy must be individualized according to the needs of each particular patient.

Emerging and experimental therapeutics

Almost all patients with severe Parkinson’s who take levodopa or levodopa-carbidopa will, over time, experience motor fluctuations and dyskinesias. Thus, many emerging therapies are designed to make the treatment more effective and reduce the side effects.

There are three therapies work to extend the effectiveness of levodopa by maintaining increased dopamine concentrations in the brain. Xadago (safinamide) inhibits monoamine oxidase, an enzyme that normally breaks down dopamine. Opicapone works by preventing a different enzyme, catechol-O-methyltransferase (COMT), from breaking down dopamine. Gocovri (amandine) prevents cells from recycling dopamine.

Several new formulations of levodopa are intended to stretch the effects of a single dose, or act almost immediately to help patients recover from “off” episodes between doses.  

Rytary, a capsule that can be taken orally, contains beads of carbidopa-levodopa that dissolve and release the medicine at different times. Since the treatment needs to be taken more than once a day, patients end up ingesting a higher dose of levodopa than they would otherwise. But the effects start sooner and last longer than the common formulation of carbidopa-levodopa.

Researchers have experimented with administering the treatment continuously for 24 hours using an intestinal gel, which is surgically implanted into the small intestine and programmed to consistently administer the treatment at the appropriate dose.

But choosing this surgery “cannot be taken lightly,” Jankovic said. While patients did increase their “on” time without dyskinesia (by 4.11 hours for those who used the intestinal gel compared with 2.24 hours for those who used oral levodopa), almost all of the 66 patients in a 2014 study experienced gastrointestinal side effects as a result of the device insertion.

Jankovic also described the “accordion” pill currently being tested in a Phase 3 trial (NCT02605434). The pill, developed by Intec Pharma, is a multilayer film that unfolds in the stomach and stays there for 12 hours, releasing a combination of levodopa and carbidopa.

Rather than extending the life of a dose of levodopa, some companies develop “rescue therapies” that can be taken during “off” periods, or when treatment wears off. These therapies take effect almost immediately, and help the patient make it until their next scheduled dose of levodopa. Several forms — both approved and in trials — are dopamine agonists injected under the skin.

Other companies are developing dopamine agonists they hope will be delivered through less invasive methods, such as under the tongue, in the case of APL-130277, or through inhalation, like Inbrija.

Surgical therapies are gaining more attention, with scientists testing focused ultrasound, which was approved by the FDA at the end of 2018. However, it is available in very few centers, and costs more than $4 million.

Also during 2018, researchers conducted a pilot study of five patients suggesting that spinal cord stimulation may be able to help patients improve gait.

Jankovic says it is too early to meaningfully discuss several other experimental therapies, such as gene therapies or stem cell treatments. “Ask me in 10 years,” he said.

Different agents are being investigated to treat non-motor symptoms, including Exelon (rivastigmine) and memantine (sold under the brand name Namenda, among others) for cognitive impairment, paroxetine and venlafaxine for depression, and SEP-363856 for psychosis. Nuplazid (pimavanserin) is the only therapy currently approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

In addition to all the therapies on the market, Jankovic said, he “couldn’t emphasize enough the importance of physiotherapy,” and high-intensity exercise — “something that really makes you huff and puff.”

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Mouse Studies Suggest Protective Effects of Caffeine in Parkinson’s Disease

caffeine and Parkinson's

Two new studies in mice suggest that caffeine might have protective effects in the brains of Parkinson’s disease patients.

The studies, “Chronic Caffeine Treatment Modulates  Disease Progression in a Transgenic Alpha-Synuclein Prion-Like Spreading Mouse Model of Parkinson’s Disease,” and “Chronic Caffeine Treatment Reverses A-Synuclein-Induced Cognitive Impairment With Enhanced Dendritic Spine Density and Morphology in Mice,” will be presented during the 14th​ International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders, March 26-31 in Lisbon, Portugal.

Previous epidemiological studies have suggested that consuming caffeine might protect against the development of Parkinson’s. These more-recent studies set out to test this premise more directly in an animal model.

Both studies used mouse models of Parkinson’s that involved injecting mice with alpha-synuclein. This protein is a major component of Lewy bodies, irregular “clumps” in brain cells that are a hallmark of Parkinson’s pathology. Specifically, both research teams used a mutant form of the protein called A53T, which forms these clumps even more effectively than the wild-type protein.

In both studies, injection with A53T led to changes characteristic of Parkinson’s disease, such as impaired motor function and memory, as well as changes in brain physiology, like the development of the aforementioned Lewy bodies and loss of dendritic spines (parts of neurons involved in making connections in the brain).

However, when the mice were given caffeine in their drinking water, these effects were lessened. Both studies showed similarly beneficial results, though the exact parameters that were measured were different.

In the first study, researchers at Aarhus University, Denmark, report that mice given caffeine had less alpha-synuclein in their brains. Caffeine also caused a three–week delay in the onset of clasping, which is a behavior mice do with their hind limbs that is indicative of brain damage. Furthermore, caffeine-treated mice lived, on average, 40% longer than their counterparts who weren’t given caffeine.

In the second study, researchers at Wenzhou Medical University, China, reported that mice given caffeine had fewer memory problems and more dendritic spines than their untreated counterparts.

Both studies support the previous epidemiological evidence that caffeine can be protective for Parkinson’s disease, although there is the usual caveat that experiments in animal models are never a perfect replica of actual human disease.

It also is not clear why or how caffeine might have such protective effects, and further research will be needed to figure out just how caffeine might benefit Parkinson’s patients.

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ProMIS to Present Data on Potential of Antibodies to Target Toxic Alpha-Synuclein in Parkinson’s

ProMIS Neurosciences antibodies

ProMIS Neurosciences will present evidence of the selectivity of several of its antibody candidates to target the toxic forms of alpha-synuclein, a key component of Lewy bodies that underlie the development of Parkinson’s disease.

Neil Cashman, PhD, chief scientific officer of ProMIS, will present the study, “Targeting of Pathogenic Aggregated Alpha-Synuclein: Refining Antibody Epitopes by Design,” at the 14th​ International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders, taking place March 26–31 in Lisbon, Portugal.

In Parkinson’s disease, alpha-synuclein’s 3D structure is abnormal, or misfolded, promoting its aggregation into clumps and causing the death of dopamine-producing nerve cells — those responsible for releasing the neurotransmitter dopamine, which is critical for regulating brain cell activity and function.

ProMIS Neurosciences developed a technology to design antibody candidates that bind only to the toxic forms of misfolded proteins like alpha-synuclein.

This means that healthy alpha-synuclein proteins are left alone, allowing the protein to function normally inside the cells — alpha-synuclein plays a key role in the healthy brain, regulating the release of synaptic vesicles, “bubbles,” filled with chemical neurotransmitters (chemical messengers). The synapse is the junction between two nerve cells that allows them to communicate.

This regulation occurs when alpha-synuclein is in its healthy state, i.e., arranged in a tetramer — four units of the protein wrapped around each other.

In lab studies, the antibody candidates were able to protect rodent neurons against the toxicity of alpha-synuclein and inhibited the mechanisms involved in the protein’s propagation.

ProMIS Neurosciences’ lead antibody candidate, PMN310, is a potential treatment for Alzheimer’s disease, and was shown to attack only toxic forms of a protein linked to the disease — amyloid-beta — and not normal forms. This investigational therapy is expected to enter Phase 1 clinical trials in 2019.

“The ability to bind toxic forms and only the toxic forms of misfolded proteins in the brain has been a frustratingly elusive challenge in both Parkinson’s and Alzheimer’s drug development,” Cashman said in a press release. “This is largely because the toxic species of the affected proteins still share many similarities with the healthy forms of the protein, making them impossible to target with precision using traditional tools for developing antibodies.”

“Using our unique discovery platform, we have been able to successfully address this problem. Our data show we can raise antibodies that bind the toxic species and only the toxic species of alpha-synuclein with exquisite precision while preserving the healthy forms of the protein,” he added.

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Alpha-Synuclein Impairs ClpP Enzyme, Causing Mitochondrial Damage, Study Says

ClpP, mitochondrial damage

Alpha-synuclein reduces the levels and impairs the function of ATP-dependent Clp protease (ClpP), an enzyme found in mitochondria — the cell compartments responsible for the production of energy — causing mitochondrial damage and oxidative stress, a study shows.

The study, “Alpha-synuclein suppresses mitochondrial protease ClpP to trigger mitochondrial oxidative damage and neurotoxicity,” was published in Acta Neuropathologica.

Parkinson’s disease mainly results from the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for movement control.

The disease also seems to be associated with overproduction of the protein alpha-synuclein in nerve cells of the brain. When this protein clumps together, it gives rise to small toxic deposits inside brain cells, inflicting damage and eventually killing them. Besides the accumulation of alpha-synuclein, Parkinson’s disease has also been linked to mitochondrial dysfunction.

Previous studies have shown that alpha-synuclein, in particular its A53T mutant form, accumulates in mitochondria, progressively causing mitochondrial damage. However, the mechanisms by which alpha-synuclein and mitochondrial proteins interact and regulate each other during this process are not fully understood.

ClpP, a mitochondrial enzyme that breaks down proteins (protease), is important for maintaining healthy mitochondria. In addition, ClpP dysfunctions have been associated with neurodegenerative diseases, suggesting that this enzyme might be one of the missing links that could explain the relationship between alpha-synuclein and mitochondria dysfunction in Parkinson’s disease.

To explore this idea, a group of researchers from the Case Western Reserve University School of Medicine and their collaborators set out to investigate if and how alpha-synuclein and its A53T mutant form affected the levels and function of ClpP in neurons isolated from patients with Parkinson’s and in animal models of disease.

Researchers showed that the levels of ClpP dropped significantly in the presence of high levels of alpha-synuclein. This was true for neurons derived from patients’ induced pluripotent stem cells (iPSCs), in dopamine-producing neurons isolated from mice genetically engineered to produce the A53T mutant form of alpha-synuclein and in postmortem brain samples from patients. iPSCs are fully matured cells that are reprogrammed back to a stem cell state, where they are able to grow into almost any type of cell.

On the other hand, a strong reduction in the levels of ClpP led to an overproduction of abnormal misfolded mitochondrial proteins, a reduction in mitochondrial activity, and increase in oxidative stress and cell death. Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them, resulting in cellular damage as a consequence of high levels of oxidant molecules.

Interestingly, forcing the production of ClpP successfully reduced oxidative stress associated with alpha-synuclein and prevented the accumulation of phosphorylated alpha-synuclein in neurons derived from iPSCs of patients carrying the alpha-synuclein A53T mutant.

Phosphorylation is a chemical modification in which a phosphate group is added to the protein. Alpha-synuclein phosphorylation 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 alpha-synuclein aggregates.

In addition, investigators found that both the normal and A53T mutant forms of alpha-synuclein physically interacted with ClpP, blocking its activity. Remarkably, when researchers induced the production of an artificial form of ClpP in the brains of mice that produced the A53T mutant form of alpha-synuclein, they managed to prevent mitochondrial damage and oxidative stress, and to slow disease progression and behavioral impairments.

“In this study, we have identified, for the first time, an important role of mitochondrial matrix protease ClpP in [alpha-synuclein]-associated neuropathology [in Parkinson’s disease]. Thus, our findings should stimulate the development of ClpP modulators as potential disease-modifying therapeutic agents in [Parkinson’s disease] and other synucleinopathies,” the researchers concluded.

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Manganese Exposure May Be Linked to Parkinson’s Development, Study Suggests

manganese

Exposure to the metal manganese may lead to the development of Parkinson’s disease by promoting the release from nerve cells of alpha-synuclein, the subsequent aggregation of which causes inflammation and neurodegeneration, according to a study.

The study, “Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein,” was published in the journal Science Signaling.

Increasing studies have reported that aggregated alpha-synuclein — the main component of Lewy bodies, a Parkinson’s characteristic — is able to migrate within the central nervous system (brain and spinal cord), a process associated with Parkinson’s progression.

Alpha-synuclein induces brain inflammation and neurodegeneration after being secreted from nerve cells in exosomes — tiny vesicles thought to play a role in cell-to-cell transmission of misfolded proteins.

Small amounts of manganese are essential for the proper functioning of certain enzymes in the body. However, exposure to this metal — which has a range of industrial uses as an alloy — in contaminated air and drinking water, as well as in agricultural products, may lead to a movement disorder called manganism with manifestations similar to those of Parkinson’s. Additionally, occupational exposure to manganese in welding fumes has been linked to a higher risk of parkinsonism, a general term for disorders causing movement problems that resemble Parkinson’s.

However, the precise mechanisms through which manganese exerts a neurotoxic effect, as well as its role in alpha-synuclein propagation, are not well-understood by scientists yet.

Researchers at Iowa State University conducted a range of in vitro (in the lab) and in vivo (in animal models) experiments to address this lack of knowledge as well as to evaluate whether exosomes are involved in the transmission of alpha-synuclein.

The in vitro assessments in dopamine-producing nerve cells of mice revealed that exposure to manganese induced the release of misfolded alpha-synuclein through exosomes. These exosomes were then taken up by immune cells called microglia, producing neuroinflammatory responses as reflected by the release of proinflammatory molecules TNF-alpha, interleukin (IL)-12, IL-1beta, and IL-6.

“These results support recent observations indicating that neuroinflammation plays a major role in [Parkinson’s],” the researchers wrote.

In a model of human dopaminergic neurons, exosomes caused toxicity or apoptosis — which refers to “programmed” cell death, as opposed to cell death caused by injury.

A subsequent imaging analysis found that orally delivered manganese accelerated cell-to-cell transmission of aggregated alpha-synuclein, leading to toxicity in dopamine-producing cells. This was assessed in mice injected with a viral vector to produce alpha-synuclein coupled with a fluorescent tag to enable visualization.

Mice that were given both the viral vectors and manganese exhibited more impaired motor function than those injected with the vectors alone, as well as severe loss of dopamine-producing nerve cells in the substantia nigra — an area of the brain known to be affected in Parkinson’s disease.

Researchers also found higher levels of alpha-synuclein in exosomes in blood samples from eight welders, at a mean age of 46 years, with no symptoms of Parkinson’s, compared with 10 healthy individuals used as controls.

“As a group, welders are at risk of prolonged exposures to environmental levels of metals, including [manganese],” the researchers wrote.

The team also observed that injecting alpha-synuclein-containing exosomes collected from cells exposed to manganese into the mouse striatum — a brain region connected to the substantia nigra that also shows lower levels of dopamine in Parkinson’s disease — induced more lethargic behavior as observed by reduced exploratory activity after six months. This was associated with an inflammatory response in the brain.

“Together, these results indicate that [manganese] exposure promotes [alpha-synuclein] secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models,” the researchers wrote.

“As the disease advances, it’s harder to slow it down with treatments,” Anumantha Kanthasamy, PhD, the study’s senior author, said in a press release. “Earlier detection, perhaps by testing for misfolded alpha-synuclein, can lead to better outcomes for patients. Such a test might also indicate whether someone is at risk before the onset of the disease.”

Kanthasamy is the Clarence Hartley Covault distinguished professor in veterinary medicine and the Eugene and Linda Lloyd endowed chair of neurotoxicology at Iowa.

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Potential Parkinson’s Therapy ABBV-0805 Enters Phase 1 Testing in Healthy Volunteers

ABBV-0805 alpha-synuclein

AbbVie has launched a Phase 1 trial in the United States to assess the safety and tolerability of an investigational antibody targeting alpha-synuclein called ABBV-0805 in healthy volunteers.

This study comes after the U.S. Food and Drug Administration approved an investigational new drug application for ABBV-0805 in February.

Findings of this initial Phase 1 trial will provide critical information for the design and progression of future clinical studies on this antibody as a potential disease-modifying treatment for patients with Parkinson’s disease.

Formerly known as BAN0805, ABBV-0805 was initially engineered and developed by BioArctic. It is a monoclonal antibody designed to specifically bind and destroy toxic aggregates of alpha-synuclein protein, which are known to contribute to the development of Parkinson’s disease.

In preclinical studies, this investigational antibody effectively decreased the levels of alpha-synuclein clumps by 65% compared with placebo. In addition, treatment with ABBV-0805 also delayed disease progression, reduced Parkinson’s-associated motor symptoms, and improved overall survival in a mouse model of Parkinson’s disease.

BioArctic and AbbVie established a strategic collaboration agreement in 2016 for the further development and future marketing rights on BioArctic’s portfolio of antibodies directed against alpha-synuclein.

More recently, in December 2018, AbbVie exercised its option to acquire full rights over ABBV-0805. The company is now responsible for the clinical program and regulatory approval of the new antibody as a treatment for Parkinson’s and other potential indications.

“It is gratifying that our partner AbbVie has started the first clinical trial, a Phase 1 study, with ABBV-0805,” Gunilla Osswald, PhD, CEO of BioArctic, said in a press release. “We are now looking forward to ABBV-0805 moving forward in the clinical program and developing into a therapy with the potential to provide meaningful advances for patients with Parkinson’s disease.”

BioArctic will continue to develop other potential therapies targeting misfolded and abnormal proteins linked to Parkinson’s disease in the continued collaboration with AbbVie.

“I am looking forward to continuing the successful partnership with the ambition to deliver a new innovative disease modifying treatment to improve the quality of life for the large number of patients with Parkinson’s disease,” Osswald said in a previous press release.

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Leukemia Treatment Tasigna Improves Brain Dopamine Use In Parkinson’s Patients, Trial Finds

dopamine, Tasigna

Treatment with a single dose of the leukemia therapy Tasigna (nilotinib) improves the brain’s ability to use dopamine in people with Parkinson’s by reducing inflammation and levels of toxic alpha-synuclein, according to Phase 2 trial results.

The research, “Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson’s disease,” was published in the journal Pharmacology Research & Perspectives.

Previous studies by the team at Georgetown University Medical Center showed that a low dose of Novartis’ Tasigna is able to reach the brain, ease inflammation and degrade misfolded alpha-synuclein — the main component of Parkinson’s characteristic Lewy bodies — in animal models of neurodegenerative disease. Tasigna also increased levels of dopamine — the neurotransmitter found at reduced levels in this disease — and improved motor and cognitive function.

A pilot study in 12 individuals with Parkinson’s disease dementia and dementia with Lewy bodies suggested that this therapy could effectively treat Parkinson’s motor and non-motor symptoms, while also increasing dopamine metabolism — its use in the brain — and lowering alpha‐synuclein levels.

The scientists now studied the pharmacological profile of Tasigna in patients with Parkinson’s. The study, part of a Phase 2 trial (NCT02954978), included 75 participants, randomized into five groups of 15, who received either placebo or one of four doses of Tasigna — 150 mg, 200 mg, 300 mg, or 400 mg.

At one, two, three, and four hours after treatment, researchers measured Tasigna’s levels in the blood and cerebrospinal fluid (CSF, the liquid surrounding the brain and spinal cord). They also measured DOPAC and homovanillic acid (HVA) — both byproducts of dopamine metabolism — oligomers (small bits of alpha-synuclein), and the TREM-2 protein, an indicator of neuroinflammation. Levels of alpha-synuclein oligomers are typically increased and are potentially toxic in Parkinson’s disease.

The findings revealed that the ability of Tasigna to enter the brain was independent of the dose used. However, the optimal dose to increase the levels of DOPAC and HVA compared to placebo, thereby dopamine use, was 200 mg.

“This is exciting because this kind of potential treatment for Parkinson’s could increase use of a patient’s own dopamine instead of using or periodically increasing drugs that mimic dopamine,” Charbel Moussa, PhD, the study’s senior author, said in a press release.

The same 200 mg dose significantly increased the CSF level of TREM-2. The lowest dose (150 mg) induced a significant decrease in plasma levels of alpha-synuclein at two hours of treatment, while the 200 mg and 400 mg doses reduced the ratio of oligomers to total alpha‐synuclein in the CSF.

“This suggests an elevated beneficial immune activity that targets misfolded alpha-synuclein for destruction,” said Moussa, also the scientific and clinical research director of the Translational Neurotherapeutics Program at Georgetown.

“Taken together, 200 mg Nilotinib appears to be an optimal single dose that concurrently reduces inflammation and engages surrogate disease biomarkers, including dopamine metabolism and alpha‐synuclein,” researchers stated.

Overall, the effects of Tasigna in the brain are “unprecedented for any drug now used to treat Parkinson’s,” Moussa said.

The scientists said that the effects seen at lower but not higher doses may be due to Tasigna having multiple targets, which may cause lower specificity if too much of the therapy is used.

Moussa said alpha-synuclein helps release dopamine from the tiny vesicles containing this neurotransmitter. However, in Parkinson’s, the increasing production of misfolded alpha-synuclein impairs dopamine breakdown.

In preclinical studies, Tasigna improved dopamine release by triggering brain cells to attack the misfolded protein, which could help explain the increase in TREM-2 and dopamine breakdown in the CSF of patients, Moussa noted.

Fernando Pagan, MD, the trial’s principal investigator, agreed that Tasigna appears to lessen toxic alpha-synuclein and brain inflammation, while preserving dopamine and dopamine-producing nerve cells.

“Whether or not, or how much, the drug demonstrates improved clinical outcomes will be determined when the [Phase 2] clinical trial results are in,” Pagan said.

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