Posts tagged parkinson's disease
Articles and news from the latest research reports.
Medtronic, Inc. (NYSE: MDT) announced the first implant of a novel deep brain stimulation (DBS) system that, for the first time, enables the sensing and recording of select brain activity while simultaneously providing targeted DBS therapy. This initiates research on how the brain responds to the therapy and could yield insights that one day significantly change the way people with devastating neurological and psychological disorders, such as Parkinson’s disease, essential tremor, dystonia, and treatment-resistant obsessive-compulsive disorder, are treated.
The Activa® PC+S DBS system delivers proven Medtronic DBS Therapy while at the same time sensing and recording electrical activity in key areas of the brain using sensing technology and an adjustable algorithm, which enable the system to gather brain signals at various moments as selected by a physician. Initially, this new technology will be made available to a select group of physicians worldwide for use in clinical studies. These physicians will use the system to map the brain’s responses to Medtronic DBS Therapy and explore applications for the therapy across a range of neurological and psychological conditions.
The Activa PC+S system, which delivers stimulation to targeted areas of the brain like existing Medtronic DBS systems, was implanted for the first time at Ludwig Maximilians University in Munich, Germany in a person with Parkinson’s disease. This patient will be treated by a team that includes neurologist Kai Bötzel, department of neurology, Ludwig Maximilian University and neurosurgeon Jan Mehrkens, M.D., head of functional neurosurgery, Ludwig Maximilian University, who implanted the system.
Dr. Bötzel will be the first to use data gathered by the Activa PC+S system to gain unprecedented insight into how the brain responds to DBS therapy.
“DBS therapy works for people with Parkinson’s disease and other movement disorders, but there is much to learn about how the brain responds to the therapy,” said Dr. Bötzel. “This new system will allow us to treat patients with conventional DBS therapy, while at the same time opening the door for research that was not possible until now. We hope these insights will lead to the development of effective new treatments tailored to the needs of individuals. ”
“Devastating conditions like Parkinson’s disease and obsessive-compulsive disorder take a significant toll on countless people, as well as their loved ones,” said Lothar Krinke, Ph.D., vice president and general manager of the Deep Brain Stimulation business in Medtronic’s Neuromodulation division. “Medtronic is excited to provide this new system to researchers worldwide, and we expect that their respective studies will lead to accelerated understanding of how neurological and psychological conditions develop and progress. This represents a significant milestone for DBS therapy and the long-term journey toward a closed-loop DBS system, which could personalize therapy by using device data to automatically adjust to the needs of individual patients.”
Medtronic’s Activa PC+S system received CE (Conformité Européenne) mark in January 2013. It is not approved by the U.S. Food and Drug Administration for commercial use in the United States, and will be made available to select physicians for investigational use only. Additional implants of the Activa PC+S system, including the first implant in the United States, will take place in the coming months.
MIT researchers reveal how the brain keeps eyes on the prize.
“Are we there yet?”
As anyone who has traveled with young children knows, maintaining focus on distant goals can be a challenge. A new study from MIT suggests how the brain achieves this task, and indicates that the neurotransmitter dopamine may signal the value of long-term rewards. The findings may also explain why patients with Parkinson’s disease — in which dopamine signaling is impaired — often have difficulty in sustaining motivation to finish tasks.
The work is described this week in the journal Nature.
Previous studies have linked dopamine to rewards, and have shown that dopamine neurons show brief bursts of activity when animals receive an unexpected reward. These dopamine signals are believed to be important for reinforcement learning, the process by which an animal learns to perform actions that lead to reward.
Taking the long view
In most studies, that reward has been delivered within a few seconds. In real life, though, gratification is not always immediate: Animals must often travel in search of food, and must maintain motivation for a distant goal while also responding to more immediate cues. The same is true for humans: A driver on a long road trip must remain focused on reaching a final destination while also reacting to traffic, stopping for snacks, and entertaining children in the back seat.
The MIT team, led by Institute Professor Ann Graybiel — who is also an investigator at MIT’s McGovern Institute for Brain Research — decided to study how dopamine changes during a maze task approximating work for delayed gratification. The researchers trained rats to navigate a maze to reach a reward. During each trial a rat would hear a tone instructing it to turn either right or left at an intersection to find a chocolate milk reward.
Rather than simply measuring the activity of dopamine-containing neurons, the MIT researchers wanted to measure how much dopamine was released in the striatum, a brain structure known to be important in reinforcement learning. They teamed up with Paul Phillips of the University of Washington, who has developed a technology called fast-scan cyclic voltammetry (FSCV) in which tiny, implanted, carbon-fiber electrodes allow continuous measurements of dopamine concentration based on its electrochemical fingerprint.
“We adapted the FSCV method so that we could measure dopamine at up to four different sites in the brain simultaneously, as animals moved freely through the maze,” explains first author Mark Howe, a former graduate student with Graybiel who is now a postdoc in the Department of Neurobiology at Northwestern University. “Each probe measures the concentration of extracellular dopamine within a tiny volume of brain tissue, and probably reflects the activity of thousands of nerve terminals.”
Gradual increase in dopamine
From previous work, the researchers expected that they might see pulses of dopamine released at different times in the trial, “but in fact we found something much more surprising,” Graybiel says: The level of dopamine increased steadily throughout each trial, peaking as the animal approached its goal — as if in anticipation of a reward.
The rats’ behavior varied from trial to trial — some runs were faster than others, and sometimes the animals would stop briefly — but the dopamine signal did not vary with running speed or trial duration. Nor did it depend on the probability of getting a reward, something that had been suggested by previous studies.
“Instead, the dopamine signal seems to reflect how far away the rat is from its goal,” Graybiel explains. “The closer it gets, the stronger the signal becomes.” The researchers also found that the size of the signal was related to the size of the expected reward: When rats were trained to anticipate a larger gulp of chocolate milk, the dopamine signal rose more steeply to a higher final concentration.
In some trials the T-shaped maze was extended to a more complex shape, requiring animals to run further and to make extra turns before reaching a reward. During these trials, the dopamine signal ramped up more gradually, eventually reaching the same level as in the shorter maze. “It’s as if the animal were adjusting its expectations, knowing that it had further to go,” Graybiel says.
An ‘internal guidance system’
“This means that dopamine levels could be used to help an animal make choices on the way to the goal and to estimate the distance to the goal,” says Terrence Sejnowski of the Salk Institute, a computational neuroscientist who is familiar with the findings but who was not involved with the study. “This ‘internal guidance system’ could also be useful for humans, who also have to make choices along the way to what may be a distant goal.”
One question that Graybiel hopes to examine in future research is how the signal arises within the brain. Rats and other animals form cognitive maps of their spatial environment, with so-called “place cells” that are active when the animal is in a specific location. “As our rats run the maze repeatedly,” she says, “we suspect they learn to associate each point in the maze with its distance from the reward that they experienced on previous runs.”
As for the relevance of this research to humans, Graybiel says, “I’d be shocked if something similar were not happening in our own brains.” It’s known that Parkinson’s patients, in whom dopamine signaling is impaired, often appear to be apathetic, and have difficulty in sustaining motivation to complete a long task. “Maybe that’s because they can’t produce this slow ramping dopamine signal,” Graybiel says.
Sudden Decline in Testosterone May Cause Parkinson’s Disease Symptoms in Men
The results of a new study by neurological researchers at Rush University Medical Center show that a sudden decrease of testosterone, the male sex hormone, may cause Parkinson’s like symptoms in male mice. The findings were recently published in the Journal of Biological Chemistry.
One of the major roadblocks for discovering drugs against Parkinson’s disease is the unavailability of a reliable animal model for this disease.
“While scientists use different toxins and a number of complex genetic approaches to model Parkinson’s disease in mice, we have found that the sudden drop in the levels of testosterone following castration is sufficient to cause persistent Parkinson’s like pathology and symptoms in male mice,” said Dr. Kalipada Pahan, lead author of the study and the Floyd A. Davis endowed professor of neurology at Rush. “We found that the supplementation of testosterone in the form of 5-alpha dihydrotestosterone (DHT) pellets reverses Parkinson’s pathology in male mice.”
“In men, testosterone levels are intimately coupled to many disease processes,” said Pahan. Typically, in healthy males, testosterone level is the maximum in the mid-30s, which then drop about one percent each year. However, testosterone levels may dip drastically due to stress or sudden turn of other life events, which may make somebody more vulnerable to Parkinson’s disease.
“Therefore, preservation of testosterone in males may be an important step to become resistant to Parkinson’s disease,” said Pahan.
Understanding how the disease works is important to developing effective drugs that protect the brain and stop the progression of Parkinson’s disease. Nitric oxide is an important molecule for our brain and the body.
"However, when nitric oxide is produced within the brain in excess by a protein called inducible nitric oxide synthase, neurons start dying,” said Pahan.
“This study has become more fascinating than we thought,” said Pahan. “After castration, levels of inducible nitric oxide synthase (iNOS) and nitric oxide go up in the brain dramatically. Interestingly, castration does not cause Parkinson’s like symptoms in male mice deficient in iNOS gene, indicating that loss of testosterone causes symptoms via increased nitric oxide production.”
“Further research must be conducted to see how we could potentially target testosterone levels in human males in order to find a viable treatment,” said Pahan.
Other researchers at Rush involved in this study were Saurabh Khasnavis, PhD, student, Anamitra Ghosh, PhD, student, and Avik Roy, PhD, research assistant professor.
This research was supported by a grant from the National Institutes of Health that received the highest score for its scientific merit in the particular cycle it was reviewed.
Parkinson’s is a slowly progressive disease that affects a small area of cells within the mid-brain known as the substantia nigra. Gradual degeneration of these cells causes a reduction in a vital chemical neurotransmitter, dopamine. The decrease in dopamine results in one or more of the classic signs of Parkinson’s disease that includes resting tremor on one side of the body; generalized slowness of movement; stiffness of limbs and gait or balance problems. The cause of the disease is unknown. Both environmental and genetic causes of the disease have been postulated.
Parkinson’s disease affects about 1.2 million patients in the United States and Canada. Although 15 percent of patients are diagnosed before age 50, it is generally considered a disease that targets older adults, affecting one of every 100 persons over the age of 60. This disease appears to be slightly more common in men than women.
(Source: rush.edu)
Scientists Find a Potential Cause of Parkinson’s Disease that Points to a New Therapeutic Strategy
Biologists at The Scripps Research Institute (TSRI) have made a significant discovery that could lead to a new therapeutic strategy for Parkinson’s disease.
The findings, recently published online ahead of print in the journal Molecular and Cell Biology, focus on an enzyme known as parkin, whose absence causes an early-onset form of Parkinson’s disease. Precisely how the loss of this enzyme leads to the deaths of neurons has been unclear. But the TSRI researchers showed that parkin’s loss sharply reduces the level of another protein that normally helps protect neurons from stress.
“We now have a good model for how parkin loss can lead to the deaths of neurons under stress,” said TSRI Professor Steven I. Reed, who was senior author of the new study. “This also suggests a therapeutic strategy that might work against Parkinson’s and other neurodegenerative diseases.”
Genetic Clues
Parkinson’s is the world’s second-most common neurodegenerative disease, affecting about one million people in the United States alone. The disease is usually diagnosed after the appearance of the characteristic motor symptoms, which include tremor, muscle rigidity and slowness of movements. These symptoms are caused by the loss of neurons in the substantia nigra, a brain region that normally supplies the neurotransmitter dopamine to other regions that regulate muscle movements.
Most cases of Parkinson’s are considered “sporadic” and are thought to be caused by a variable mix of factors including advanced age, subtle genetic influences, chronic neuroinflammation and exposure to pesticides and other toxins. But between 5 and 15 percent of cases arise specifically from inherited gene mutations. Among these, mutations to the parkin gene are relatively common. Patients who have no functional parkin gene typically develop Parkinson’s-like symptoms before age 40.
Parkin belongs to a family of enzymes called ubiquitin ligases, whose main function is to regulate the levels of other proteins. They do so principally by “tagging” their protein targets with ubiquitin molecules, thus marking them for disposal by roving protein-breakers in cells known as proteasomes. Because parkin is a ubiquitin ligase, researchers have assumed that its absence allows some other protein or proteins to evade proteasomal destruction and thus accumulate abnormally and harm neurons. But since 1998, when parkin mutations were first identified as a cause of early-onset Parkinson’s, consensus about the identity of this protein culprit has been elusive.
“There have been a lot of theories, but no one has come up with a truly satisfactory answer,” Reed said.
Oxidative Stress
In 2005, Reed and his postdoctoral research associate (and wife) Susanna Ekholm-Reed decided to investigate a report that parkin associates with another ubiquitin ligase known as Fbw7. “We soon discovered that parkin regulates Fbw7 levels by tagging it with ubiquitin and thus targeting it for degradation by the proteasome,” said Ekholm-Reed.
Loss of parkin, they found, leads to rises in Fbw7 levels, specifically for a form of the protein known as Fbw7β. The scientists observed these elevated levels of Fbw7β in embryonic mouse neurons from which parkin had been deleted, in transgenic mice that were born without the parkin gene, and even in autopsied brain tissue from Parkinson’s patients who had parkin mutations.
Subsequent experiments showed that when neurons are exposed to harmful molecules known as reactive oxygen species, parkin appears to work harder at tagging Fbw7β for destruction, so that Fbw7β levels fall. Without the parkin-driven decrease in Fbw7β levels, the neurons become more sensitive to this “oxidative stress”—so that more of them undergo a programmed self-destruction called apoptosis. Oxidative stress, to which dopamine-producing substantia nigra neurons may be particularly vulnerable, has long been considered a likely contributor to Parkinson’s.
“We realized that there must be a downstream target of Fbw7β that’s important for neuronal survival during oxidative stress,” said Ekholm-Reed.
A New Neuroprotective Strategy
The research slowed for a period due to a lack of funding. But then, in 2011, came a breakthrough. Other researchers who were investigating Fbw7’s role in cancer reported that it normally tags a cell-survival protein called Mcl-1 for destruction. The loss of Fbw7 leads to rises in Mcl-1, which in turn makes cells more resistant to apoptosis. “We were very excited about that finding,” said Ekholm-Reed. The TSRI lab’s experiments quickly confirmed the chain of events in neurons: parkin keeps levels of Fbw7β under control, and Fbw7β keeps levels of Mcl-1 under control. Full silencing of Mcl-1 leaves neurons extremely sensitive to oxidative stress.
Members of the team suspect that this is the principal explanation for how parkin mutations lead to Parkinson’s disease. But perhaps more importantly, they believe that their discovery points to a broad new “neuroprotective” strategy: reducing the Fbw7β-mediated destruction of Mcl-1 in neurons, which should make neurons more resistant to oxidative and other stresses.
“If we can find a way to inhibit Fbw7β in a way that specifically raises Mcl-1 levels, we might be able to prevent the progressive neuronal loss that’s seen not only in Parkinson’s but also in other major neurological diseases, such as Huntington’s disease and ALS [amyotrophic lateral sclerosis],” said Reed.
Finding such an Mcl-1-boosting compound, he added, is now a major focus of his laboratory’s work.
(Source: scripps.edu)
Study Finds Factors That May Cause Fluctuations in Deep Brain Stimulation Levels Over Time
Deep brain stimulation therapy blocks or modulates electrical signals in the brain to improve symptoms in patients suffering from movement disorders such as Parkinson’s disease, essential tremor and dystonia, but a new study suggests that several factors may cause electrical current to vary over time.
Led by Michele Tagliati, MD, director of Cedars-Sinai Medical Center’s Movement Disorders Program, the study identified variables that affect impedance – resistance in circuits that affect intensity and wavelength of electrical current. Doctors who specialize in programming DBS devices fine-tune voltage, frequency and other parameters for each patient; deviations from these settings may have the potential to alter patient outcomes.
“Deep brain stimulation devices are currently designed to deliver constant, steady voltage, and we believe consistency and reliability are critical in providing therapeutic stimulation. But we found that we cannot take impedance stability for granted over the long term,” said Tagliati, the senior author of a journal article that reveals the study’s findings.
“Doctors with experience in DBS management can easily make adjustments to compensate for these fluctuations, and future devices may do so automatically,” he added. “Although our study was not designed to link changes in impedance and voltage with clinical outcomes, we believe it is important for patients to have regular, ongoing clinic visits to be sure they receive a steady level of stimulation to prevent the emergence of side effects or the re-emergence of symptoms.”
Findings of the study – one of the largest of its kind and possibly the first to follow patients for up to five years – were published online ahead of print in Brain Stimulation. Researchers collected 2,851 impedance measurements in 94 patients over a period of six months to five years, evaluating fluctuations in individual patients and in individual electrodes. They looked at a variety of factors, including how long a patient had undergone treatment, the position of the implanted electrode, the side of the brain where the electrode was implanted, and even placement and function of contact positions along electrodes.
Medications usually are the first line of treatment for movement disorders, but if drugs fail to provide adequate relief or side effects are excessive, neurologists and neurosurgeons may supplement them with deep brain stimulation. Electrical leads are implanted in the brain, and an electrical pulse generator is placed near the collarbone. The device is then programmed with a remote, hand-held controller.
(Source: newswise.com)
Dissecting the Distinctive Walk of Disease
Pitt multidisciplinary research team proposes mathematical model that examines multiple walking patterns and movements in adults older than 65
Older adults diagnosed with brain disorders such as Parkinson’s disease often feel a loss of independence because of their lack of mobility and difficulty walking. To better understand and improve these mobility issues—and detect them sooner—a University of Pittsburgh multidisciplinary research team is working toward building a more advanced motion test that addresses a wider range of walking patterns and movements.
In a recent issue of IEEE Transactions on Neural Systems and Rehabilitation Engineering, researchers from Pitt’s Swanson School of Engineering, School of Health and Rehabilitation Sciences, and School of Medicine propose a mathematical model that can examine multiple walking, or gait-related, features in healthy and clinical populations. To date, no study has brought together such a team to examine such a high number of movement features comparing healthy and clinical older adults. Previous studies have typically only measured one or two types of movement features in just one population.
“Right away, you can tell whether an older individual has difficulties walking by conducting a simple gait test,” said Ervin Sejdic, lead author of the paper and an assistant professor of engineering in the Swanson School. “But can we quantify these changes and document them earlier? That’s the biggest issue here and what we’re trying to model.”
Thirty-five adults older than 65 were recruited for the study, including 14 healthy participants, 10 individuals with Parkinson’s disease, and 11 adults who had impaired feeling in their legs owing to peripheral neuropathy (nerve damage). Walking trials were performed using a computer-controlled treadmill, and participants wore an accelerometer—a small box attached with a belt—and a set of reflective markers on their lower body that allowed for tracking of the participants’ movements through a camera-based, motion-analysis system. These two systems allowed the team to examine the torso and lower body movements of patients as they walked. Participants completed three walking trials on the treadmill—one at a usual walking pace, another while walking slowly, and another that included working on a task while walking (i.e. pushing a button in response to a sound).
The accelerometer signals were used to examine three aspects of movement: participants moving forward and backward, side to side, and up and down. The researchers then used advanced mathematical computations to extract data from these signals.
The results—integrated into the mathematical models—showed significant differences between the healthy and clinical populations. These metrics were able to discriminate between the three groups, identifying critical features in how the participants walked.
The Pitt team is now looking to conduct this type of study on a larger scale—evaluating the gait patterns of older adults residing within independent living facilities.
“Our results indicate that we can potentially develop these mathematical models as biomarkers to predict changes in walking due to diseases like Parkinson’s disease,” said Sejdic. “Now, we want to take it further. We’re especially hoping to help those individuals in independent living facilities by predicting the declines in their walking even earlier.”
“What also makes this study unique is the multidisciplinary team approach we used,” said Jennifer S. Brach (SHRS ’94G, ’00G) coprincipal investigator of the study and associate professor in Pitt’s Department of Physical Therapy. “Here we brought together a research team that included engineers, physical therapists, and experts in geriatrics to work on an important problem in older adults—changes in mobility.”
(Source: news.pitt.edu)
Shape-shifting Disease Proteins May Explain Variable Appearance of Neurodegenerative Diseases
Neurodegenerative diseases are not all alike. Two individuals suffering from the same disease may experience very different age of onset, symptoms, severity, and constellation of impairments, as well as different rates of disease progression. Researchers in the Perelman School of Medicine at the University of Pennsylvania have shown one disease protein can morph into different strains and promote misfolding of other disease proteins commonly found in Alzheimer’s, Parkinson’s and other related neurodegenerative diseases.
Virginia M.Y. Lee, PhD, MBA, professor of Pathology and Laboratory Medicine and director of the Center for Neurodegenerative Disease Research, with co-director, John Q. Trojanowski MD, PhD, postdoctoral fellow Jing L. Guo, PhD, and colleagues, discovered that alpha-synuclein, a protein that forms sticky clumps in the neurons of Parkinson’s disease patients, can exist in at least two different structural shapes, or “strains,” when it clumps into fibrils, despite having precisely the same chemical composition.
These two strains differ in their ability to promote fibril formation of normal alpha-synuclein, as well as the protein tau, which forms neurofibrillary tangles in individuals with Alzheimer’s disease.
Importantly, these alpha-synuclein strains are not static; they somehow evolve, such that fibrils that initially cannot promote tau tangles acquire that ability after multiple rounds of “seeded” fibril formation in test tubes.
The findings appear in the July 3rd issue of Cell.
Morphed Misfolding Proteins Found In Overlapping Neurodegenerative Diseases
Tau and alpha-synuclein protein clumps are hallmarks of separate diseases – Alzheimer’s and Parkinson’s, respectively. Yet these two proteins are often found entangled in diseased brains of patients who may manifest symptoms of both disorders.
One possible explanation for this convergence of Alzheimer’s and Parkinson’s disease pathology in the same patient is a global disruption in protein folding. But, Guo and Lee showed that one strain of alpha-synuclein fibrils which cannot promote tau fibrillization actually evolved into another strain that could efficiently cause tau to fibrillize in cultured neurons, although both strains are identical at the amino acid sequence level. Guo and Lee called the starting conformation “Strain A,” and the evolved conformation, “Strain B.”
To figure out how A and B differ, Guo showed that the two strains folded into different shapes, as indicated by their differential reactivity to antibodies and sensitivity to protein-degrading enzymes. The two strains also differed in their ability to promote tau fibrillization and pathology in mouse brains, mimicking the results from cultured cells. When analyzing post-mortem brains of Parkinson’s patients, the team found at least two distinct forms of pathological alpha-synuclein.
Lee and her team speculate that in humans, alpha-synuclein aggregates may shift their shapes as they pass from cell to cell (much like a cube of silly putty being re-shaped to form a sphere), possibly developing the ability to entangle other proteins such as tau along the way. That process, in turn, could theoretically yield distinct types of alpha-synuclein pathologies that are observed in different brain regions of Parkinson’s disease patients.
While further research is needed to confirm and extend these findings, they have potentially significant implications for patients afflicted with Parkinson’s and other neurodegenerative diseases. For example, Lee explains, they could account for some of the heterogeneity observed in Parkinson’s disease. Different strains of pathological alpha-synuclein may promote formation of distinct types of alpha-synuclein aggregates that may or may not induce tau pathology in different brain regions and in different patients. That, in turn, could explain why some Parkinson’s patients, for example, experience only motor impairments while others ultimately develop cognitive impairments.
The findings also have potential therapeutic implications, Lee says. By recognizing that pathological alpha-synuclein can exist in different forms that are linked with different impairments, researchers can now selectively target one or the other, or both, for instance with strain-selective antibodies.
“What we’ve found opens up new areas for developing therapies, and particularly immunotherapies, for Parkinson’s and other neurodegenerative diseases,” Lee says.
(Source: uphs.upenn.edu)
Scientists view ‘protein origami’ to help understand, prevent certain diseases
Scientists using sophisticated imaging techniques have observed a molecular protein folding process that may help medical researchers understand and treat diseases such as Alzheimer’s, Lou Gehrig’s and cancer.
The study, reported this month in the journal Cell, verifies a process that scientists knew existed but with a mechanism they had never been able to observe, according to Dr. Hays Rye, Texas A&M AgriLife Research biochemist.
“This is a step in the direction of understanding how to modulate systems to prevent diseases like Alzheimer’s. We needed to understand the cell’s folding machines and how they interact with each other in a complicated network,” said Rye, who also is associate professor of biochemistry and biophysics at Texas A&M.
Rye explained that individual amino acids get linked together like beads on a string as a protein is made in the cell.
“But that linear sequence of amino acids is not functional,” he explained. “It’s like an origami structure that has to fold up into a three-dimensional shape to do what it has to do.”
Rye said researchers have been trying to understand this process for more than 50 years, but in a living cell the process is complicated by the presence of many proteins in a concentrated environment.
"The constraints on getting that protein to fold up into a good ‘origami’ structure are a lot more demanding,” he said. “So, there are special protein machines, known as molecular chaperones, in the cell that help proteins fold.”
But how the molecular chaperones help protein fold when it isn’t folding well by itself has been the nagging question for researchers.
“Molecular chaperones are like little machines, because they have levers and gears and power sources. They go through turning over cycles and just sort of buzz along inside a cell, driving a protein folding reaction every few seconds,” Rye said.
The many chemical reactions that are essential to life rely on the exact three-dimensional shape of folded proteins, he said. In the cell, enzymes, for example, are specialized proteins that help speed biological processes along by binding molecules and bringing them together in just the right way.
“They are bound together like a three-dimensional jigsaw puzzle,” Rye explained. “And the proteins — those little beads on the string that are designed to fold up like origami — are folded to position all these beads in three-dimensional space to perfectly wrap around those molecules and do those chemical reactions.
“If that doesn’t happen — if the protein doesn’t get folded up right – the chemical reaction can’t be done. And if it’s essential, the cell dies because it can’t convert food into power needed to build the other structures in the cell that are needed. Chemical reactions are the structural underpinning of how cells are put together, and all of that depends on the proteins being folded in the right way.”
When a protein doesn’t fold or folds incorrectly it turns into an “aggregate,” which Rye described as “white goo that looks kind of like a mayonnaise, like crud in the test tube.
“You’re dead; the cell dies,” he said.
Over the past 20 years, he said, researchers have linked that aggregation process “pretty convincingly” to the development of diseases — Alzheimer’s disease, Lou Gehrig’s disease, Huntington’s disease, to name a few. There’s evidence that diabetes and cancer also are linked to protein folding disorders.
“One of the main roles for the molecular chaperones is preventing those protein misfolding events that lead to aggregation and not letting a cell get poisoned by badly folded or aggregated proteins,” he said.
Rye’s team focused on a key molecular chaperone — the HSP60.
“They’re called HSP for ‘heat shock protein’ because when the cell is stressed with heat, the proteins get unstable and start to fall apart and unfold,” Rye said. “The cell is built to respond by making more of the chaperones to try and fix the problem.
“This particular chaperone takes unfolded protein and goes through a chemical reaction to bind the unfolded protein and literally puts it inside a little ‘box,’” Rye said.
He added that the mystery had long been how the folding worked because, while researchers could see evidence of that happening, no one had ever seen precisely how it happened.
Rye and the team zeroed in on a chemically modified mutant that in other experiments had seemed to stall at an important step in the process that the “machine” goes through to start the folding action. This clued the researchers that this stalling might make it easier to watch.
They then used cryo-electron microscopy to capture hundreds of thousands of images of the process at very high resolutions which allowed them to reconstruct from two-dimensional flat images a three-dimensional model. A highly sophisticated computer algorithm aligns the images and classifies them in subcategories.
“If you have enough of them you can actually reconstruct and view a structure as a three-dimensional model,” Rye said.
What the team saw was this: The HSP60 chaperone is designed to recognize proteins that are not folded from the ones that are. It binds them and then has a separate co-chaperone that puts a “lid” on top of the box to keep the folding intermediate in the box. They could see the box move, and parts of the molecule moved to peel the chaperone box away from the bound protein — or “gift” in the box. But the bound protein was kept inside the package where it could then initiate a folding reaction. They saw tiny tentacles, “like a little octopus in the bottom of the box rising up and grabbing hold of the substrate protein and helping hold it inside the cavity.”
"The first thing we saw was a large amount of an unfolded protein inside of this cavity,” he said. “Even though we knew from lots and lots of other studies that it had to go in there, nobody had ever seen it like this before. We can also see the non-native protein interacting with parts of the box that no one had ever seen before. It was exciting to see all of this for the first time. I think we got a glimpse of a protein in the process of folding, which we actually can compare to other structures.”
“By understanding the mechanism of these machines, the hope is that one of the things we can learn to do is turn them up or turn them off when we need to, like for a patient who has one of the protein folding diseases,” he said.
(Source: today.agrilife.org)
Scientists Design a Potential Drug Compound that Attacks Parkinson’s Disease on Two Fronts
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have found a compound that could counter Parkinson’s disease in two ways at once.
In a new study published recently online ahead of print by the journal ACS Chemical Biology, the scientists describe a “dual inhibitor”—two compounds in a single molecule—that attacks a pair of proteins closely associated with development of Parkinson’s disease.
“In general, these two enzymes amplify the effect of each other,” said team leader Phil LoGrasso, a TSRI professor who has been a pioneer in the development of JNK inhibitors for the treatment of neurodegenerative diseases. “What we were looking for is a high-affinity, high-selectivity treatment that is additive or synergistic in its effect—a one-two punch.”
That could be what they found.
This new dual inhibitor attacks two enzymes—the leucine-rich repeat kinase 2 (LRRK2) and the c-jun-N-terminal kinase (JNK)—pronounced “junk.” Genetic testing of several thousand Parkinson’s patients has shown that mutations in the LRRK2 gene increase the risk of Parkinson’s disease, while JNK has been shown to play an important role in neuron (nerve cell) survival in a range of neurodegenerative diseases. As such, they have become highly viable targets for drugs to treat disorders such as Parkinson’s disease.
A dual inhibitor ultimately would be preferred over separate individual JNK and LRRK2 inhibitors because a combination molecule would eliminate complications of drug-drug interactions and the need to optimize individual inhibitor doses for efficacy, the study noted.
Now the team’s new dual inhibitor will need to be optimized for potency, high selectivity (which reduces off-target side effects) and bioavailability so it can be tested in animal models of Parkinson’s disease.
(Source: scripps.edu)
Antioxidant shows promise in Parkinson’s disease
Diapocynin, a synthetic molecule derived from a naturally occurring compound (apocynin), has been found to protect neurobehavioral function in mice with Parkinson’s disease symptoms by preventing deficits in motor coordination.
The findings are published in the May 28, 2013 edition of Neuroscience Letters.
Brian Dranka, PhD, postdoctoral fellow at the Medical College of Wisconsin (MCW), is the first author of the paper. Balaraman Kalyanaraman, PhD, Harry R. & Angeline E. Quadracci Professor in Parkinson’s Research, Chairman and Professor of Biophysics, and Director of the MCW Free Radical Research Center, is the corresponding author.
In a specific type of transgenic mouse called LRRK2R1441G, the animals lose coordinated movements and develop Parkinson’s-type symptoms by ten months of age. In this study, the researchers treated those mice with diapocynin starting at 12 weeks. That treatment prevented the expected deficits in motor coordination.
“These early findings are encouraging, but in this model, we still do not know how this molecule exerts neuroprotective action. Further studies are necessary to discover the exact mode of action of the diaopocynin and other molecules with a similar structure,” said Dr. Kalyanaraman.
Clinicians have expressed a need for earlier disease detection in Parkinson’s disease patients; the researchers believe further study of this specific mouse model may allow them to identify new biomarkers that would enable early disease detection, and ultimately allow for better patient care and quality of life.
(Source: mcw.edu)