Posts tagged parkinson's disease
Articles and news from the latest research reports.
New lead for potential Parkinson’s treatment: Effects of high-risk Parkinson’s mutation are reversible
Mutations in a gene called LRRK2 carry a well-established risk for Parkinson’s disease, however the basis for this link is unclear.
(Image caption: A microscope image of a cultured cell)
The team, led by Parkinson’s UK funded researchers Dr Kurt De Vos from the Department of Neuroscience and Dr Alex Whitworth from the Department of Biomedical Sciences, found that certain drugs could fully restore movement problems observed in fruit flies carrying the LRRK2 Roc-COR Parkinson’s mutation.
These drugs, deacetylase inhibitors, target the transport system and reverse the defects caused by the faulty LRRK2 within nerve cells. The study is published in Nature Communications.
Dr De Vos, a Lecturer in Translational Neuroscience at the world-leading Sheffield Institute for Translational Neuroscience (SITraN), said: “Our study provides compelling evidence that there is a direct link between defective transport within nerve cells and movement problems caused by the LRRK2 Parkinson’s mutation in flies.”
Co-investigator Dr Alex Whitworth explained: “We could also show that these neuronal transport defects caused by the LRRK2 mutation are reversible.
“By targeting the transport system with drugs, we could not only prevent movement problems, but also fully restore movement abilities in fruit flies who already showed impaired movement marked by a significant decrease in both climbing and flight ability.”
The LRRK2 gene produces a protein that affects many processes in the cell. It is known to bind to the microtubules, the cells’ transport tracks. A defect in this transport system has been suggested to contribute to Parkinson’s disease. The researchers have investigated this link and have now found the evidence that certain LRRK2 mutations affect transport in nerve cells which leads to movement problems observed in the fruit fly (Drosophila).
The team then used several approaches to show that preventing the association of the mutant LRRK2 protein with the microtubule transport system rescues the transport defects in nerve cells, as well as the movement deficits in fruit flies.
Dr De Vos added: “We successfully used drugs called deacetylase inhibitors to increase the acetylated form of α-tubulin within microtubules which does not associate with the mutant LRRK2 protein. We found that increasing microtubule acetylation had a direct impact on cellular axonal transport.
“These are very promising results which point to a potential Parkinson’s therapy. However, further studies are needed to confirm that this rescue effect also applies in humans.“
Dr Beckie Port, Research Communications Officer at Parkinson’s UK, which helped to fund the study, said: “This research gives hope that, for people with a particular mutation in their genes, it may one day be possible to intervene and stop the progression of Parkinson’s.
“The study has only been carried out in fruit flies, so much more research is needed before we know if these findings could lead to new treatment approaches for people with Parkinson’s.”
(Source: sheffield.ac.uk)
Disputed theory on Parkinson’s origin strengthened
Parkinson’s disease is strongly linked to the degeneration of the brain’s movement center. In the last decade, the question of where the disease begins has led researchers to a different part of the human anatomy. In 2003, the German neuropathologist Heiko Braak presented a theory suggesting that the disease begins in the gut and spreads to the brain. The idea has since, despite vocal critics, gained a lot of ground. Researchers at Lund University in Sweden now present the first direct evidence that the disease can actually migrate from the gut to the brain.
The so-called Braak’s hypothesis proposes that the disease process begins in the digestive tract and in the brain’s center of smell. The theory is supported by the fact that symptoms associated with digestion and smell occur very early on in the disease.
Researchers at Lund University have previously mapped the spread of Parkinson’s in the brain. The disease progression is believed to be driven by a misfolded protein that clumps together and “infects” neighboring cells. Professor Jia-Yi Li’s research team has now been able to track this process further, from the gut to the brain in rat models. The experiment shows how the toxic protein, alpha-synuclein, is transported from one cell to another before ultimately reaching the brain’s movement center, giving rise to the characteristic movement disorders in Parkinson’s disease.
“We have now been able to prove that the disease process actually can travel from the peripheral nervous system to the central nervous system, in this case from the wall of the gut to the brain. In the longer term, this may give us new therapeutic targets to try to slow or stop the disease at an earlier stage”, says Professor Jia-Yi Li, research group leader for Neural Plasticity and Repair at Lund University.
The research team will now carry out further studies in which the mechanisms behind the transport of the harmful protein will be examined in detail. The current study suggests that the protein is transferred during nerve cell communication. It is at this point of interaction that the researchers want to intervene in order to put a stop to the further spread of the disease.
Similar but different: new discovery for degenerative disease
Progressive Supranuclear palsy (PSP) and Parkinson’s Disease (PD) have overlapping symptoms but remain difficult to distinguish.
However, a first ever paper on the topic published in the Journal of Neuropsychology (British Psychological Society publication) now suggests that people with PSP experience more severe and extensive cognitive impairments than those with PD early on.
The study indicates that patients with PSP experience more severe and extensive impairments in higher order functions such as planning, abstract thinking, memory retrieval than those with PD.
Lead researcher Dr Young-Eun Claire Lee said the two conditions are so similar that in some cases, patients with PSP often go undiagnosed for the main part of their illness.
“PD and PSP are the two of the most common forms of neurodegenerative diseases resulting in loss of balance and deterioration in mobility,” said Dr Lee.
“Telling these differences apart can be challenging because most patients with PSP do not develop distinctive symptoms such as paralysis or weakness of the eye muscles and episodes of frequent falling until later stages,” she said.
While the study sample was small, the results indicate that cognitive profiles may aid differential diagnosis in earlier stages. PSP claimed the life of musician/actor Dudley Moore.
There are no current treatments for PSP.
Researchers find that drug used for another disease slows progression of Parkinson’s
A new study from UCLA found that a drug being evaluated to treat an entirely different disorder helped slow the progression of Parkinson’s disease in mice.
The study, published in the October edition of the journal Neurotherapeutics, found that the drug, AT2101, which has also been studied for Gaucher disease, improved motor function, stopped inflammation in the brain and reduced levels of alpha-synuclein, a protein critically involved in Parkinson’s.
Although the exact cause of Parkinson’s is unknown, evidence points to an accumulation of alpha-synuclein, which has been found to be common to all people with the disorder. The protein is thought to destroy the neurons in the brain that make dopamine, a neurotransmitter that helps regulate a number of functions, including movement and coordination. Dopamine deficiency is associated with Parkinson’s disease.
Gaucher disease is a rare genetic disorder in which the body cannot produce enough of an enzyme called β-glucocerebrosidase, or GCase. Researchers seeking genetic factors that increase people’s risk for developing Parkinson’s have determined that there may be a close relationship between Gaucher and Parkinson’s due to a GCase gene. Mutation of this gene, which leads to decreased GCase activity in the brain, has been found to be a genetic risk factor for Parkinson’s, although the majority of patients with Parkinson’s do not carry mutations in the Gaucher gene.
“This is the first time a compound targeting Gaucher disease has been tested in a mouse model of Parkinson’s disease and was shown to be effective,” said the study’s senior author, Marie-Francoise Chesselet, the Charles H. Markham Professor of Neurology at UCLA and director of the UCLA Center for the Study of Parkinson’s Disease. “The promising findings in this study suggest that further investigation of this compound in Parkinson’s disease is warranted.”
In the study, the researchers used mice that were genetically engineered to make too much alpha-synuclein which, over time, led the animals to develop deficits similar to those observed in humans with Parkinson’s. The researchers found that the mice’s symptoms improved after they received AT2101 for four months.
The researchers also observed that AT2101 was effective in treating Parkinson’s in mice even though they did not carry a mutant version of the Gaucher gene, suggesting that the compound may have a clinical effect in the broader Parkinson’s population.
AT2101 is a first-generation “pharmacological chaperone” — a drug that can bind malfunctioning, mutated enzymes and lead them through the cell to their normal location, which allows the enzymes to carry on with their normal work. This was the first time that a pharmacological chaperone showed promise in a model of Parkinson’s, according to Chesselet.
Parkinson’s disease affects as many as 1 million Americans, and 60,000 new cases are diagnosed each year. The disorder continues to puzzle scientists. There is no cure and researchers have been unable to pin down its cause and no drug has been proven to stop the progression of the disease, which causes tremors, stiffness and other debilitating symptoms. Current Parkinson’s treatments only address its symptoms.
(Source: newsroom.ucla.edu)
Applying Proteomics to Parkinson’s
Scientists studying two genes that are mutated in an early-onset form of Parkinson’s disease have deciphered how normal versions of these genes collaborate to help rid cells of damaged mitochondria. Mitochondria are the cell’s primary energy source, and maintaining their health is critical for cellular function. Mitochondrial dysfunction may underlie multiple neurodegenerative diseases, including Parkinson’s.
(Image caption: PARKIN (green) is localized on damaged mitochondria. Image: Harper Lab)
In their analysis published in Molecular Cell, Harvard Medical School researchers used powerful quantitative mass spectrometry and live-cell imaging approaches to elucidate a multistep mechanism by which the two proteins mutated in Parkinson’s disease—PINK1 and PARKIN—mark mitochondria as damaged by attaching chains of a small protein called ubiquitin. This work paves the way for a deeper understanding of what molecular steps are defective when these proteins are mutated in patients with Parkinson’s disease.
“The PINK1-PARKIN pathway has been studied for many years, yet its mechanisms weren’t clearly defined,” said Wade Harper, Bert and Natalie Vallee Professor of Molecular Pathology in the Department of Cell Biology at HMS and senior author of the paper. “Combining imaging and advanced mass spectrometry approaches has allowed us for the first time to determine with molecular precision the biochemical output of the PINK1-PARKIN pathway in living cells.”
One hypothesis about the origin of Parkinson’s disease suggests that neurons place high energy demands on their mitochondria. When mitochondria become damaged and their energy production falls, they must be cleared away; if not, cell death results when the damaged mitochondria create harmful chemicals called reactive oxygen species.
People who have certain early-onset mutations in PINK1 or PARKIN genes may live normal lives until they enter their 30s when movement disorders begin to appear, reflecting the loss of neurons that make the neurotransmitter dopamine. These neurons seem to be the cells that are the most sensitive to an inability to remove damaged mitochondria.
Only in the last few years have scientists understood that the enzymes PARKIN and PINK1 work together to remove damaged mitochondria. The PINK1 kinase, an enzyme that transfers phosphate to other proteins, is activated specifically on damaged mitochondria where it then functions to promote accumulation of PARKIN on the mitochondrial surface. Once there, PARKIN—a ubiquitin ligase— marks numerous proteins on the surface of the mitochondria with chains of ubiquitin, which in turn target the damaged mitochondria for removal from the cell.
In their new work, Harper’s team identifies a multistep “feed-forward” mechanism that involves intertwined ubiquitylation and phosphorylation in a sequence of reactions that successively build on one another. To the authors’ knowledge, this is the first report of a feed-forward mechanism of this type.
The team, led by postdoctoral fellow Alban Ordureau, found that PINK1 actually has two functions in a multistep pathway. First, PINK1 phosphorylates PARKIN, greatly stimulating its ability to attach ubiquitin to mitochondrial substrates. Second, PINK1 phosphorylates ubiquitin chains that PARKIN has just built. Unexpectedly, these phosphorylated ubiquitin chains then bind tightly to activated PARKIN, thereby facilitating its retention on the mitochondrial surface and furthering ubiquitin chain assembly through a feed-forward mechanism. Eventually these chains become so dense that the damaged mitochondria are marked for degradation.
“Our finding that PARKIN binds phosphorylated-ubiquitin chains as its mechanism of retention on damaged mitochondria was completely unexpected,” Harper said. “Ubiquitin has been studied for almost 40 years, but only recently has regulation of ubiquitin by phosphorylation emerged as a major focus for the field.”
Methods employed in this study have their origins in prior work of Steven Gygi, HMS professor of cell biology and a co-author of the paper, who developed ways to quantify ubiquitin chains more than a decade ago. Harper says there is “enormous potential in the application of these approaches to understand how defects in the ubiquitin system lead to disease.”
The team also included Brenda Schulman, a Howard Hughes Medical Institute investigator, the co-director of the Cancer Genetics, Biochemistry and Cell Biology Program at St. Jude Children’s Research Hospital and a leading expert on ubiquitin biochemistry.
“This is a very intricate pathway,” Ordureau said. “We were surprised by our findings at every step.”
(Source: hms.harvard.edu)
Mechanism of Parkinson’s spread demonstrated
An international, interdisciplinary group of researchers led by Gabor G. Kovacs from the Clinical Institute of Neurology at the MedUni Vienna has demonstrated, through the use of a new antibody, how Parkinson’s disease spreads from cell to cell in the human brain. Until now, this mechanism has only been observed in experimental models, but has now been demonstrated for the first time in humans too.
At the focus of the study, recently published in the highly respected journal “Neurobiology of Disease”, is the protein α-synuclein. This protein is present in the human brain but develops into a pathologically modified form in the presence of Parkinson’s disease and a common type of age-related dementia (known as Lewy body dementia, responsible for up to a quarter of all dementia-related diseases).
This study, which was carried out by a team from the MedUni Vienna in collaboration with researchers from the USA, Germany and Hungary, demonstrates for the first time that human nerve cells take up the pathological α-synuclein and thereby transfer the disease from one cell to the next. “This explains why patients with Parkinson’s disease deteriorate more and more from a clinical perspective and develop new symptoms, because the disease is able to spread to other parts of the brain through this infection process,” says Gabor G Kovacs, commenting on the central finding of the study.
New antibody achieved major breakthrough
The researchers demonstrated this mechanism using an antibody that scientists from the MedUni Vienna played a key role in helping to develop in collaboration with the German biotech firm Roboscreen. As the study shows, this antibody is the first to distinguish between the physiologically present and disease-associated form of α-synuclein and reacts exclusively with the pathological form.
Mechanism of spread demonstrated for the first time could provide a basis for new treatments for Parkinson’s
"For patients with Parkinson’s disease, this means that α-synuclein’s mechanism of spread from cell to cell could serve as a point of therapeutic attack if we are able to block this cell-to-cell transfer mechanism", continues Kovacs. In diagnostic terms, this antibody also represents a major breakthrough, since the antibodies used previously were unable to distinguish between the physiological and disease-associated form, which meant that they could not be used as easily for diagnostic purposes, e.g. in body fluids.
New antibody improves diagnosis
The fact that this is now possible for the first time has been demonstrated by a further study, also recently published in the specialist publication “Clinical Neuropathology”. According to this study, the new antibody can be used to detect disease-associated α-synuclein in the cerebrospinal fluid of patients with brain disease associated with α-synuclein. This is of major importance for clinical practice, because it means it will be possible to clinically determine whether the dementia is caused by Lewy bodies or not. This study arose through close collaboration between the Clinical Institute of Neurology (Gabor G. Kovacs) and the University Department of Neurology (Walter Pirker) at the MedUni Vienna.
(Source: meduniwien.ac.at)
Researchers debunk myth about Parkinson’s disease
Using advanced computer models, neuroscience researchers at the University of Copenhagen have gained new knowledge about the complex processes that cause Parkinson’s disease. The findings have recently been published in the prestigious Journal of Neuroscience.
The defining symptoms of Parkinson’s disease are slow movements, muscular stiffness and shaking. There is currently no cure for the condition, so it is essential to conduct innovative research with the potential to shed some light on this terrible disruption to the central nervous system that affects one person in a thousand in Denmark.
Dopamine is an important neurotransmitter which affects physical and psychological functions such as motor control, learning and memory. Levels of this substance are regulated by special dopamine cells. When the level of dopamine drops, nerve cells that constitute part of the brain’s ‘stop signal’ are activated.
“This stop signal is rather like the safety lever on a motorised lawn mower: if you take your hand off the lever, the mower’s motor stops. Similarly, dopamine must always be present in the system to block the stop signal. Parkinson’s disease arises because for some reason the dopamine cells in the brain are lost, and it is known that the stop signal is being over-activated somehow or other. Many researchers have therefore considered it obvious that long-term lack of dopamine must be the cause of the distinctive symptoms that accompanies the disease. However, we can now use advanced computer simulations to challenge the existing paradigm and put forward a different theory about what actually takes place in the brain when the dopamine cells gradually die,” explains Jakob Kisbye Dreyer, Postdoc at the Department of Neuroscience and Pharmacology, University of Copenhagen.
A thorn in the side
Scanning the brain of a patient suffering from Parkinson’s disease reveals that in spite of dopamine cell death, there are no signs of a lack of dopamine – even at a comparatively late stage in the process.
“The inability to establish a lack of dopamine until advanced cases of Parkinson’s disease has been a thorn in the side of researchers for many years. On the one hand, the symptoms indicate that the stop signal is over-activated, and patients are treated accordingly with a fair degree of success. On the other hand, data prove that they are not lacking dopamine,” says Postdoc Jakob Kisbye Dreyer.
Computer models predict the progress of the disease
“Our calculations indicate that cell death only affects the level of dopamine very late in the process, but that symptoms can arise long before the level of the neurotransmitter starts to decline. The reason for this is that the fluctuations that normally make up a signal become weaker. In the computer model, the brain compensates for the shortage of signals by creating additional dopamine receptors. This has a positive effect initially, but as cell death progresses further, the correct signal may almost disappear. At this stage, the compensation becomes so overwhelming that even small variations in the level of dopamine trigger the stop signal – which can therefore cause the patient to develop the disease.”
The new research findings may pave the way for earlier diagnosis of Parkinson’s disease.
(Source: healthsciences.ku.dk)
Say ‘ahh’ to let your smartphone check for Parkinson’s disease
Smartphones are designed to be curious. Having already learned about your friendships, your family and the pattern of your daily routine, designers are now interested in your health and fitness.
A new crop of apps and wearable devices continuously measure and analyse vital signs such as movement and heart rate, claiming to count calories, optimise sleep quality and guide diet. While cynics might be tempted to dismiss these products as glorified pedometers for lycra-clad smartphone addicts, new research shows that the hardware inside existing consumer devices can already reliably detect degenerative, life-changing disorders, including Parkinson’s disease.
Parkinson’s currently affects between seven to 10m people worldwide, and there is no cure. The disease can be diagnosed from a number of characteristic symptoms, including muscle tremor, changes in speech and difficulty of movement. However, diagnosis is challenging and usually involves regular visits to the doctor. It is estimated that one in five people with Parkinson’s are never diagnosed. Even if diagnosed, it can be difficult to accurately assess the how efficient treatment is in managing the disease.
Device to help people with Parkinson’s disease communicate better now available
SpeechVive Inc. announced Wednesday (Sept. 10) the commercial launch of the SpeechVive device intended to help people with a soft voice due to Parkinson’s disease speak more loudly and communicate more effectively.
The device is now available to try as a demo through the National Parkinson’s Disease Foundation’s Centers of Excellence prior to purchasing. People who suffer from a soft voice due to Parkinson’s disease can make an appointment at any of these centers: the Muhammad Ali Parkinson Center at Barrow Neurological Institute in Phoenix; the University of Florida, Gainesville, Florida; University of North Carolina, Chapel Hill, North Carolina; Struthers Parkinson’s Center, Minneapolis, Minnesota; and Baylor College of Medicine, Waco, Texas.
"We are providing demo units and training at no cost to as many of the National Parkinson’s Centers of Excellence as are interested in offering SpeechVive in conjunction with or as an alternative to speech therapy," said Steve Mogensen, president and CEO of SpeechVive. "We also are offering the SpeechVive units and training to professionals at Veterans Administration Medical Centers across the country. The first VAMC to offer SpeechVive is in Cincinnati, Ohio."
The SpeechVive device also is available to try at the M.D. Steer Speech and Hearing Clinic at Purdue University in West Lafayette, Indiana.
The technology was developed over the past decade by Jessica Huber, associate professor in Purdue’s Department of Speech, Language and Hearing Sciences and licensed through the Purdue Office of Technology Commercialization. The focus of Huber’s research is the development and testing of behavioral treatments to improve communication and quality of life in older adults and people with degenerative motor diseases.
SpeechVive reduces the speech impairments associated with Parkinson’s disease, which cause people with the disease to speak in a hushed, whispery voice and to have mumbled speech. People with Parkinson’s disease are commonly affected in their ability to communicate effectively.
"The clinical data we have collected over the past four years demonstrates that SpeechVive is effective in 90 percent of the people using the device," Huber said. "I am proud of the improvements in communication and quality of life demonstrated in our clinical studies. I look forward to seeing the device on the market so that more people with Parkinson’s disease will have access to it."
More than 1.5 million people in the United States are diagnosed with Parkinson’s disease, and it is one of the most common degenerative neurological diseases. About 89 percent of those with the disease have voice-related change affecting how loudly they speak, and at least 45 percent have speech-related change affecting how clearly they speak.
Lipid Deficiency Linked to Neuron Degeneration
A type of lipid that naturally declines in the aging brain impacts – within laboratory models used to study Parkinson’s disease – a protein associated with the disease, according to a study co-authored by University of Alabama researchers.
The study, which published today in the Proceedings of the National Academy of Sciences, focuses on lipids, fat-like molecules that naturally occur in organisms, and their potential roles in a complex process that leads to the death of neurons that produce dopamine. When dopamine-producing neurons malfunction or die, this leads to the symptoms associated with Parkinson’s disease.
“This gets right to the heart of understanding, possibly, the mechanism by which one form of lipid is impacting the process of neuron degeneration,” said Dr. Guy Caldwell, UA professor of biological sciences and one of the study’s co-authors.
The study, led by researchers at the Louisiana State University Health Sciences Center, focused on phosphatidylethanolamine, a lipid known as PE. Today’s scholarly article details how low levels of PE lead to high-levels of alpha-synuclein, a protein previously linked to Parkinson’s. It also show the promise a second lipid, ethanolamine, or ETA, has in boosting PE levels.
To function correctly, proteins must fold properly within cells. One misfolding, as can occur when extra copies of the protein alpha-synuclein are present, can lead to others and, subsequently, to aggregation, or clumping, of proteins. Aggregation of proteins can lead to neuron malfunction or cell death.
Previous research had shown that excess alpha-synuclein can serve as an intra-cellular “roadblock,” preventing proteins, dopamine and other things cells need from being delivered to their necessary locations. This delivery disruption can lead to serious disorders.
“That situation is being applied here, but in a different way,” Caldwell said. “We’re gaining a better understanding of the importance these lipids, which are components of cellular membranes, have in maintaining proper trafficking.”
A proper link with alpha-synuclein helps “lipid rafts” in their transport of proteins.
“As the name implies, lipid rafts are like rafts of fat,” Caldwell said. “If alpha-synuclein can’t associate with those rafts, it could be a toxic situation for these cells.”
Using yeast and the tiny nematode C. elegans as laboratory models, the researchers showed they could reverse the delivery problem by adding ETA to the mix.
“This supplementation of ETA basically tells us that if we can restore the amount of PE that is being made, we can create a healthier situation in neurons, and this might help them to survive longer.”
UA’s lead author on the study is Siyuan “Alice” Zhang, a third-year UA doctoral student who works in the Caldwell lab. Dr. Kim Caldwell, UA professor of biological sciences, is also a co-author. LSU’s senior researcher on the project is Dr. Stephan Witt.
Additional study is needed in rodents and patient-derived stem cells before knowing how beneficial the discovery could eventually prove, Caldwell said.
Perhaps one day, Caldwell said, a supplement could be developed to prevent the decline of PE or possibly a drug could be developed to activate an enzyme that converts ETA to PE.
“I think it has promise as a new way of looking at alleviating toxicity,” Caldwell said. “It’s a different angle.”
(Source: uanews.ua.edu)