Posts tagged parkinson

ScienceDaily (May 10, 2012) — Researchers at the Medical Research Council (MRC) Toxicology Unit at the University of Leicester have identified a major pathway leading to brain cell death in mice with neurodegenerative disease. The team was able to block the pathway, preventing brain cell death and increasing survival in the mice.

Scientists have identified a major pathway leading to brain cell death in mice with neurodegenerative disease. The team was able to block the pathway, preventing brain cell death and increasing survival in the mice. (Credit: © pressmaster / Fotolia)

In human neurodegenerative diseases, including Alzheimer’s, Parkinson’s and prion diseases, proteins “mis-fold” in a variety of different ways resulting in the build up of mis-shapen proteins. These form the plaques found in Alzheimer’s and the Lewy bodies found in Parkinson’s disease.

The researchers studied mice with neurodegeneration caused by prion disease. These mouse models currently provide the best animal representation of human neurodegenerative disorders, where it is known that the build up of mis-shapen proteins is linked with brain cell death.

They found that the build up of mis-folded proteins in the brains of these mice activates a natural defense mechanism in cells, which switches off the production of new proteins. This would normally switch back ‘on’ again, but in these mice the continued build-up of mis-shapen protein keeps the switch turned ‘off’. This is the trigger point leading to brain cell death, as those key proteins essential for nerve cell survival are not made.

By injecting a protein that blocks the ‘off’ switch of the pathway, the scientists were able to restore protein production, independently of the build up of mis-shapen proteins,and halt the neurodegeneration. The brain cells were protected, protein levels and synaptic transmission (the way in which brain cells signal to each other) were restored and the mice lived longer, even though only a very small part of their brain had been treated.

Mis-shapen proteins in human neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, also over-activate this fundamental pathway controlling protein synthesis in the brains of patients, which represents a common target underlying these different clinical conditions. The scientists’ results suggest that treatments focused on this pathway could be protective in a range of neurodegenerative disease in which mis-shapen proteins are building up and causing neurons to die.

Professor Giovanna Mallucci, who led the team, said, “What’s exciting is the emergence of a common mechanism of brain cell death, across a range of different neurodegenerative disorders, activated by the different mis-folded proteins in each disease. The fact that, in mice with prion disease, we were able to manipulate this mechanism and protect the brain cells means we may have a way forward in how we treat other disorders. Instead of targeting individual mis-folded proteins in different neurodegenerative diseases, we may be able to target the shared pathways and rescue brain cell degeneration irrespective of the underlying disease.”

Professor Hugh Perry, chair of the MRC’s Neuroscience and Mental Health Board, said, “Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are debilitating and largely untreatable conditions. Alzheimer’s disease and related disorders affect over seven million people in Europe, and this figure is expected to double every 20 years as the population ages across Europe. The MRC believes that research such as this, which looks at the fundamental mechanisms of these devastating diseases, is absolutely vital. Understanding the mechanism that leads to neuronal dysfunction prior to neuronal loss is a critical step in finding ways to arrest disease progression.”

Source: Science Daily

ScienceDaily (Apr. 25, 2012) — University of California, San Diego scientists have used powerful computational tools and laboratory tests to discover new support for a once-marginalized theory about the underlying cause of Parkinson’s disease.

This image shows a construction of a possible ring oligomer position in the cell membrane after four nanoseconds of molecular dynamics simulations. Image courtesy of Igor Tsigelny, San Diego Supercomputer Center and Department of Neurosciences, UC San Diego. (Credit: Image courtesy of University of California, San Diego)

The new results conflict with an older theory that insoluble intracellular fibrils called amyloids cause Parkinson’s disease and other neurodegenerative diseases. Instead, the new findings provide a step-by-step explanation of how a “protein-run-amok” aggregates within the membranes of neurons and punctures holes in them to cause the symptoms of Parkinson’s disease.

The discovery, published in the March 2012 issue of the FEBS Journal, describes how α-synuclein (a-syn), can turn against us, particularly as we age. Modeling results explain how α-syn monomers penetrate cell membranes, become coiled and aggregate in a matter of nanoseconds into dangerous ring structures that spell trouble for neurons.

"The main point is that we think we can create drugs to give us an anti-Parkinson’s effect by slowing the formation and growth of these ring structures," said Igor Tsigelny, lead author of the study and a research scientist at the San Diego Supercomputer Center and Department of Neurosciences, both at UC San Diego.

Familial Parkinson’s disease is caused in many cases by a limited number of protein mutations. One of the most toxic is A53T. Tsigelny’s team showed that the mutant form of α-syn not only penetrates neuronal membranes faster than normal α-syn, but the mutant protein also accelerates ring formation.

"The most dangerous assault on the neurons of Parkinson’s patients appears to be the relatively small α-syn ring structures themselves," said Tsigelny. "It was once heretical to suggest that these ring structures, rather than long fibrils found in neurons of people having Parkinson’s disease, were responsible for the symptoms of the disease; however, the ring theory is becoming more and more accepted for this neurodegenerative disease and others such as Alzheimer’s disease. Our results support this shift in thinking."

The modeling results also are consistent with the electron microscopy images of neurons in Parkinson’s disease patients; the damaged neurons are riddled with ring structures.

Wasting no time, the modeling discoveries have spawned an intense hunt at UC San Diego for drug candidates that block ring formation in neuron membranes. The sophisticated modeling required involves a complex realm of science at the intersection of chemistry, physics, and statistical probabilities. A kaleidoscope of interacting forces in this realm makes α-syn proteins bump and tremble like they’re in an earthquake, coil and uncoil, and join together in pairs or larger groups of inventive ballroom dancers.

The modeling is creating a much better understanding of the mysterious a-syn protein itself, according to Tsigelny. A few years ago it was shown to accumulate in the central nervous system of patients with Parkinson’s disease and a related disorder called dementia with Lewy bodies.

The new modeling study has revealed precisely how two α-syn proteins insert their molecular toes into the membrane of a neuron, wiggle into it in only a few nanoseconds and immediately join together as a pair. The pair isn’t itself toxic; however, when more α-syn proteins join the dance, a key threshold is eventually crossed; polymerization accelerates into a ring structure that perforates the membrane, damaging the cell.

Tsigelny said many ring structures may be required to actually kill neurons, which are known for their durability. The nerve cells may be able to repair dozens of ring-induced perforations, keeping pace with a-syn assault. But at some point, the rate of perforations surpasses the ability of neurons to repair them. As a result, symptoms of Parkinson’s disease gradually appear and worsen.

"We think we can create a drug that stops the α-syn polymerization at the point of non-propagating dimers," Tsigelny said. "By interrupting the polymerization at this crucial step, we may be able to slow the disease significantly."

Tsigelny’s research team included Yuriy Sharikov, with SDSC and UC San Diego’s Department of Neurosciences; Wolfgang Wrasidlo, with the university’s Moores Cancer Center; and Tania Gonzalez, Paula A. Desplats, Leslie Crews, and Brian Spencer, all with UC San Diego’s Department of Neurosciences. The experimental validation studies were performed by Eliezer Masliah, a professor in the UC San Diego departments of Neurosciences and Pathology, and his associates. They relied on 3-D models of proteins, plus molecular dynamics simulations of the proteins, other modeling techniques and cell-culture experiments.

Given their deeper understanding of α-syn polymerization in neurons, they are now focused on understanding how monomers of α-syn stick to one another. Their search for drug candidates will include molecules that induce different conformations of α-syn proteins that are less inclined to stick together. Tsigelny said this effect, even if small, could reduce symptoms.

This computationally intensive approach includes an examination of the many possible three-dimensional arrangements of α-syn dimers, trimmers and tetramers. Pharmaceutical companies have used versions of the approach to develop drug candidates designed to bind to ‘anchor residues’ or ‘hot spots’ within target proteins. Algorithms assess in virtual experiments the theoretical ability of thousands of candidate drugs to bind to human proteins in the ever-expanding database of known 3-D structures of those proteins.

However, attempts to find drugs this way have generated promising candidates that fail in clinical trials with expensive regularity.

"Out of these failures we’ve come to appreciate that proteins change their shapes so often that what would appear to be a primary drug target may be present one nanosecond, gone the next, or it wasn’t relevant in the first place," said Tsigelny, a physicist-turned-drug-designer.

Tsigelny’s approach takes advantage of classical drug-discovery algorithms, but adds additional analytical techniques to expand the search to include how a target protein’s conformations change in response to the forces operating on the scale of molecules.

"Sometimes, the drug-discovery models, despite being ‘nice looking,’ can be completely wrong," Tsigelny said. "Scientists involved in drug discovery need to know when and to what extent to trust them. Even a slight shift in a cell’s environment can profoundly change the interactions of proteins with neighboring molecules. We think it’s realistically possible to design a drug to treat neurodegenerative diseases such as Parkinson’s disease and other diseases like diabetes with a more fundamental understanding of the proteins involved in those diseases."

Source: Science Daily

ScienceDaily (Apr. 17, 2012) — Last year, researchers from the Perelman School of Medicine at the University of Pennsylvania found that small amounts of a misfolded brain protein can be taken up by healthy neurons, replicating within them to cause neurodegeneration. The protein, alpha-synuclein (a-syn), is commonly found in the brain, but forms characteristic clumps called Lewy bodies, in neurons of patients with Parkinson’s disease (PD) and other neurodegenerative disorders. They found that abnormal forms of a-syn called fibrils acted as “seeds” that induced normal a-syn to misfold and form aggregates.

These images show the brainstem from a control animal (top) and an animal injected with pathologic alpha-synuclein. Brown spots are immunostaining using an antibody specifically recognizing an abnormal form of alpha-synuclein. (Credit: Kelvin C. Luk, Ph.D., Perelman School of Medicine, University of Pennsylvania.)

In earlier studies at other institutions, when fetal nerve cells were transplanted into the brains of PD patients, some of the transplanted cells developed Lewy bodies. This suggested that the corrupted form of a-syn could somehow be transmitted from diseased neurons to healthy ones.

Now, in a follow-up study published in the Journal of Experimental Medicine, the team, led by senior author Virginia M.-Y Lee, PhD, director of the Center for Neurodegenerative Disease Research and professor of Pathology and Laboratory Medicine, showed that brain tissue from a PD mouse model, as well as synthetically produced a-syn fibrils, injected into young, symptom-free PD mice led to spreading of a-syn pathology. By three months after a single injection, neurons containing abnormal a-syn clumps were detected throughout the mouse brains. The inoculated mice died between 100 to 125 days post-inoculation, out of their typical two-year life span.

"We think the spreading is via white-matter tracks through brain neural network connections," explains Lee. "This study will open new opportunities for novel Parkinson’s disease therapies."

One of the remaining questions is how, once inside a neuron, does the misfolded a-syn protein spread from cell to cell.

"It’s like a biochemical chain reaction," says first author Kelvin C. Luk, Ph.D., research associate, in the CNDR. Once inside the confines of a neuron, the misfolded a-syn recruits normally shaped a-syn protein that is present in the cell, causing them to eventually misfold. This occurs along the axons and dendrites (neuronal extensions that reach other neurons), leading to a dramatic accumulation of the abnormal protein. The misshapen a-syn then invades other neurons when they reach the synapse, the small space between neurons.

This transmission process is remarkably similar to what is seen in prions, the protein agents responsible for conditions such as transmissible spongiform encephalopathies ( mad cow disease). However, the researchers are quick to caution that there is no evidence that Parkinson’s or any related neurodegenerative diseases is either infectious or acquired.

The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases, but the factors that trigger aggregation of a-syn are poorly understood.

The Penn team saw that misfolded a-syn propagated along major central nervous system pathways, reaching regions far beyond injection sites. What’s more, they showed for the first time that synthetically produced a-syn fibrils are sufficient to initiate a vicious cycle of Lewy body formation and transmission of the misfolded a-syn in mice.

The study demonstrates just how the Parkinson’s disease protein can spread in a patient’s brain in terms of uptake into a healthy neuron, expansion within the cell, and finally release to a neighboring neuron.

"Knowing this mechanism allows for possible immunotherapies to interrupt the chain reaction by stopping the mutant protein from spreading at the synapse," says Lee.

"Shedding light on how a-synuclein contributes to Parkinson’s disease and related Lewy body disorders is of significant interest both for understanding these diseases and developing potential treatments," said Beth-Anne Sieber, Ph.D., of the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health. "This study provides evidence for the progressive, pathological spread of a-synuclein through the brain."

Source: Science Daily

March 12th, 2012

Regular use of cholesterol-lowering statin drugs may be associated with a modest reduction in risk for developing Parkinson disease, particularly among younger patients, according to a study in the March issue of Archives of Neurology, one of the JAMA Archives journals.

Statins are one of the most prescribed classes of drugs in the United States and some researchers have hypothesized that the anti-inflammatory and immunomodulating effects of these medications may be neuroprotective. However, statins also may have unfavorable effects on lowering the level of plasma coenzyme Q10, which may be neuroprotective in patients with Parkinson disease (PD), the researchers write in their study background.

Xiang Gao, M.D., Ph.D., of Brigham and Women’s Hospital and Harvard School of Public Health, Boston, and colleagues conducted a prospective study that included 38,192 men and 90,874 women participating in the Health Professional Follow-up study and the Nurses’ Health study.

During 12 years of follow-up from 1994 to 2006, researchers documented 644 incident PD cases (338 in women and 306 in men).

“In summary, we observed an association between regular use of statins and lower risk of developing PD, particularly among younger patients,” the researchers comment. “However, our results should be interpreted with caution because only approximately 70 percent of users of cholesterol-lowering drugs at baseline were actual statin users. Further, the results were only marginally significant and could be due to chance.”

Researchers note that because they classified the use of any cholesterol-lowering drugs before 2000 as statin use, misclassification was inevitably introduced. They also did not collect information on the use of specific statins, which could have different effects on the central nervous system.

When researchers did observe a significant interaction between statin use and age in relation to PD risk it was among study participants younger than 60 years at the start of follow-up, not among those participants who were older.

The authors note that not only have epidemiologic studies produced mixed results on statin use and PD risk, but statins also may have unfavorable effects on the central nervous system.

“In contrast with use of ibuprofen, which has been consistently found to be inversely associated with PD risk in these cohorts as well as in other longitudinal studies, the overall epidemiological evidence relating stain use to PD risk remains unconvincing,” the authors conclude. “Given the potential adverse effects of statins, further prospective observational studies are needed to explore the potential effects of different subtypes of statin on risk of PD and other neurodegenerative diseases.”
(Arch Neurol. 2012;69[3]:380-384).

Source: Neuroscience News

ScienceDaily (Mar. 2, 2012) — Millions of people suffer from Parkinson’s disease, a disorder of the nervous system that affects movement and worsens over time. As the world’s population ages, it’s estimated that the number of people with the disease will rise sharply. Yet despite several effective therapies that treat Parkinson’s symptoms, nothing slows its progression.

Artist’s rendering of neurons. (Credit: iStockphoto)

While it’s not known what exactly causes the disease, evidence points to one particular culprit: a protein called α-synuclein. The protein, which has been found to be common to all patients with Parkinson’s, is thought to be a pathway to the disease when it binds together in “clumps,” or aggregates, and becomes toxic, killing the brain’s neurons.

Now, scientists at UCLA have found a way to prevent these clumps from forming, prevent their toxicity and even break up existing aggregates.

UCLA professor of neurology Jeff Bronstein and UCLA associate professor of neurology Gal Bitan, along with their colleagues, report the development of a novel compound known as a “molecular tweezer,” which in a living animal model blocked α-synuclein aggregates from forming, stopped the aggregates’ toxicity and, further, reversed aggregates in the brain that had already formed. And the tweezers accomplished this without interfering with normal brain function.

Read more …

 February 9th, 2012

New technique holds promise for better understanding of brain disorders.

Quantum dot film. Optically excited quantum dots in close proximity to a cell control the opening of ion channels. Credit: Lugo et al., University of Washington.

Source: Neuroscience News

ScienceDaily (Feb. 7, 2012) — 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.

Source: ScienceDaily