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Study of Manganese Exposure in Welders Could Help in Treating Parkinson’s

cognitive problems

A $3.7 million federal grant is funding a project aiming to clarify how exposure to manganese, a trace metal, affects the brain and causes cognitive problems.

Findings from this research may help in better understanding Parkinson’s disease.

Manganese is an essential nutrient, a mineral that is necessary in very small quantities (usually obtained from food) for the body to function. However, exposure to high amounts of manganese can cause problems in the nervous system, including movement and cognitive difficulties.

These symptoms of high manganese exposure (sometimes called manganism) are similar to Parkinson’s symptoms, possibly because both manganism and Parkinson’s are caused by similar types of damage to the brain.

Previous research has shown that high amounts of manganese can kill dopamine-producing neurons in the brain. These are the same neurons that die off in Parkinson’s disease, which is the primary cause of its motor symptoms. Therapies that replace lost dopamine (e.g., levodopa) are mainstays of treatment for both manganism and Parkinson’s.

However, while this mechanism explains motor problems in both conditions, it’s less clear how cognitive problems — such as memory issues, irritability, aggression, and confusion — arise in manganism, or in Parkinson’s.

“People think of Parkinson’s disease as a movement disorder, and it is, but cognitive problems are also very common,” Susan Criswell, MD, a professor at Washington University School of Medicine who is leading the project, said in a press release.

“The cognitive issues you see in people exposed to manganese are very similar to mild cognitive impairment and dementia in Parkinson’s disease. Understanding the causes of these cognitive issues is going to be very helpful in ultimately finding better treatments for people exposed to manganese and people with dementia linked to Parkinson’s,” Criswell added.

Funded by the National Institute of Environmental Health Sciences of the National Institutes of Health, the project focuses on welders, who are often exposed to high amounts of manganese through fumes they inhale as part of their job. Previous research by Criswell and colleagues has shown that welders with higher manganese exposure tend to have more Parkinson’s-like symptoms.

“When we do screenings with welders, we always find some with very mild symptoms that only a trained neurologist would detect,” Criswell said. “But their symptoms can worsen over time, and that progression does seem to be related to the amount of manganese exposure. The welders … could yield real insight into how the disease develops and how we can stop it.”

Some 60 welders working in the Midwest are undergoing a series of cognitive tests, as well as a positron emission tomography (PET) brain scan. This scan can assess the health of two types of neurons: those that produce dopamine (dopaminergic neurons), and those that produce acetylcholine (cholinergic neurons).

While the involvement of dopaminergic neurons in manganism is well established, little is known about the role of cholinergic neurons.

Because these two neuron types are located close together in the brain, Criswell and other researchers believe that they could be involved, too. Namely, the researchers think that damage to cholinergic neurons may account for some of the cognitive issues not explained by damage to dopaminergic neurons.

By studying the brains of these welders, the project could shed light on the underlying neurology of manganism. Since the conditions are so similar, these insights may also help in better understanding — and, eventually, finding ways to better treat — Parkinson’s disease.

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Metabolism of Metals in Blood May Be Affected by Parkinson’s Disease, Study Says

blood and metal concentrations

Cooper concentrations are significantly affected in the blood serum of Parkinson’s patients, suggesting this metal metabolism could somewhat influence the mechanisms behind this neurodegenerative disorder, a study reports.

The results, “Assessment of copper, iron, zinc and manganese status and speciation in patients with Parkinson’s disease: A pilot study,” were published in the Journal of Trace Elements in Medicine and Biology.

Environmental factors are thought to contribute to Parkinson’s disease (PD). Metals such as copper, iron, zinc, and manganese are known to be neurotoxic. Evidence indicates that metal exposure can contribute to Parkinson’s-related neurodegeneration, mainly by modulating alpha-synuclein protein aggregation — one of the key events in the development of PD.

For instance, higher-than-usual iron levels have been found in a brain region important to motor control, called the substantia nigra, of Parkinson’s patients. This brain area is one of the most affected by the disease.

High levels of zinc and copper have also been found in the cerebrospinal fluid (surrounds the brain and spinal cord) of people with Parkinson’s. In addition, severe manganese overexposure can cause Parkinson’s-like symptoms. Manganese is a compound present in ground water.

Although metal exposure is known to play some role in neurodegeneration, available data on their trace amounts in Parkinson’s patients are rather contradictory.

A team of researchers in Russia assessed the levels of iron, copper, zinc, and manganese in the hair, blood serum, and urine of 13 patients, as well as the species of these metals in patients’ serum.

These 13 people (nine women and four men; mean age of 73.6) and 14 gender-matched healthy controls had their serum, urine, and hair metal content analyzed. Scientists also assessed the specific forms/species of iron, copper, zinc, and manganese that were present in participants’ serum samples.

Several exclusion criteria were used in the study to “decrease the impact of side factors.” Namely, these factors are the presence of other neurological disorders; being a vegetarian; endocrine (hormone imbalance) disorders; recurrent gastrointestinal problems; acute infectious, surgical and traumatic diseases;  metallic implants; smoking and alcohol use; and occupational or environmental exposure to metals.

While no significant differences were found in hair, urine and serum metal levels between these two groups, “a trend towards decreased hair (−22%) and urine (−41%) copper levels was observed in PD patients as compared to controls,” the researchers wrote.

Hair iron and manganese levels showed a tendency to rise in the Parkinson’s group: iron concentrations in patients exceeded those of controls by 24% and manganese levels by 21%.

Urine iron and zinc levels were 38% and 47% lower in the patient than control group. Blood serum metal levels were almost similar across the two.

In circulation, cooper is usually carried by ceruloplasmin, the major copper-carrying protein in the blood. This protein also plays a role in iron metabolism. In Parkinson’s, the binding of copper to ceruloplasmin is reduced, this way increasing the pool of free cooper available in the blood. Free cooper is thought to play a significant role in neurodegeneration, mainly by promoting oxidative stress: cellular damage as a consequence of high levels of oxidant molecules.

According to the researchers, “reduced ceruloplasmin levels may ultimately lead to increased iron sequestration in brain structures including substantia nigra.”

Speciation analysis — a process by which one can identify the quantities and concentrations of individual elements in a sample — revealed a significant decrease in the molecular binding of copper to ceruloplasmin, resulting in “a nearly ten-fold increase in serum free copper levels in PD patients.”

These results need to be interpreted carefully, as the levels of free copper in both groups were still within normal range, the researchers said.

Though metal speciation appears to be significantly affected in the serum of Parkinson’s patients, how these molecular changes impact the patients’ disease course remains to be understood.

The scientists believe that their “findings are indicative of the potential role of metal metabolism and PD pathogenesis [its origin and progression], although the exact mechanisms of such associations require further detailed studies.”

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FDA Approves Generic Version of Sinemet for Parkinson’s Treatment, Company Says

Sinemet generic

The U.S. Food and Drug Administration (FDA) has approved a generic equivalent to Sinemet (carbidopa/levodopa) for the treatment of Parkinson’s disease, according to a press release.

The oral therapy, produced by India-based Alembic Pharmaceuticals, will be available as extended-release tablets containing either 50 mg of carbidopa and 200 mg of levodopa, or 25 mg of carbidopa and 100 mg of levodopa.

Sinemet, marketed by Merck, was approved by the FDA in 2014 and is sold as controlled-release tablets in three different strengths: 25 mg of carbidopa and 100 mg of levodopa; 10 mg of carbidopa and 100 mg of levodopa; or 25 mg of carbidopa and 250 mg of levodopa.

People with Parkinson’s have low levels of the neurotransmitter dopamine in the brain. Neurotransmitters are substances produced in response to nerve signals that act as chemical messengers. Direct administration of dopamine cannot be used to increase its levels because it is unable to reach the brain due to the blood-brain barrier, a thin membrane that protects the central nervous system (brain and spinal cord) from the circulatory blood system.

Levodopa and carbidopa act to increase dopamine levels in the brain. Levodopa, a molecule involved in the chemical reaction that produces dopamine, has the ability to cross the blood-brain barrier.

Meanwhile, Carbidopa inhibits enzymes known as decarboxylases that would degrade levodopa, ensuring it reaches the brain. However, carbidopa cannot cross the blood-brain barrier, which allows decarboxylases in the brain to then convert the levodopa to dopamine. Using carbidopa together with levodopa enables the use of lower doses of levodopa, which decreases its side effects, including nausea and vomiting.

The carbidopa and levodopa extended-release tablets also are approved for treatment of postencephalitic parkinsonism, a progressive neurodegenerative disease with clinical features of Parkinson’s, likely caused by an infection, and for people with Parkinson’s symptoms following intoxication by carbon monoxide or manganese.

Brief exposure to air pollution, including to carbon monoxide, has been suggested to increase the risk of Parkinson’s disease and other neurological diseases.

Exposure to the metal manganese may trigger the development of Parkinson’s by promoting the release from nerve cells of the alpha-synuclein protein. The clustering of this protein causes inflammation and neurodegeneration.

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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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Mutations in Gene Associated With Hereditary Parkinson’s Disease Lead to Toxic Accumulation of Manganese

SLC30A10 study

Researchers have found that mutations in a gene linked to hereditary forms of Parkinson’s disease — SLC30A10 — cause accumulation of toxic levels of manganese inside cells, which disturbs protein transport and alters nerve cell function, leading to parkinsonian symptoms.

The study “SLC30A10 Mutation Involved in Parkinsonism Results in Manganese Accumulation within Nanovesicles of the Golgi Apparatus” was published in the journal ACS Chemical Neuroscience.

Manganese is an essential metal that helps enzymes carry out their functions in the body. However, too much manganese is toxic, especially for the central nervous system (brain and spinal cord), where its accumulation can lead to parkinsonian-like syndromes.

The SLC30A10 gene encodes an important manganese transport protein, which sits at the membrane of cells and pumps out manganese, to protect cells against this metal’s toxicity. However, mutations in the SLC30A10 gene block the protein’s pumping activity, resulting in manganese accumulation.

Mutations in this gene have been identified as the cause of new forms of hereditary Parkinson’s disease.

“Understanding the means by which mutations in SLC30A10 alter cellular Mn [manganese] homeostasis [manganese equilibrium] is expected to enhance understanding of the principles underlying Mn toxicity itself,” researchers wrote, which may render important information to fight certain forms of familial Parkinson’s disease.

A team of French researchers used advanced imaging techniques to find where manganese accumulates inside cells (cell lines available for laboratory research) carrying disease-causing SLC30A10 mutations versus cells carrying a normal, functional SLC30A10 gene (control cells).

Intracellular manganese levels were undetectable in control cells, confirming cells’ ability to expel the metal and avoid its toxicity. On the contrary, manganese levels were higher in cells carrying disease-causing SLC30A10 mutations.

The team then looked at cells that lacked SLC30A10 and were exposed to increasing levels of manganese. Researchers found that manganese accumulated in an organelle, called the Golgi apparatus, that works as the cell’s dispatching center for proteins. The same was true for cells carrying disease-causing SLC30A10 mutations.

Mutant SLC30A10 proteins lost their ability to expel manganese out of the cells, with cells behaving as if they had no SLC30A10 protein at all.

Using the an imaging technique known as Synchrotron X-ray fluorescence spectrometry, which allows researchers to look deeper into cells and their smaller structures, the team discovered that the main compartment for manganese accumulation in SLC30A10 mutated cells were tiny vesicles released from the Golgi apparatus.

These vesicles are important mediators of communication inside the cell. Researchers believe that disturbing this vesicular trafficking is probably the root of the toxicity induced by the disease-causing mutations of SLC30A10.

“It would be interesting to investigate whether Mn causes defects in Golgi vesicular trafficking and consequently on neurotransmitters,” researchers wrote.

Moreover, these results suggest that small molecules targeting the mutated SLC30A10 protein at the cell surface could become a potential therapeutic strategy.

Future experiments will show if a similar pattern of manganese accumulation is seen in animal models of Parkinson’s disease.

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Nicotine May Protect the Brain from Toxic Trace Metals Linked to Parkinson’s, Cell Study Finds

nicotine study

Nicotine may protect the brain from manganese and iron metal trace elements thought to be involved in the onset of Parkinson’s disease, a study based on a disease cell model reported.

The study, “Nicotine protects against manganese and iron-induced toxicity in SH-SY5Y cells: Implication for Parkinson’s disease,” was published in Neurochemistry International.

Parkinson’s is characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — leading to motor and cognitive impairments.

Although the exact causes of Parkinson’s are not yet fully understood, scientists believe the accumulation of metal trace elements, such as manganese and iron, could play a role in its onset. At low concentrations, these elements are crucial for cell growth and physiological functions; indeed, they are important for all growth and healthy workings of the body. But at high levels, they become toxic, and have been associated with several neurodegenerative disorders, including Parkinson’s.

Nicotine, a potent stimulant originally found in plants that activates the nicotinic acetylcholine receptor (nAChR) in the brain, has been shown to protect dopaminergic neurons from damage caused by different types of toxins. However, no study had addressed possible neuroprotective effects of nicotine against specific metal trace elements.

The new study from Howard University College of Medicine examined the effects of nicotine on toxic manganese and iron elements in a neuroblastoma cell line (SH-SY5Y), a standard in vitro model to study Parkinson’s disease cells, due to their dopaminergic activity.

When researchers exposed SH-SY5Y cells to high concentrations of manganese or iron for a day, toxicity levels increased by 30% and 35%, respectively. Pretreatment with nicotine was seen to completely prevent these toxic effects.

As expected, nicotine’s neuroprotective properties against toxic trace elements were lost when researchers used different types of nicotinic receptor antagonists (molecules that block the activity of nAChRs). This was true for “dihydro-beta erythroidine (DHBE), a selective alpha4-beta2 subtype antagonist and methyllycaconitine (MLA), a selective alpha7 antagonist,” the study noted.  

“In summary, the results of this study provide evidence for neuroprotective effects of nicotine against toxicity induced by Mn [manganese] or Fe [iron] in a cellular model of PD [Parkinson’s disease],” the researchers wrote.

“Moreover, both high and low affinity nicotinic receptors (i.e., alpha4-beta2 and alpha7 subtypes) appear to mediate the effects of nicotine. Thus, utility of nicotine or nicotinic agonists in trace element-induced Parkinson-like syndrome may be suggested,” they concluded.

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