Category: Parkinson’s

Tokyo Tech's Yoshihiro Miyake and colleagues have developed an innovative, non-invasive therapeutic intervention that may improve the mobility, stability, and quality of life of Parkinson's disease patients.

The technology is also described in the August issue of Tokyo Institute of Technology Bulletin: http://www.titech.ac.jp/bulletin/index.html

The unintentional synchronizing of people's gait as they walk together is a familiar phenomenon. Understanding the mechanisms behind this synchronization could help people with a disturbed gait, such as patients suffering from Parkinson's disease. Research by Yoshihiro Miyake at the Department of Computational Intelligence and Systems Science at Tokyo Institute of Technology has helped to demystify the process and led to a new walking support device — 'Walk Mate'.

Yoshihiro Miyake investigated coupled walking processes between a walking robot and a walking person. The study included people with a healthy gait and people suffering from Parkinson's disease or hemiplegia due to brain infraction. He used the timing of the walking person as a sensory input for the robot and the sound of a walking rhythm as the robot's output. An algorithm based on travelling wave dynamics controlled the timing difference between the Walk Mate's input and output.

The study revealed how people adjust their pace in response to the robot's audible output. Patients' stride patterns were healthier using 'Walk Mate' and they reported a greater stability and "sense of togetherness" compared with more traditional walking aids that have a fixed rhythm. Further studies in collaboration with researchers at the Max Planck Institute for Human Cognitive and Brain Sciences and the Department of Neurology at Kanto Central Hospital have underlined the great potential of the device.

"Our approach offers a flexible, portable, low-cost, non-invasive therapeutic intervention that may improve the mobility, stability, and quality of life of Parkinson's disease patients," say the inventors.

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Journal References:

1. Y. Miyake. Interpersonal Synchronization of Body Motion and the Walk-Mate Walking Support Robot. IEEE Transactions on Robotics, 2009; 25 (3): 638 DOI: 10.1109/TRO.2009.2020350
2. Michael J. Hove, Kazuki Suzuki, Hirotaka Uchitomi, Satoshi Orimo, Yoshihiro Miyake. Interactive Rhythmic Auditory Stimulation Reinstates Natural 1/f Timing in Gait of Parkinson's Patients. PLoS ONE, 2012; 7 (3): e32600 DOI: 10.1371/journal.pone.0032600

Scientists at the Gladstone Institutes, an independent and nonprofit biomedical-research organization, have identified a protein that exacerbates symptoms of Parkinson's disease — a discovery that could one day lead to new treatments for people who suffer from this devastating neurodegenerative illness.

In a paper being published online in Neuron, Gladstone Investigator Anatol Kreitzer, PhD, and Talia Lerner, PhD, who worked at Gladstone while completing her graduate studies at the University of California, San Francisco (UCSF), describe how a protein called RGS4 normally helps regulate the activity of neurons in the striatum — the part of the brain that controls movement. But in experimental models of Parkinson's disease, RGS4 does the opposite by actually contributing to problems with motor control. The result is a deterioration of movement and motor coordination, which are the hallmark symptoms of Parkinson's. More than 10 million people suffer from Parkinson's worldwide, including the boxer Muhammad Ali and the actor Michael J. Fox.

Scientists have long known that a drop in dopamine — an important chemical in the brain — is associated with Parkinson's. And for decades patients have taken a drug called Levodopa to boost the brain's dopamine levels. Unfortunately, however, Levodopa's efficacy begins to fade as the disease progresses. So scientists have begun looking for other targets for which they can develop new therapeutic strategies.

"About 60,000 Americans are diagnosed with Parkinson's annually, and dopamine-based therapies often do not provide a long-term solution," said Dr. Kreitzer, who is also an assistant professor of physiology and neurology at UCSF, with which Gladstone is affiliated. "Our discovery that RGS4 may play a role in the development of Parkinson's symptoms, helps us lay the groundwork for a new therapeutic strategy — independent of dopamine."

Drs. Kreitzer and Lerner found that RGS4 is required for dopamine to regulate brain circuits during learning. But when dopamine levels drop dramatically, as in Parkinson's, RGS4 becomes overactive and disrupts these circuits — thereby leading to Parkinson's symptoms. Therefore, they tested whether removing RGS4 could prevent these symptoms.

Drs. Kreitzer and Lerner treated mice lacking RGS4 with a chemical that lowers dopamine levels, mimicking the effects of Parkinson's. They then monitored the mice's motor skills — including their ability to move freely in an open arena and traverse a balance beam — and compared them to Parkinson's mice in which RGS4 remained intact.

As expected, Parkinson's mice with RGS4 intact exhibited major problems with movement. They lacked coordination and often remained frozen in place for long periods of time. When attempting to cross the balance beam, many had repeated slips and falls, while others could not even attempt the task.

But Parkinson's mice without RGS4 performed fluid, coordinated movements with no major problems, even though they also had lower dopamine levels. The vast majority crossed the balance beam without any missteps. Many of the physical traces of Parkinson's had disappeared.

"By discovering how the removal of RGS4 affects brain circuitry at the molecular level, we gained a deeper understanding of the protein's role — both normally and in Parkinson's disease," said Dr. Lerner. "We've also shed light on a previously unknown mechanism by which the dopamine depletion causes the symptoms of Parkinson's disease. We are optimistic that our work could pave the way for a much-needed alternative to Levodopa — such as a drug that has the ability to inactivate RGS4 in Parkinson's patients."

Funding for this research came from a variety of sources, including the National Institutes of Health, the Pew Biomedical Scholars Program, the W.M. Keck Foundation and the McKnight Foundation.

Parkinson's disease researchers at the University at Buffalo have discovered how mutations in the parkin gene cause the disease, which afflicts at least 500,000 Americans and for which there is no cure.

The results are published in the current issue of Nature Communications. The UB findings reveal potential new drug targets for the disease as well as a screening platform for discovering new treatments that might mimic the protective functions of parkin. UB has applied for patent protection on the screening platform.

"This is the first time that human dopamine neurons have ever been generated from Parkinson's disease patients with parkin mutations," says Jian Feng, PhD, professor of physiology and biophysics in the UB School of Medicine and Biomedical Sciences and the study's lead author.

As the first study of human neurons affected by parkin, the UB research overcomes a major roadblock in research on Parkinson's disease and on neurological diseases in general. The problem has been that human neurons live in a complex network in the brain and thus are off-limits to invasive studies, Feng explains.

"Before this, we didn't even think about being able to study the disease in human neurons," he says. "The brain is so fully integrated. It's impossible to obtain live human neurons to study."

But studying human neurons is critical in Parkinson's disease, Feng explains, because animal models that lack the parkin gene do not develop the disease; thus, human neurons are thought to have "unique vulnerabilities."

"Our large brains may use more dopamine to support the neural computation needed for bipedal movement, compared to quadrupedal movement of almost all other animals," he says. Since in 2007, when Japanese researchers announced they had converted human cells to induced pluripotent stem cells (iPSCs) that could then be converted to nearly any cells in the body, mimicking embryonic stem cells, Feng and his UB colleagues saw their enormous potential. They have been working on it ever since.

"This new technology was a game-changer for Parkinson's disease and for other neurological diseases," says Feng. "It finally allowed us to obtain the material we needed to study this disease."

The current paper is the fruition of the UB team's ability to "reverse engineer" human neurons from human skin cells taken from four subjects: two with a rare type of Parkinson's disease in which the parkin mutation is the cause of their disease and two healthy subjects who served as controls.

"Once parkin is mutated, it can no longer precisely control the action of dopamine, which supports the neural computation required for our movement," says Feng.

The UB team also found that parkin mutations prevent it from tightly controlling the production of monoamine oxidase (MAO), which catalyzes dopamine oxidation.

"Normally, parkin makes sure that MAO, which can be toxic, is expressed at a very low level so that dopamine oxidation is under control," Feng explains. "But we found that when parkin is mutated, that regulation is gone, so MAO is expressed at a much higher level. The nerve cells from our Parkinson's patients had much higher levels of MAO expression than those from our controls. We suggest in our study that it might be possible to design a new class of drugs that would dial down the expression level of MAO."

He notes that one of the drugs currently used to treat Parkinson's disease inhibits the enzymatic activity of MAO and has been shown in clinical trials to slow down the progression of the disease.

Parkinson's disease is caused by the death of dopamine neurons. In the vast majority of cases, the reason for this is unknown, Feng explains. But in 10 percent of Parkinson's cases, the disease is caused by mutations of genes, such as parkin: the subjects with Parkinson's in the UB study had this rare form of the disease.

"We found that a key reason for the death of dopamine neurons is oxidative stress due to the overproduction of MAO," explains Feng. "But before the death of the neurons, the precise action of dopamine in supporting neural computation is disrupted by parkin mutations. This paper provides the first clues about what the parkin gene is doing in healthy controls and what it fails to achieve in Parkinson's patients."

He noted in this study that these defects are reversed by delivering the normal parkin gene into the patients' neurons, thus offering hope that these neurons may be used as a screening platform for discovering new drug candidates that could mimic the protective functions of parkin and potentially even lead to a cure for Parkinson's.

While the parkin mutations are only responsible for a small percentage of Parkinson's cases, Feng notes that understanding how parkin works is relevant to all Parkinson's patients. His ongoing research on sporadic Parkinson's disease, in which the cause is unknown, also points to the same direction.

In addition to Feng, co-authors are Houbo Jiang, PhD, Yong Ren, PhD, Eunice Y. Yuen, all research assistant professors at UB; Ping Zhong, PhD, research scientist, Mahboobe Ghaedi, PhD, postdoctoral associate, Zhixing Hu, PhD, postdoctoral associate, and Zhen Yan, PhD, professor, all of the UB Department of Physiology and Biophysics. Other co-authors are Gissou Azabdaftari, MD, of the Roswell Park Cancer Institute, and Kazuhiro Nakaso, MD, of Tottori University in Japan.

 In the US alone, at least 500,000 people suffer from Parkinson's disease, a neurological disorder that affects a person's ability to control his or her movement. New technology from the University of Bonn in Germany lets researchers observe the development of the brain cells responsible for the disease.

Up until now, research into the brain cells responsible for Parkinson's disease has focused on the function and degeneration of these neurons in the adult and aging brain. The new tissue slicing method, which will be published in the world's only peer-reviewed science video journal, the Journal of Visualized Experiments (JoVE), allows scientists to observe the development of these brain cells for the first time.

"Little is known about the behavior of these neurons during their differentiation and migration phase," said article author Dr. Sandra Blaess, "and with this technique, we can really observe how these cells behave during development."

The new technique also makes the cells available for genetic manipulation, and more information about how these cells develop and function could lead to new treatment options.

"Being able to visualize cell deve

Treatments for Parkinson's disease, estimated to affect 1 million Americans, have yet to prove effective in slowing the progression of the debilitating disease.

However, University of Alabama researchers have identified how a specific gene protects dopamine-producing neurons from dying in both animal models and in cultures of human neurons, according to a scientific article publishing in the Feb. 8 edition of The Journal of Neuroscience.

This increased understanding of the gene's neuro-protective capability is, the researchers said, another step toward the potential development of a new drug treatment.

"This gene represents a previously unexplored protein therapeutic target for Parkinson's disease," said Dr. Guy Caldwell, professor of biological sciences at The University of Alabama and a co-author of the article.

The gene, known as VPS41, was one of five genes that UA scientists showed in 2008 had protective capabilities against a hallmark trait of Parkinson's, the age-associated loss of dopamine neurons. The latest announcement reflects the better understanding since gained of how the gene functions.

The latest UA research was primarily funded by the Michael J. Fox Foundation for Parkinson's Research. The scientific journal, published by the Society of Neuroscience, is the largest weekly journal dedicated to neuroscience discovery.

The researchers also found that specific, and rare changes in human DNA — changes sometimes also evident in non-Parkinson's patients — appear to impact how VPS41 functions.

"Mutations like these may represent previously unreported susceptibility factors for Parkinson's disease," Caldwell said.

The article's lead author is Dr. Adam Harrington, who earned his doctoral degree from UA in December 2011 while working in the Caldwell Lab. The additional UA co-author is Dr. Kim Caldwell, associate professor of biological sciences. Dr. Talene Yacoubian, a physician, and Sunny Slone, both of the University of Alabama at Birmingham, are also co-authors.

The researchers used both specific strains of tiny nematode worms as animal models for the work along with the human cultures.

The genetically engineered worms contain a human protein, alpha-synuclein within their cells. Scientists have learned that people with too many copies of the code for alpha-synuclein within their DNA will contract Parkinson's.

Extra copies of alpha-synuclein can lead to repeated protein misfolding and the death of the dopamine-producing neurons in the brain. In Parkinson's patients, the death of these neurons leads to rigid and tremoring limbs, difficulty in movement and impaired reflexes.

"The main advance here is that we have mechanistically defined how VPS41 appears to convey its protective capacity to neurons — not only in worms, but also in human dopamine-producing neuron cultures," said Caldwell.

The next phase in this research involves translating these findings into potential therapies.

"The obstacles of finding any disease-modifying therapy are diminished once protective mechanisms, like this one, become revealed and better defined," said Caldwell.

A University of Kentucky faculty member is a contributing author on a new study demonstrating a connection between a common solvent chemical and Parkinson's disease. Dr. Franca Cambi of the UK Kentucky Neuroscience Institute collaborated with researchers from across the U.S. on a paper recently published in the Annals of Neurology.

The novel study looked at a cohort of human twins wherein one twin had been occupationally exposed to trichloroethylene (TCE) and other chemicals believed to be linked to development of Parkinson's.

TCE has been previously linked to Parkinson's disease through prior research by UK authors and others, including the 2008 paper, "Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity," and the 2010 paper, "Trichloroethylene induces dopaminergic neurodegeneration in Fisher 344 rats." The 2008 paper was based upon a study of factory workers in a facility using chemicals that have been linked to development of Parkinson's disease.

In the most recent paper, the authors demonstrated that in addition to TCE, increase in Parkinson's disease risk is also associated with exposure to percholorethylene (PERC) and carbon tetrachloride (CCI₄).

Occupational or environmental exposure to TCE, PERC and CCI₄ is common due to the extensive use of the chemicals in dry-cleaning solutions, adhesives, paints, and carpet cleaners. Despite the Food and Drug Administration (FDA) banning the use of TCE as a general anesthetic, skin disinfectant, and coffee decaffeinating agent in 1977, it is still widely used today as a degreasing agent. In the U.S., millions of pounds of TCE are still released into the environment each year and it is the most common organic contaminant found in ground water, detected in up to 30 percent of drinking water supplies in the country.

The current epidemiological study, led by Drs. Samuel Goldman and Caroline Tanner of The Parkinson's Institute in Sunnyvale, Ca., investigated exposure to TCE, PERC and CCI₄ as they related to risk of developing Parkinson's disease. The team interviewed 99 twin pairs from the National Academy of Sciences/National Research Council World War II Veteran Twins Cohort in which one twin had Parkinson's and one didn't, inquiring about lifetime occupations and hobbies. Lifetime exposures to six specific solvents previously linked to Parkinson's in medical literature — n-hexane, xylene, toluene, CCl₄, TCE and PERC — were inferred for each job or hobby typically involving exposure to the chemicals.

While prior research has indicated a link between TCE exposure and Parkinson's disease, the current findings are the first to report a statistically significant association — a more than six-fold increased risk. Researchers also found that exposure to PERC and CCI₄ tended toward significant risk of developing the disease.

This study focused on occupational exposures, but the solvents under investigation are pervasive in the environment. Lead author Goldman concluded: "Our findings, as well as prior case reports, suggest a lag time of up to 40 years between TCE exposure and onset of Parkinson's, providing a critical window of opportunity to potentially slow the disease process before clinical symptoms appear."

The National Institute of Neurological Disorders and Stroke (NINDS) estimates that as many as 500,000 Americans have Parkinson's disease and more than 50,000 new cases are diagnosed annually. While there is much debate regarding the causes of Parkinson's disease, studies suggest that genetic and environmental factors likely trigger the disease — which is characterized by symptoms such as limb tremors, slowed movement, muscle stiffness, and speech impairment. Several studies have reported that exposure to solvents may increase risk of Parkinson's, but research assessing specific agents is limited.

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Journal Reference:

1. Samuel M. Goldman, Patricia J. Quinlan, G. Webster Ross, Connie Marras, Cheryl Meng, Grace S. Bhudhikanok, Kathleen Comyns, Monica Korell, Anabel R. Chade, Meike Kasten, Benjamin Priestley, Kelvin L. Chou, Hubert H. Fernandez, Franca Cambi, J. William Langston, Caroline M. Tanner. Solvent exposures and parkinson disease risk in twins. Annals of Neurology, 2011; DOI: 10.1002/ana.22629

A University of Kentucky faculty member is a contributing author on a new study demonstrating a connection between a common solvent chemical and Parkinson's disease. Dr. Franca Cambi of the UK Kentucky Neuroscience Institute collaborated with researchers from across the U.S. on a paper recently published in the Annals of Neurology.

The novel study looked at a cohort of human twins wherein one twin had been occupationally exposed to trichloroethylene (TCE) and other chemicals believed to be linked to development of Parkinson's.

TCE has been previously linked to Parkinson's disease through prior research by UK authors and others, including the 2008 paper, "Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity," and the 2010 paper, "Trichloroethylene induces dopaminergic neurodegeneration in Fisher 344 rats." The 2008 paper was based upon a study of factory workers in a facility using chemicals that have been linked to development of Parkinson's disease.

In the most recent paper, the authors demonstrated that in addition to TCE, increase in Parkinson's disease risk is also associated with exposure to percholorethylene (PERC) and carbon tetrachloride (CCI₄).

Occupational or environmental exposure to TCE, PERC and CCI₄ is common due to the extensive use of the chemicals in dry-cleaning solutions, adhesives, paints, and carpet cleaners. Despite the Food and Drug Administration (FDA) banning the use of TCE as a general anesthetic, skin disinfectant, and coffee decaffeinating agent in 1977, it is still widely used today as a degreasing agent. In the U.S., millions of pounds of TCE are still released into the environment each year and it is the most common organic contaminant found in ground water, detected in up to 30 percent of drinking water supplies in the country.

The current epidemiological study, led by Drs. Samuel Goldman and Caroline Tanner of The Parkinson's Institute in Sunnyvale, Ca., investigated exposure to TCE, PERC and CCI₄ as they related to risk of developing Parkinson's disease. The team interviewed 99 twin pairs from the National Academy of Sciences/National Research Council World War II Veteran Twins Cohort in which one twin had Parkinson's and one didn't, inquiring about lifetime occupations and hobbies. Lifetime exposures to six specific solvents previously linked to Parkinson's in medical literature — n-hexane, xylene, toluene, CCl₄, TCE and PERC — were inferred for each job or hobby typically involving exposure to the chemicals.

While prior research has indicated a link between TCE exposure and Parkinson's disease, the current findings are the first to report a statistically significant association — a more than six-fold increased risk. Researchers also found that exposure to PERC and CCI₄ tended toward significant risk of developing the disease.

This study focused on occupational exposures, but the solvents under investigation are pervasive in the environment. Lead author Goldman concluded: "Our findings, as well as prior case reports, suggest a lag time of up to 40 years between TCE exposure and onset of Parkinson's, providing a critical window of opportunity to potentially slow the disease process before clinical symptoms appear."

The National Institute of Neurological Disorders and Stroke (NINDS) estimates that as many as 500,000 Americans have Parkinson's disease and more than 50,000 new cases are diagnosed annually. While there is much debate regarding the causes of Parkinson's disease, studies suggest that genetic and environmental factors likely trigger the disease — which is characterized by symptoms such as limb tremors, slowed movement, muscle stiffness, and speech impairment. Several studies have reported that exposure to solvents may increase risk of Parkinson's, but research assessing specific agents is limited.

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Journal Reference:

1. Samuel M. Goldman, Patricia J. Quinlan, G. Webster Ross, Connie Marras, Cheryl Meng, Grace S. Bhudhikanok, Kathleen Comyns, Monica Korell, Anabel R. Chade, Meike Kasten, Benjamin Priestley, Kelvin L. Chou, Hubert H. Fernandez, Franca Cambi, J. William Langston, Caroline M. Tanner. Solvent exposures and parkinson disease risk in twins. Annals of Neurology, 2011; DOI: 10.1002/ana.22629

Parkinson disease (PD) is a devastating incurable disease in which degeneration of dopamine neurons in the brainstem leads to tremors and problems with movement and coordination. An increasing proportion of patients appear to be genetically predisposed to disease. Now, two independent research groups have identified a mutation associated with an inherited form of PD.

The papers, published by Cell Press in the July 9 issue of The American Journal of Human Genetics, provide new insight into the pathogenesis of late-onset PD and present compelling evidence that implicates a novel protein-recycling pathway in neurodegeneration.

"Previous studies of familial parkinsonism have identified pathogenic mutations in several genes, providing mechanistic insight and novel targets for therapeutic intervention," say the lead authors of one of the studies, Dr. Carles Vilariño-Güell and Dr. Matthew J. Farrer from the University of British Columbia. "In our study, we identified a pathogenic mutation associated with PD in a Swiss family where multiple individuals presented with disease. Confirmation of the discovery was an international effort embraced by neurologists in Canada, Israel, Norway, Switzerland, Taiwan, Tunisia, and the United States."

A second independent study, led by Dr. Tim M. Strom from the Institute of Human Genetics in Neuherberg, Germany and Dr. Alexander Zimprich from the Medical University of Vienna, used the same sophisticated sequencing techniques to look for causal mutations in a family from Austria with multiple incidences of late-onset PD.

Both groups discovered the same mutation in the vacuolar protein-sorting-associated protein 35 (VPS35) gene in affected family members. The VPS35 protein is part of a complex called the "retromer" that mediates the intracellular transport and sorting of membrane-associated cell-surface proteins that are going to be recycled or destroyed. "A single variant in the VPS35 gene was found in all affected family members investigated, was absent in general population samples, and was detected in two additional PD families," say Dr. Strom and Dr. Zimprich.

Taken together, the findings suggest that the VPS35 mutation is the genetic determinant of the late-onset PD examined in the studies and that perturbation of retromer-mediated protein sorting is linked with neurodegeneration. Interestingly, recent studies have suggested that retromer sorting defects are also associated with Alzheimer disease.

"Screening of VPS35 and its interacting partners, not only in PD patients but in other movement and cognitive disorders, is warranted to fully understand the role of the retromer in disease development. However, it is unclear how mutant VPS35 impairs retromer function or the transport of specific cargos or why dopaminergic neurons are selectively vulnerable," concludes Dr. Farrer's team. "Model systems based on VPS35 mutations can now focus on these issues and will facilitate the development of novel therapeutics."

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Journal References:

1. Carles Vilariño-Güell, Christian Wider, Owen A. Ross, Justus C. Dachsel, Jennifer M. Kachergus, Sarah J. Lincoln, Alexandra I. Soto-Ortolaza, Stephanie A. Cobb, Greggory J. Wilhoite, Justin A. Bacon, Bahareh Behrouz, Heather L. Melrose, Emna Hentati, Andreas Puschmann, Daniel M. Evans, Elizabeth Conibear, Wyeth W. Wasserman, Jan O. Aasly, Pierre R. Burkhard, Ruth Djaldetti, Joseph Ghika, Faycal Hentati, Anna Krygowska-Wajs, Tim Lynch, Eldad Melamed, Alex Rajput, Ali H. Rajput, Alessandra Solida, Ruey-Meei Wu, Ryan J. Uitti, Zbigniew K. Wszolek, François Vingerhoets, Matthew J. Farrer. VPS35 Mutations in Parkinson Disease. American Journal of Human Genetics, 2011; 89 (1): 162-167 DOI: 10.1016/j.ajhg.2011.06.001
2. Alexander Zimprich, Anna Benet-Pagès, Walter Struhal, Elisabeth Graf, Sebastian H. Eck, Marc N. Offman, Dietrich Haubenberger, Sabine Spielberger, Eva C. Schulte, Peter Lichtner, Shaila C. Rossle, Norman Klopp, Elisabeth Wolf, Klaus Seppi, Walter Pirker, Stefan Presslauer, Brit Mollenhauer, Regina Katzenschlager, Thomas Foki, Christoph Hotzy, Eva Reinthaler, Ashot Harutyunyan, Robert Kralovics, Annette Peters, Fritz Zimprich, Thomas Brücke, Werner Poewe, Eduard Auff, Claudia Trenkwalder, Burkhard Rost, Gerhard Ransmayr, Juliane Winkelmann, Thomas Meitinger, Tim M. Strom. A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease. American Journal of Human Genetics, 2011; 89 (1): 168-175 DOI: 10.1016/j.ajhg.2011.06.008

— In a new article published in the journal Molecular Neurodegeneration, researchers at the University of Missouri School of Medicine take some of the first steps toward unraveling the molecular dysfunction that occurs when proteins are exposed to environmental toxins. Their discovery helps further explain recent NIH findings that demonstrate the link between Parkinson's disease and two particular pesticides — rotenone and paraquat.

"Fewer than 5 percent of Parkinson's cases are attributed to genetics, but more than 95 percent of cases have unknown causes," said Zezong Gu, MD, PhD, assistant professor of pathology and anatomical sciences. "This study provides the evidence that oxidative stress, possibly due to sustained exposure to environmental toxins, may serve as a primary cause of Parkinson's. This helps us begin to unveil why many people, such as farmers exposed to pesticides, have an increased incidence of the disease."

Scientists previously understood that Parkinson's is associated with oxidative stress, which is when electronically unstable atoms or molecules damage cells. The MU study yields more specific information about how oxidative stress causes parkin, a protein responsible for regulating other proteins, to malfunction.

These findings come as the result of collaborative research conducted by Gu and the paper's primary author, Fanjun Meng, an MU visiting scholar from the Chinese Academy of Sciences Beijing Institute of Genomics, as well as colleagues at the Sanford-Burnham Medical Research Institute and the University of California at San Diego. The article also represents the first published work from researchers at the new MU Center for Translational Neuroscience.

Gu and his with his Burnham colleagues invented a new antibody that allowed them to detect how oxidative stress affected proteins when exposed to a variety of environmental toxins, such as the pesticide rotenone. They then specifically demonstrated how oxidative stress caused parkin proteins to cluster together and malfunction, rather than performing normally by cleaning up damaged proteins.

"This whole process progresses into Parkinson's disease," Gu said. "We illustrated the molecular events that lead to the more common form of the disorder in the vast majority of cases with unknown causes. Knowing this, we can find ways to correct, prevent and reduce the incidence of this disease."

Researchers used mass spectrometry to analyze findings. They measured parkin fragments, pinpointed whether the proteins were modified and where that modification occurred. This enabled them to map the location of parkin oxidation and further compare these events with genetic mutations in patients with Parkinson's disease reported in the literature. Their findings demonstrated that parkin protein oxidation in certain locations corresponds with the location of mutations. They then sought to determine the outcome of the modification — finding their results to be consistent in multiple disease models, including cell cultures and tissue samples from rodents, monkeys and human postmortem Parkinson's patients.

Gu and Meng hope to extend their investigation into preventive treatments and therapies through work at MU's Center for Botanical Interaction Studies. Created with a new $7.6 million grant from the National Institutes of Health, MU's center is one of five in the country selected to lead interdisciplinary and collaborative research on botanical dietary supplements.

After Alzheimer's disease, Parkinson's disease is the most common neurodegenerative disorder. Approximately 60,000 new cases of Parkinson's disease are diagnosed each year. By some estimates, at least one million people in the United States have the disease, which has no cure.

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Journal Reference:

1. Fanjun Meng, Dongdong Yao, Yang Shi, Jonathan Kabakoff, Wei Wu, Joshua Reicher, Yuliang Ma, Bernd Moosmann, Eliezer Masliah, Stuart A Lipton, Zezong Gu. Oxidation of the Cysteine-Rich Regions of Parkin Perturbs Its E3 Ligase Activity and Contributes to Protein Aggregation. Molecular Neurodegeneration, 2011; 6 (1): 34 DOI: 10.1186/1750-1326-6-34

Researchers at the Keck School of Medicine of the University of Southern California (USC) have uncovered structural clues about the protein linked to Parkinson's disease (PD), which ultimately could lead to finding a cure for the degenerative neurological disorder.

The alpha-synuclein (α-synuclein) protein is commonly found in the healthy human brain even though its function is not clear. The protein has been the subject of substantial Parkinson's research, however, because it is a major component in the protein clumps found in PD cases.

Unlike most proteins, which are typically rigid and occur in one definitive form, the alpha-synuclein protein can fold and change its structure. Researchers Tobias S. Ulmer, Ph.D. and Sowmya Bekshe Lokappa, Ph.D. at the Keck School-affiliated Zilkha Neurogenetic Institute have determined that the energy difference between two particular alpha-synuclein structures is less than previously speculated.

Their study, to be published in the June 17 issue of The Journal of Biological Chemistry, is the first to quantify that energy difference, 1.2±0.4 kcal/mol.

"We're trying to understand the mechanisms of protein folding and misfolding," said Ulmer, the study's principal investigator and an assistant professor in the Department of Biochemistry and Molecular Biology at the Zilkha Neurogenetic Institute. "Then we can say why something is going wrong, which is essential to treating neurodegenerative disorders like Parkinson's."

If proteins misfold, they are repaired or they break down. However, when alpha-synuclein misfolds it aggregates and becomes toxic to surrounding nerve cells, Ulmer said. Understanding its folding and finding what causes aberrant folding is therefore key to determining the root cause of the disorder, he added.

To put the discovery into perspective, Ulmer compared the energy that researchers thought was needed to change the protein's structure to hurricane-force winds and the actual energy required to a light summer breeze. The experiments were conducted in 2010, measuring the energy of elongated and broken helix forms of alpha-synuclein through circular dichroism spectroscopy, fluorescence spectroscopy and isothermal titration calorimetry.

"There may be a continuous interconversion between folded alpha-synuclein structural states that might contribute to its pathological misfolding," said Lokappa, a post-doctoral research associate at the Center for Craniofacial Molecular Biology at USC and the study's co-author. "But we need to have even better insight into the mechanisms of protein folding and misfolding to explain what's going wrong in the brain."

The paper is the sixth in a series of studies that Ulmer has published on alpha-synuclein.

Parkinson's is a neurological disorder that has no cure or determined cause. It is a slow-progressing degenerative disease that most commonly affects motor function. According to the National Parkinson Foundation, the disorder is the second-most common neurodegenerative disease after Alzheimer's, affecting 1 million people in the United States and some 4 million worldwide

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Journal Reference:

1. S. B. Lokappa, T. S. Ulmer. α-synuclein populates both elongated and broken helix states on small unilamellar vesicles. Journal of Biological Chemistry, 2011; DOI: 10.1074/jbc.M111.224055