Genetic manipulation of urate alters neurodegeneration in mouse model of Parkinson’s disease

A study by Massachusetts General Hospital researchers adds further support to the possibility that increasing levels of the antioxidant urate may protect against Parkinson’s disease. In their report published in PNAS Early Edition, the investigators report that mice with a genetic mutation increasing urate levels were protected against the kind of neurodegeneration that underlies Parkinson’s disease, while the damage was worse in animals with abnormally low urate.

"These results strengthen the rationale for investigating whether elevating urate in people with Parkinson’s can slow progression of the disease," says Xiqun Chen, MD, PhD, of the MassGeneral Institute for Neurodegenerative Diseases (MGH-MIND) and lead author of the PNAS report. “Our study is the first demonstration in an animal model that genetic elevation of urate can protect dopamine neurons from degeneration and that lowering urate can conversely exacerbate neurodegeneration.”

Characterized by tremors, rigidity, difficulty walking and other symptoms, Parkinson’s disease is caused by destruction of brain cells that produce the neurotransmitter dopamine. Healthy people whose urate levels are at the high end of the normal range have been found to be at reduced risk of developing Parkinson’s disease. Studies led by Michael Schwarzschild, MD, PhD, director of Molecular Neurobiology Laboratory at MGH-MIND, showed that, among Parkinson’s patients, symptoms appear to progress more slowly in those with higher urate levels. These observations led Schwarzschild and his colleagues to develop the SURE-PD (Safety of URate Elevation in Parkinson’s Disease) clinical trial, conducted at sites across the country through the support of the Michael J. Fox Foundation. Expected in early 2013, the results of SURE-PD will determine whether a medication that elevates urate levels should be tested further for its ability to slow the progression of disability in Parkinson’s disease.

Silent stroke can cause Parkinson’s disease

Scientists at The University of Manchester have for the first time identified why a patient who appears outwardly healthy may develop Parkinson’s disease.

Whilst conditions such as a severe stroke have been linked to the disease, for many sufferers the tremors and other symptoms of Parkinson’s disease can appear to come out of the blue. Researchers at the university’s Faculty of Life Sciences have now discovered that a small stroke, also known as a silent stroke, can cause Parkinson’s disease. Their findings have been published in the journal “Brain Behaviour and Immunity”.

Unlike a severe stroke, a silent stroke can show no outward symptoms of having taken place. It happens when a blood vessel in the brain is blocked for only a very short amount of time and often a patient won’t know they have suffered from one. However, it now appears one of the lasting effects of a silent stroke can be the death of dopaminergic neurons in the substantia nigra in the brain, which is an important region for movement coordination.

Dr. Emmanuel Pinteaux led the research: “At the moment we don’t know why dopaminergic neurons start to die in the brain and therefore why people get Parkinson’s disease. There have been suggestions that oxidative stress and aging are responsible. What we wanted to do in our study was to look at what happens in the brain away from the immediate area where a silent stroke has occurred and whether that could lead to damage that might result in Parkinson’s disease.”

The team induced a mild stroke similar to a silent stroke in the striatum area of the brain in mice. They found there was inflammation and brain damage in the striatum following the stroke, which they had expected. What the researchers didn’t expect was the impact on another area of the brain, the substantia nigra. When they analysed the substantia nigra they recorded a rapid loss of Substance P (a key chemical involved in its functions) as well as inflammation.

The team then analysed changes in the brain six days after the mild stroke and found neurodegeneration in the substantia nigra. Dopaminergic neurones had been killed.

Talking about the findings Dr Pinteaux said: “It is well known that inflammation following a stroke can be very damaging to the brain. But what we didn’t fully appreciate was the impact on areas of the brain away from the location of the stroke. Our work identifying that a silent stroke can lead to Parkinson’s disease shows it is more important than ever to ensure stroke patients have swift access to anti-inflammatory medication. These drugs could potentially either delay or stop the on-set of Parkinson’s disease.”

Dr Pinteaux continued: “What our findings also point to is the importance of maintaining a healthy lifestyle. There are already guidelines about exercise and healthy eating to help reduce the risk of having a stroke and our research suggests that a healthy lifestyle can be applied to Parkinson’s disease as well.”

Following the publication of these findings, Dr Pinteaux hopes to set up a clinical investigation on people who have had a silent stroke to assess dopaminergic neuron degeneration. In the meantime he will be working closely will colleagues at The University of Manchester to better understand the mechanisms of inflammation in the substantia nigra. 

Rice opens new window on Parkinson’s disease

Rice University scientists have discovered a new way to look inside living cells and see the insoluble fibrillar deposits associated with Parkinson’s disease.

The combined talents of two Rice laboratories – one that studies the misfolded proteins that cause neurodegenerative diseases and another that specializes in photoluminescent probes – led to the spectroscopic technique that could become a valuable tool for scientists and pharmaceutical companies.

The research by the Rice labs of Angel Martí and Laura Segatori appeared online today in the Journal of the American Chemical Society.

The researchers designed a molecular probe based on the metallic element ruthenium. Testing inside live neuroglioma cells, they found the probe binds with the misfolded alpha-synuclein proteins that clump together and form fibrils and disrupt the cell’s functions. The ruthenium complex lit up when triggered by a laser – but only when attached to the fibril, which allowed aggregation to be tracked using photoluminescence spectroscopy.

Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques

A cell-based therapy for the replacement of dopaminergic neurons has been a long-term goal in Parkinson’s disease research. Here, we show that autologous engraftment of A9 dopaminergic neuron-like cells induced from mesenchymal stem cells (MSCs) leads to long-term survival of the cells and restoration of motor function in hemiparkinsonian macaques. Differentiated MSCs expressed markers of A9 dopaminergic neurons and released dopamine after depolarization in vitro. The differentiated autologous cells were engrafted in the affected portion of the striatum. Animals that received transplants showed modest and gradual improvements in motor behaviors. Positron emission tomography (PET) using [¹¹C]-CFT, a ligand for the dopamine transporter (DAT), revealed a dramatic increase in DAT expression, with a subsequent exponential decline over a period of 7 months. Kinetic analysis of the PET findings revealed that DAT expression remained above baseline levels for over 7 months. Immunohistochemical evaluations at 9 months consistently demonstrated the existence of cells positive for DAT and other A9 dopaminergic neuron markers in the engrafted striatum. These data suggest that transplantation of differentiated autologous MSCs may represent a safe and effective cell therapy for Parkinson’s disease.

Promising Drug Slows Down Advance of Parkinson’s Disease and Improves Symptoms

Treating Parkinson’s disease patients with the experimental drug GM1 ganglioside improved symptoms and slowed their progression during a two and a half-year trial, Thomas Jefferson University researchers report in a new study published online November 28 in the Journal of the Neurological Sciences.

Although the precise mechanisms of action of this drug are still unclear, the drug may protect patients’ dopamine-producing neurons from dying and at least partially restore their function, thereby increasing levels of dopamine, the key neurochemical missing in the brain of Parkinson’s patients.

The research team, led by senior author Jay S. Schneider, Ph.D., Director of the Parkinson’s Disease Research Unit and Professor in the Department of Pathology, Anatomy and Cell Biology and the Department of Neurology at Jefferson, found that administration of GM1 ganglioside, a substance naturally enriched in the brain that may be diminished in Parkinson’s disease brains, acted as a “neuroprotective” and a “neurorestorative” agent to improve symptoms and over an extended period of time slow the progression of symptoms.

What’s more, once the study participants went off the drug, their disease worsened. The study enrolled 77 subjects and followed them over a 120-week period and also followed 17 subjects who received current standard of care treatment for comparison.

“The drugs currently available for Parkinson’s disease are designed to treat symptoms and to improve function, but at this time there is no drug that has been shown unequivocally to slow disease progression,” said Dr. Schneider. “Our data suggest that GM1 ganglioside has the potential to have symptomatic and disease-modifying effects on Parkinson’s disease. If this is substantiated in a larger clinical study, GM1 could provide significant benefit for Parkinson’s disease patients.”

Biking Restores Brain Connectivity in Parkinson’s

PROBLEM: It’s commonly known that Parkinson’s Disease is a chronic, progressive, disease of central nervous system that affects motor ability — its recognizable early stages are characterized by shakiness and difficulty walking. No cure exists, which is why back in 2003, the best Dr. Jay Alberts of the Cleveland Clinic Lerner Research Institute rode a tandem bicycle across Iowa with a Parkinson’s patient (to raise awareness). Unexpectedly, the patient showed improvements in her condition after the trip. In what now much be common lore at the Institute, Alberts attempted to explain the inexplicable by noticing that his own pace was faster than that of his partner, who was forced, by the cruel mechanics of tandem cycling, to pedal faster in order to keep up.

METHODOLOGY: Alberts and his colleagues used functional connectivity MRI to study the brains of 26 patients with Parkinson’s Disease before and after they engaged in an 8-week exercise program and then, as a follow-up, one month later. Three times a week, the patients worked out on stationary bicycles. The experimental group used a modified bike that, using an algorithm in the place of a super in-shape doctor, would measure their rate of exertion and use it as a basis to push them harder than they would otherwise choose.

RESULTS: What the researchers referred to as “forced rate activity,” others might feel is more accurately labeled “torture.” But when they calculated the brain activation of the patients forced to pedal past their comfort level, they found lasting increases in connectivity between two areas of the brain responsible for motor ability: the primary motor cortex and the posterior region of the thalamus.

CONCLUSION: Forced-rate bicycle exercise appears to be an effective therapy for Parkinson’s disease. 

IMPLICATION: The treatment delivered dramatic results, and has the distinction of being inexpensive and accessible. Alberts contends that even those without access to their own algorithm for forced-rate activity may be able to see improvement by using an at-home stationary bike. The next step is to evaluate the possible effects of other forms of exercise, like swimming. 

The full study was presented at the annual meeting of the Radiological Society of North America.

Scientists image brain structures that deteriorate in Parkinson’s

A new imaging technique developed at MIT offers the first glimpse of the degeneration of two brain structures affected by Parkinson’s disease.

The technique, which combines several types of magnetic resonance imaging (MRI), could allow doctors to better monitor patients’ progression and track the effectiveness of potential new treatments, says Suzanne Corkin, MIT professor emerita of neuroscience and leader of the research team. The first author of the paper is David Ziegler, who received his PhD in brain and cognitive sciences from MIT in 2011.

The study, appearing in the Nov. 26 online edition of the Archives of Neurology, is also the first to provide clinical evidence for the theory that Parkinson’s neurodegeneration begins deep in the brain and advances upward.

“This progression has never been shown in living people, and that’s what was special about this study. With our new imaging methods, we can see these structures more clearly than anyone had seen them before,” Corkin says.