cure

Manganese and Parkinson’s: Mechanism may explain link

New research, published in the journal Science Signaling, details the mechanism through which exposure to manganese can trigger protein misfolding in the brain — which may, in turn, lead to Parkinson’s-like symptoms. The findings may enable an earlier diagnosis of the neurological condition.
Manganese is an essential nutrient present in “legumes, pineapples, beans, nuts, tea, and grains.”

In the human body, manganese aids blood sugar regulation, bone formation, and immunity.

However, exposure to excessive levels of manganese may trigger Parkinson’s-like neurological symptoms. Manganese builds up in the basal ganglia area of the brain.

Researchers have known about these links between manganese and Parkinson’s for decades, but new research helps elucidate the mechanisms behind these associations.

Anumantha Kanthasamy, the Linda Lloyd Endowed Chair of Neurotoxicology at Iowa State University in Ames, led the new research.

Manganese helps transfer a faulty protein

Parkinson’s disease is characterized by clumps formed by misfolded alpha-synuclein protein. These protein aggregates are toxic to neurons.

Kanthasamy and colleagues set out to investigate how these misfolding proteins might interact with manganese to trigger the progression of Parkinson’s.

To do so, they examined data from mice and blood serum samples collected from eight welders. As a group, welders have a higher risk of prolonged manganese exposure. The research also examined a control group of 10 people.

The analyses revealed that welders with exposure to manganese had higher levels of misfolded alpha-synuclein, which puts them at a higher risk of Parkinson’s.

Additional cell culture tests showed that misfolded alpha-synuclein was secreted through small vesicles called exosomes into the extracellular space. In other words, the vesicles enabled the proteins to travel from cell to cell and further spread the misfolded protein.

The scientists also isolated alpha-synuclein-containing exosomes from alpha-synuclein-expressing cells that had exposure to manganese and delivered them to a brain area in the mice called the corpus striatum. This induced Parkinson’s-like symptoms in the mice.

Manganese seemed to accelerate the “cell-to-cell transmission” of alpha-synuclein, which, in turn, led to neurotoxicity. Kanthasamy and colleagues explain:

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.”

“[W]e identified a possible mechanism involving the exosome-mediated, cell-to-cell transmission of [alpha-synuclein] during exposure to the environmental neurotoxicant,” write the authors.

Findings may lead to earlier detection

According to the National Institutes of Health (NIH), around 50,000 individuals in the United States receive a diagnosis of Parkinson’s each year, and 500,000 people currently live with the condition.

Though the condition does not yet have a cure, diagnosing it earlier may prevent irreversible brain damage and help accelerate human clinical trials of new drugs.

The results that Kanthasamy and colleagues have just published may help scientists devise a new diagnostic test for Parkinson’s that could detect the disease much earlier on. The results may also help scientists test how effective new Parkinson’s drugs are.

“As the disease advances, it’s harder to slow it down with treatments,” Kanthasamy says. He adds: “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.”

However, the study authors also caution that their findings are still experimental, and that such a diagnostic test may not be available for years.

Article from Medical News Today.

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Radical PD treatment tested in patients

A radical Parkinson’s treatment that delivers a drug directly to the brain has been tested in people.

Patients in the trial were either given the drug, which is administered via a “port” in the side of the head, or a dummy treatment (placebo). Both groups showed improved symptoms, meaning it was not clear if the drug was responsible for the benefits. However, scans did find visual evidence of improvements to affected areas of the brain in those given the drug. The study’s authors say it hints at the possibility of “reawakening” brain cells damaged by the condition.

Other experts, though, say it is too early to know whether this finding might result in improvements in Parkinson’s symptoms. Researchers believe the port implant could also be used to administer chemotherapy to those with brain tumours or to test new drugs for Alzheimer’s and stroke patients.

Parkinson’s causes parts of the brain to become progressively damaged, resulting in a range of symptoms, such as involuntary shaking and stiff, inflexible muscles. About 145,000 people in the UK have been diagnosed with the degenerative condition, which cannot be slowed down or reversed.

For this new study, scientists gave patients an experimental treatment called glial cell line-derived neurotrophic factor (GDNF), in the hope it could regenerate dying brain cells and even reverse the condition. Participants underwent robot-assisted surgery to have four tubes placed into their brains, which allowed GDNF to be infused directly to the affected areas with pinpoint accuracy, via a port in their head.

After an initial safety study of six people, 35 patients took part in a nine-month “blinded” trial, where half were randomly assigned to receive monthly infusions of GDNF and the other half dummy infusions.

Dr Alan Whone, principal investigator, said patients in the trial had, on average, been diagnosed eight years previously, but brain scans of those given the drug showed images that would be expected just two years after diagnosis.

He said: “We’ve shown with the Pet [positron emission tomography] scans that, having arrived, the drug then engages with its target, dopamine nerve endings, and appears to help damaged cells regenerate or have a biological response.”

Tom Phipps, 63, from Bristol, said he had noticed an improvement during the trial and had been able to reduce the drugs he takes for his condition. Since it ended, he has slowly increased his medication but is continuing to ride his bike, dig his allotment and chair his local branch of Parkinson’s UK.

“My outcome was as positive as I could have wished for,” he said. “I feel the trial brought me some time and has delayed the progress of my condition. The best part was absolutely being part of a group of people who’ve got a similar goal – not only the team of consultants and nurses but also the participants.

“You can’t have expectations – you can only have hope.”

Following the initial nine months on GDNF or placebo, all participants had the opportunity to receive GDNF for a further nine months.

By 18 months, when all participants had received GDNF, both groups showed moderate to large improvements in symptoms compared with their scores before they started the study. But the authors say the results need to be treated with caution because of the possibility of the placebo effect – when a patient feels better despite taking a medicine with no active ingredient.

Researchers hope that further trials could look at increasing the doses of GDNF or the duration of treatment.

Experts said it was “disappointing” that the difference in symptoms was not significant. But they said the study was still of “great interest” and warranted follow up research.

The findings from the trials are published in the medical journals Brain and the Journal of Parkinson’s Disease.

The study also features in a two-part BBC Two documentary series, The Parkinson’s Drug Trial: A Miracle Cure? on 28 February and 7 March, at 21:00. (Viewable only from the UK.)

Article from BBC.

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Longtime Antidepressant Could Slow Parkinson’s

Michigan State University scientists now have early proof that an antidepressant drug that’s been around for more than 50 years could slow the progression of Parkinson’s.

In a proof-of-concept study, published in the journal Neurobiology of Disease, the drug nortriptyline, which has been used to treat depression and nerve pain, stopped the growth of abnormal proteins that can build up in the brain and lead to the development of the disease.

“Depression is a very frequent condition associated with Parkinson’s, so we became interested in whether an antidepressant could modify how the disease progresses,” said Tim Collier, lead author of the federally funded study and a neuroscientist at MSU.

Collier and collaborator Katrina Paumier, an assistant professor of molecular medicine, began looking at previous patient data to see if individuals who were on antidepressants experienced any delay in their need to go on a standard Parkinson’s therapy called levodopa. This type of therapy increases levels of dopamine, a natural chemical in the body that sends signals to other nerve cells and can significantly decrease in cases of Parkinson’s.

The medication also treats many of the symptoms associated with the disease such as tremors and poor muscle control.

“We found that those on a certain class of antidepressant, called tricyclics, didn’t need the levodopa therapy until much later compared to those who weren’t on that type of antidepressant medication,” Collier said.

Collier then began testing rats with the tricyclic antidepressant nortriptyline and found that it indeed was able to decrease the amount of abnormal protein that can build up in the brain. This protein, known as alpha-synuclein, can cause the brain’s nerve cells to die when in a clustered state and is a hallmark sign of the disease.

To further back up his research, he enlisted the help of his colleague and co-author Lisa Lapidus, who in previous studies had already detected whether certain compounds could bind to alpha-synuclein and stop it from accumulating.

“Proteins are constantly moving and changing shape,” said Lapidus, a professor in the Department of Physics and Astronomy. “By using a test tube model, we found that by adding nortriptyline to the alpha-synuclein proteins, they began to move and change shape much faster, preventing the proteins from clumping together. The idea that this clustering effect is controlled by how fast or slow a protein reconfigures itself is typically not a standard way of thinking in research on proteins, but our work has been able to show these changes.”

Understanding how these proteins can clump together could point researchers in new directions and help them find other possible drugs that could potentially treat Parkinson’s.

“What we’ve essentially shown is that an already FDA-approved drug that’s been studied over 50 years and is relatively well tolerated could be a much simpler approach to treating the disease itself, not just the symptoms,” Collier said.

Collier is already looking for funding for the next phase of his research and hopes to lead a human clinical trial using the drug in the future.

The National Institutes of Health, as well as the Michael J. Fox and Saint Mary’s Foundations, funded the study.

 

Article from Michigan State University.

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Next Stop for PD Research: Outer Space

In an effort to find new treatments for Parkinson’s disease, researchers are sending their experiments to space.

On Monday Aug. 14, researchers launched a key Parkinson’s disease protein, called LRRK2, to the International Space Station (ISS). The microgravity conditions in space should offer a better test environment for their experiments with this protein, the researchers said.

The materials for their experiments will travel aboard the SpaceX Dragon capsule as part of a mission to send supplies and science experiments to the ISS.

The work is a collaboration between The Michael J. Fox Foundation for Parkinson’s Research and the Center for the Advancement of Science in Space (CASIS).

LRRK2 is a type of protein that modifies other proteins. Mutations in the gene that codes for LRRK2 are thought to cause Parkinson’s disease in some people. Researchers have hypothesized that developing drugs to inhibit LRRK2, or block its activity, could help prevent Parkinson’s or slow its progression.

But before scientists can develop a drug to inhibit LRRK2, they need to know the precise structure of this protein. One way to get a detailed view of its structure is by growing crystals of LRRK2 in lab dishes. However, on Earth, gravity can interfere with the growth of these crystals, and keep them small.

“The quality of our crystals is just not good enough [on Earth],” Sebastian Mathea, a researcher at the University of Oxford who is involved in the LRRK2 project, said during a news conference about the project Tuesday (Aug. 8).

This is where the ISS research comes in: Researchers hope that the microgravity conditions in space will allow the crystals to grow bigger with fewer defects. The scientists can then get a sharper view of the crystal structure.

Scientists will grow the LRRK2 crystals for about a month in space. Then, the crystals will be sent back to Earth, where they will be analyzed with high-energy X-rays, Mathea said.

Parkinson’s disease is a progressive neurological disorder that affects people’s movement abilities, and can result in symptoms such as tremors, slowed movements and muscle stiffness. There are currently no treatments to stop or reverse the progression of the disease, according to The Michael J. Fox Foundation.

Article from Live Science.

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Statins may not be used for protection against Parkinson’s disease

Use of statins may speed up the onset of Parkinson’s disease symptoms in people who are susceptible to the disease, according to Penn State College of Medicine researchers.

Some previous research has suggested that statins, used to treat high cholesterol, may protect against Parkinson’s disease. Research findings have been inconsistent, however, with some studies showing a lower risk, some showing no difference and some showing a higher risk of Parkinson’s disease in statin users.

“One of the reasons that may have explained these prior inconsistent results is that higher cholesterol, the main indication to use statins, has been related to lower occurrence of Parkinson’s disease,” said Xuemei Huang, professor of neurology. “This made it hard to know if the statin protective effect was due to the drug or preexisting cholesterol status.”

Another reason for the inconsistent results is that there are two types of statins. Water-soluble statins cannot get into the brain, while fat-soluble statins, called lipophilic, can. Since people with high cholesterol are treated for both kinds, the interpretation of results as it relates to Parkinson’s disease is not easy.

The researchers analyzed data in a commercially-available database of insurance claims for more than 50 million people. They identified nearly 22,000 people with Parkinson’s disease, and narrowed the number to 2,322 patients with newly diagnosed Parkinson’s disease. They paired each Parkinson’s patient with a person in the database who did not have Parkinson’s — called a control group. Researchers then determined which patients had been taking a statin and for how long before Parkinson’s disease symptoms appeared. Researchers reported their results in the journal Movement Disorders.

After analyzing the data, researchers found that prior statin use was associated with higher risk of Parkinson’s disease and was more noticeable during the start of the drug use.

“Statin use was associated with higher, not lower, Parkinson’s disease risk, and the association was more noticeable for lipophilic statins, an observation inconsistent with the current hypothesis that these statins protect nerve cells,” Huang said. “In addition, this association was most robust for use of statins less than two-and-a-half years, suggesting that statins may facilitate the onset of Parkinson’s disease.”

Guodong Liu, assistant professor of public health sciences, said, “Our analysis also showed that a diagnosis of hyperlipidemia, a marker of high cholesterol, was associated with lower Parkinson’s disease prevalence, consistent with prior research. We made sure to account for this factor in our analysis.”

A recent study reported that people who stopped using statins were more likely to be diagnosed with Parkinson’s disease, a finding interpreted as evidence that statins protect against Parkinson’s disease.

“Our new data suggests a different explanation,” Huang said. “Use of statins may lead to new Parkinson’s disease-related symptoms, thus causing patients to stop using statins.”

Huang stressed that more research needs to be completed and that those on statins should continue to take the medication their health care provider recommends.

“We are not saying that statins cause Parkinson’s disease, but rather that our study suggests that statins should not be used based on the idea that they will protect against Parkinson’s,” Huang said. “People have individual levels of risk for heart problems or Parkinson’s disease. If your mom has Parkinson’s disease and your grandmother has Parkinson’s disease, and you don’t have a family history of heart attacks or strokes, then you might want to ask your physician more questions to understand the reasons and risks of taking statins.”

One limitation of this study was that the MarketScan data did not include Medicare patients, Medicaid patients or the uninsured. Also, because it was a private insurance sample, the patients were all under 65 years old, so the findings cannot be generalized to those who are older.

Other researchers on this study are Lan Kong and Douglas Leslie, Department of Public Health Sciences; Nicholas Sterling, Medical Scientist Training Program student; and Mechelle Lewis and Richard Mailman, Departments of Neurology and Pharmacology, all of Penn State College of Medicine; and Honglei Chen, Michigan State University.

The Center for Applied Studies in Health Economics and Penn State College of Medicine funded this research.

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Parkinson’s Tulip

You may have noticed that WPA uses an image of a tulip throughout our website and publications. Have you ever wondered why?

The tulip is the official symbol within the Parkinson’s community. In 1980, J.W.S. Van der Wereld, a Dutch horticulturalist who had Parkinson disease, developed a red and white tulip. Van der Wereld named his prized flower, the ‘Dr. James Parkinson’ tulip, to honor the English apothecary surgeon who originally described Parkinson’s in 1812.

You will see many variations, as PD organizations around the world use the tulip as a symbol of hope and optimism. The tulip unifies independent regional organizations like WPA, national organizations and their individual chapters, people with Parkinson’s and their family and friends, neurologists, research scientists, and more.

The tulip is a reminder that regardless of affiliation, we are one community working toward common goals: to help people with Parkinson’s live better longer, to discover better treatments, and to strive for a cure.

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