Posts tagged parkinson's disease
Articles and news from the latest research reports.
Putting the brakes on Parkinson’s
The earliest signs of Parkinson’s disease can be deceptively mild. The first thing that movie star Michael J. Fox noticed was twitching of the little finger of his left hand. For years, he made light of the apparently harmless tic. But such tremors typically spread, while muscles stiffen up and directed movements take longer to carry out. Research groups led by Armin Giese of LMU Munich and Christian Griesinger at the Max Planck Institute for Biophysical Chemistry in Göttingen have developed a chemical compound that slows down the onset and progression of Parkinson’s disease in mice. The scientists hope that this approach will give them a way to treat the cause of Parkinson’s and so arrest its progress.
The disease usually becomes manifest between the ages of 50 and 60, and results from the loss of dopamine-producing nerve cells in the substantia nigra, which is part of the midbrain. Under the microscope, the affected cells are seen to contain insoluble precipitates made up of a protein called alpha-synuclein. As an early step in the pathological cascade, this protein forms so-called oligomers, tiny aggregates consisting of small numbers of alpha-synuclein molecules, which are apparently highly neurotoxic. By the time the first overt symptoms appear in humans, more than half of the vulnerable cells have already been lost. Many researchers therefore focus on developing methods for early diagnosis of the condition. However, current therapies only alleviate symptoms, so the research teams led by Armin Giese and Christian Griesinger set out to address the underlying cause of nerve-cell death.
Together, the scientists have developed a substance which, in mouse models of the disease, reduces the rate of growth of the protein deposits and delays nerve cell degeneration to a yet unprecedented degree. As a consequence, mice treated with this agent remain disease-free for longer than non-medicated controls. “The most striking feature of the new compound is that it is the first that directly targets oligomers and interferes with their formation,” explains Christian Griesinger, head of the Department of NMR-based Structural Biology and Director at the Max Planck Institute for Biophysical Chemistry. The discovery is the result of years of hard work. “Combining skills from a range of disciplines has been the key to our success. Biologists, chemists, clinicians, physicists, and veterinarians have all contributed to the development of the therapeutic compound,” adds Armin Giese, who leads a research group at LMU’s Center for Neuropathology and Prion Research.
Giese and his colleagues systematically tested 20,000 candidate substances for the ability to block formation of the protein deposits that are typical for the disease. The screen made use of an extremely sensitive laser-based assay developed by Giese years ago when he was working together with Nobel Laureate Manfred Eigen at the Max Planck Institute for Biophysical Chemistry in Göttingen. Some interesting lead compounds identified during the very first phase of the screening program served as starting point for further optimization. Ultimately, one substance proved to be particularly active. Andrei Leonov a chemist in Griesinger’s team, finally succeeded in synthesizing a pharmaceutically promising derivative. This is well tolerated at dosage levels with significant therapeutic effects, can be administered with the food, and penetrates the blood-brain barrier, reaching high levels in the brain. The two teams have already applied for a patent on the compound which they called Anle138b – an abbreviation of Andrei Leonov’s first name and surname.
A complex series of experiments has provided encouraging indications that Anle138b could also be of therapeutic use in humans. These tests involved not only biochemical and structural investigations of Anle138b’s mode of action but also employed several animal models of Parkinson’s which are under study in Munich and in laboratories of the Excellence Cluster “Nanoscale Microscopy and Molecular Physiology of the Brain” in Göttingen. Mice exposed to Anle138b were found to display better motor coordination than their untreated siblings. “We use a kind of fitness test to evaluate muscle coordination,” Giese explains. “The mice are placed on a rotating rod and we measure how long the animals can keep their balance.”
Generally speaking, the earlier the onset of treatment, the longer the animals remained disease free. What’s more, the beneficial effects of Anle138b are not restricted to animals with Parkinson’s disease. “Creutzfeldt-Jakob disease is caused by toxic aggregates of the prion protein,” Griesinger points out. “And here too, Anle138b effectively inhibits clumping and significantly increases survival times.” These findings hint that Anle138b might also prevent the formation of insoluble deposits formed by other proteins, such as the tau protein that is associated with Alzheimer’s disease. Further experiments will address this issue. Anle138b will therefore be a useful research tool in medicine, as it will enable scientists to study the process of oligomer formation in the test-tube and to determine how their assembly is inhibited. The researchers hope ultimately to gain new insights into the mechanisms into how neurodegenerative disorders develop.
The drugs so far available for treatment of Parkinson’s disease only control its symptoms by enhancing the function of the surviving nerve cells in the substantia nigra. “With Anle138b, we may have the first representative of a new class of neuroprotective agents allowing to retard or even halt the progression of conditions such as Parkinson’s or Creutzfeldt-Jakob disease,” Griesinger says. However, he warns that the findings in mice cannot immediately be applied to humans. The next step will be to carry out toxicity tests in non-rodent species. Only if these are successful will clinical trials in patients become a realistic possibility. As clinician Giese emphasizes: “To successfully establish a novel therapeutic agent for treatment of real patients is a laborious task that requires a lot of work as well as serendipity.”
A noninvasive avenue for Parkinson’s disease gene therapy
Researchers at Northeastern University in Boston have developed a gene therapy approach that may one day stop Parkinson’s disease (PD) in it tracks, preventing disease progression and reversing its symptoms. The novelty of the approach lies in the nasal route of administration and nanoparticles containing a gene capable of rescuing dying neurons in the brain. Parkinson’s is a devastating neurodegenerative disorder caused by the death of dopamine neurons in a key motor area of the brain, the substantia nigra (SN). Loss of these neurons leads to the characteristic tremor and slowed movements of PD, which get increasingly worse with time. Currently, more than 1% of the population over age 60 has PD and approximately 60,000 Americans are newly diagnosed every year. The available drugs on the market for PD mimic or replace the lost dopamine but do not get to the heart of the problem, which is the progressive loss of the dopamine neurons.
The focus of Dr. Barbara Waszczak’s lab at Northeastern University in Boston is to find a way to harvest the potential of glial cell line-derived neurotrophic factor (GDNF) as a treatment for PD. GDNF is a protein known to nourish dopamine neurons by activating survival and growth-promoting pathways inside the cells. Not surprisingly, GDNF is able to protect dopamine neurons from injury and restore the function of damaged and dying neurons in many animal models of PD. However, the action of GDNF is limited by its inability to cross the blood-brain barrier (BBB), thus requiring direct surgical injection into the brain. To circumvent this problem, Waszczak’s lab is investigating intranasal delivery as a way to bypass the BBB. Their previous work showed that intranasal delivery of GDNF protects dopamine neurons from damage by the neurotoxin, 6-hydroxydopamine (6-OHDA), a standard rat model of PD.
Taking this work a step further, Brendan Harmon, working in Waszczak’s lab, has adapted the intranasal approach so that cells in the brain can continuously produce GDNF. His work utilized nanoparticles, developed by Copernicus Therapeutics, Inc., which are able to transfect brain cells with an expression plasmid carrying the gene for GDNF (pGDNF). When given intranasally to rats, these pGDNF nanoparticles increase GDNF production throughout the brain for long periods, avoiding the need for frequent re-dosing. Now, in new research presented on April 20 at 12:30 pm during Experimental Biology 2013 in Boston, MA, Harmon reports that intranasal administration of Copernicus’ pGDNF nanoparticles results in GDNF expression sufficient to protect SN dopamine neurons in the 6-OHDA model of PD.
Waszczak and Harmon believe that intranasal delivery of Copernicus’ nanoparticles may provide an effective and non-invasive means of GDNF gene therapy for PD, and an avenue for transporting other gene therapy vectors to the brain. This work, which was funded in part by the Michael J. Fox Foundation for Parkinson’s Research and Northeastern University, has the potential to greatly expand treatment options for PD and many other central nervous system disorders.
(Source: eurekalert.org)
Flies Model a Potential Sweet Treatment for Parkinson’s disease
Researchers from Tel Aviv University describe experiments that could lead to a new approach for treating Parkinson’s disease (PD) using a common sweetener, mannitol. This research is presented today at the Genetics Society of America’s 54th Annual Drosophila Research Conference in Washington D.C., April 3-7, 2013.
Mannitol is a sugar alcohol familiar as a component of sugar-free gum and candies. Originally isolated from flowering ash, mannitol is believed to have been the “manna” that rained down from the heavens in biblical times. Fungi, bacteria, algae, and plants make mannitol, but the human body can’t. For most commercial uses it is extracted from seaweed although chemists can synthesize it. And it can be used for more than just a sweetener.
The Food and Drug Administration approved mannitol as an intravenous diuretic to flush out excess fluid. It also enables drugs to cross the blood-brain barrier (BBB), the tightly linked cells that form the walls of capillaries in the brain. The tight junctions holding together the cells of these tiniest blood vessels come slightly apart five minutes after an infusion of mannitol into the carotid artery, and they stay open for about 30 minutes.
Mannitol has another, less-explored talent: preventing a sticky protein called α-synuclein from gumming up the substantia nigra part of the brains of people with PD and Lewy body dementia (LBD), which has similar symptoms to PD. In the disease state, the proteins first misfold, then form sheets that aggregate and then extend, forming gummy fibrils.
Certain biochemicals, called molecular chaperones, normally stabilize proteins and help them fold into their native three-dimensional forms, which are essential to their functions. Mannitol is a chemical chaperone. So like a delivery person who both opens the door and brings in the pizza, mannitol may be used to treat Parkinson’s disease by getting into the brain and then restoring normal folding to α-synuclein.
Daniel Segal, PhD, and colleagues at Tel Aviv University investigated the effects of mannitol on the brain by feeding it to fruit flies with a form of PD that has highly aggregated α-synuclein.
The researchers used a “locomotion climbing assay” to study fly movement. Normal flies scamper right up the wall of a test tube, but flies whose brains are encumbered with α-synuclein aggregates stay at the bottom, presumably because they can’t move normally. The percentage of flies that climb one centimeter in 18 seconds assesses the effect of mannitol.
An experimental run tested flies daily for 27 days. After that time, 72% of normal flies climbed up, in comparison to 38% of the PD flies. Their lack of ascension up the sides of the test tube indicated “severe motor dysfunction.”
In contrast, were flies bred to harbor the human mutant α-synuclein gene, who as larvae feasted on mannitol that sweetened the medium at the bottoms of their vials. These flies fared much better — 70% of them could climb after 27 days. And slices of their brains revealed a 70% decrease in accumulated misfolded protein compared to the brains of mutant flies raised on the regular medium lacking mannitol.
It’s a long way from helping climbing-impaired flies to a new treatment for people, but the research suggests a possible novel therapeutic direction. Dr. Segal, however, cautioned that people with PD or similar movement disorders should not chew a ton of mannitol-sweetened gum or sweets; that will not help their current condition. The next step for researchers is to demonstrate a rescue effect in mice, similar to improved climbing by flies, in which a rolling drum (“rotarod”) activity assesses mobility.
“Until and if mannitol is proven to be efficient for PD on its own, the more conservative and possibly more immediate use can be the conventional one, using it as a BBB disruptor to facilitate entrance of other approved drugs that have problems passing through the BBB,” Dr. Segal said. A preliminary clinical trial of mannitol on a small number of volunteers might follow if results in mice support those seen in the flies, he added, but that is still many research steps away.
(Image: Wikimedia Commons)
Sorting out the structure of a Parkinson’s protein
Clumps of proteins that accumulate in brain cells are a hallmark of neurological diseases such as dementia, Parkinson’s disease and Alzheimer’s disease. Over the past several years, there has been much controversy over the structure of one of those proteins, known as alpha synuclein.
MIT computational scientists have now modeled the structure of that protein, most commonly associated with Parkinson’s, and found that it can take on either of two proposed states — floppy or rigid. The findings suggest that forcing the protein to switch to the rigid structure, which does not aggregate, could offer a new way to treat Parkinson’s, says Collin Stultz, an associate professor of electrical engineering and computer science at MIT.
“If alpha synuclein can really adopt this ordered structure that does not aggregate, you could imagine a drug-design strategy that stabilizes these ordered structures to prevent them from aggregating,” says Stultz, who is the senior author of a paper describing the findings in a recent issue of the Journal of the American Chemical Society.
For decades, scientists have believed that alpha synuclein, which forms clumps known as Lewy bodies in brain cells and other neurons, is inherently disordered and floppy. However, in 2011 Harvard University neurologist Dennis Selkoe and colleagues reported that after carefully extracting alpha synuclein from cells, they found it to have a very well-defined, folded structure.
That surprising finding set off a scientific controversy. Some tried and failed to replicate the finding, but scientists at Brandeis University, led by Thomas Pochapsky and Gregory Petsko, also found folded (or ordered) structures in the alpha synuclein protein.
Stultz and his group decided to jump into the fray, working with Pochapsky’s lab, and developed a computer-modeling approach to predict what kind of structures the protein might take. Working with the structural data obtained by the Brandeis researchers, Stultz created a model that calculates the probabilities of many different possible structures, to determine what set of structures would best explain the experimental data.
The calculations suggest that the protein can rapidly switch among many different conformations. At any given time, about 70 percent of individual proteins will be in one of the many possible disordered states, which exist as single molecules of the alpha synuclein protein. When three or four of the proteins join together, they can assume a mix of possible rigid structures, including helices and beta strands (protein chains that can link together to form sheets).
“On the one hand, the people who say it’s disordered are right, because a majority of the protein is disordered,” Stultz says. “And the people who would say that it’s ordered are not wrong; it’s just a very small fraction of the protein that is ordered.”
“This paper seems to bridge the gap” between the two camps, says Trevor Creamer, an associate professor of molecular and cellular biochemistry at the University of Kentucky who was not involved in this research. Also important is the model’s prediction of new structures for the protein that experimental biologists can now look for, Creamer adds.
The MIT researchers also found that when alpha synuclein adopts an ordered structure, similar to that described by Selkoe and co-workers, the portions of the protein that tend to aggregate with other molecules are buried deep within the structure, explaining why those ordered forms do not clump together.
Stultz is now working to figure out what controls the protein’s configuration. There is some evidence that other molecules in the cell can modify alpha synuclein, forcing it to assume one conformation or another.
“If this structure really does exist, we have a new way now of potentially designing drugs that will prevent aggregation of alpha synuclein,” he says.
(Source: web.mit.edu)
Shedding Light on Early Parkinson’s Disease Pathology
In a mouse model of early Parkinson’s disease (PD), animals displayed movement deficits, loss of tyrosine-hydroxylase (TH)-positive fibers in the striatum, and astro-gliosis and micro-gliosis in the substantia nigra (SN), without the loss of nigral dopaminergic neurons. These findings, which may cast light on the molecular processes involved in the initial stages of PD, are available in the current issue of Restorative Neurology and Neuroscience.
“The most intriguing finding of our study was the lack of a significant decrease of TH levels in the SN of the low-dose MPTP-treated mice, suggesting that this treatment does not induce a direct loss of nigral dopaminergic neurons,” says Joost Verhaagen PhD, lead investigator of the study. “These findings appear to support the ‘dying back’ hypothesis of PD, which proposes that the TH-positive terminal loss in the striatum is the first neurodegenerative event in PD, which later induces neuronal degeneration in the SN.” Dr. Verhaagen is Head of the Workgroup on Neuroregeneration at the Netherlands Institute for Neuroscience and Professor at the Free University in Amsterdam.
The neurotoxin MPTP (1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine) was used to induce the degenerative changes. Chronic 5 week administration of 25 mg/kg MPTP combined with probenecid (250 mg/kg), which inhibits MPTP clearance and promotes its crossing of the blood-brain barrier, is known to cause dopaminergic neuron degeneration in the SN and decrease striatal dopaminergic nerve terminals. In the current study, 7 mice were treated with 25 mg/kg MPTP plus probenecid, 6 mice received a lower dose of MPTP (15 mg/kg) plus probenecid, and 8 control mice received saline plus probenecid. A grid test, known to be sensitive to striatal dopaminergic input, was used to detect motor deficits.
Immunohistochemical analysis using TH fluorescence revealed that only the higher dose of MPTP produced significant dopaminergic neuronal cell loss in the SN (65% fluorescence loss, p<0.001). The 15 mg/kg dose produced an 18% decline in fluorescence which was not significantly different than control.
Both dose levels significantly reduced TH immunoreactivity of the striatum. The authors believe that the motor deficits seen at both MPTP dose levels relate to the striatal dopamine depletion.
The study is also the first to report that low-dose MPTP produces astrogliosis and microgliosis in the SN and formation of α-synuclein positive inclusions. “The data suggests that gliosis in the substantia nigra plays a prominent initiating role in the introduction of dopaminergic deficits after MPTP treatment, and may be sufficient to significantly reduce TH levels in the striatum,” says Dr. Korecka, first author and principal investigator of the study and a post-doctoral fellow at the Netherlands Institute for Neuroscience in Amsterdam.
“We are the first to report that this early PD model provides an interesting window of opportunity to study the mechanisms that underlie the early neurodegenerative events that initiate the cellular death of dopaminergic neurons,” write the authors. They suggest that the model can be used to develop potential treatment strategies to counteract early PD cellular changes.
(Image: iStock)
Parkinson’s Disease Protein Gums up Garbage Disposal System in Cells
Clumps of α-synuclein protein in nerve cells are hallmarks of many degenerative brain diseases, most notably Parkinson’s disease.
“No one has been able to determine if Lewy bodies and Lewy neurites, hallmark pathologies in Parkinson’s disease can be degraded,” says Virginia Lee, PhD, director of the Center for Neurodegenerative Disease Research, at the Perelman School of Medicine, University of Pennsylvania.
“With the new neuron model system of Parkinson’s disease pathologies our lab has developed recently, we demonstrated that these aberrant clumps in cells resist degradation as well as impair the function of the macroautophagy system, one of the major garbage disposal systems within the cell.”
Macroautophagy, literally self eating, is the degradation of unnecessary or dysfunctional cellular bits and pieces by a compartment in the cell called the lysosome.
Lee, also a professor of Pathology and Laboratory Medicine, and colleagues published their results in the early online edition of the Journal of Biological Chemistry this week.
Alpha-synuclein (α-syn ) diseases all have clumps of the protein and include Parkinson’s disease (PD), and array of related disorders: PD with dementia , dementia with Lewy bodies, and multiple system atrophy. In most of these, α-syn forms insoluble aggregates of stringy fibrils that accumulate in the cell body and extensions of neurons.
These unwanted α-syn clumps are modified by abnormal attachments of many phosphate chemical groups as well as by the protein ubiquitin, a molecular tag for degradation. They are widely distributed in the central nervous system, where they are associated with neuron loss.
Using cell models in which intracellular α-syn clumps accumulate after taking up synthetic α-syn fibrils, the team showed that α-syn inclusions cannot be degraded, even though they are located near the lysosome and the proteasome, another type of garbage disposal in the cell.
The α-syn aggregates persist even after soluble α-syn levels within the cell are substantially reduced, suggesting that once formed, the α-syn inclusions are resistant to being cleared. What’s more, they found that α-syn aggregates impair the overall autophagy degradative process by delaying the maturation of autophagy machines known as autophagosomes, which may contribute to the increased cell death seen in clump-filled nerve cells. Understanding the impact of α-syn aggregates on autophagy may help elucidate therapies for α-syn-related neurodegeneration.
(Source: uphs.upenn.edu)
Parkinsons’ drug helps older people to make decisions
A drug widely used to treat Parkinson’s Disease can help to reverse age-related impairments in decision making in some older people, a study from researchers at the Wellcome Trust Centre for Neuroimaging has shown.
The study, published today in the journal Nature Neuroscience, also describes changes in the patterns of brain activity of adults in their seventies that help to explain why they are worse at making decisions than younger people.
Poorer decision-making is a natural part of the ageing process that stems from a decline in our brains’ ability to learn from our experiences. Part of the decision-making process involves learning to predict the likelihood of getting a reward from the choices that we make.
An area of the brain called the nucleus accumbens is responsible for interpreting the difference between the reward that we’re expecting to get from a decision and the reward that is actually received. These so called ‘prediction errors’, reported by a brain chemical called dopamine, help us to learn from our actions and modify our behaviour to make better choices the next time.
Dr Rumana Chowdhury, who led the study at the Wellcome Trust Centre for Neuroimaging at UCL, said: “We know that dopamine decline is part of the normal aging process so we wanted to see whether it had any effect on reward-based decision making. We found that when we treated older people who were particularly bad at making decisions with a drug that increases dopamine in the brain, their ability to learn from rewards improved to a level comparable to somebody in their twenties and enabled them to make better decisions.”
The team used a combination of behavioural testing and brain imaging techniques, to investigate the decision-making process in 32 healthy volunteers aged in their early seventies compared with 22 volunteers in their mid-twenties. Older participants were tested on and off L-DOPA, a drug that increases levels of dopamine in the brain. L-DOPA, more commonly known as Levodopa, is widely used in the clinic to treat Parkinson’s.
The participants were asked to complete a behavioural learning task called the two-arm bandit, which mimics the decisions that gamblers make while playing slot machines. Players were shown two images and had to choose the one that they thought would give them the biggest reward. Their performance before and after drug treatment was assessed by the amount of money they won in the task.
"The older volunteers who were less able to predict the likelihood of a reward from their decisions, and so performed worst in the task, showed a significant improvement following drug treatment," Dr Chowdhury explains.
The team then looked at brain activity in the participants as they played the game using functional Magnetic Resonance Imaging (fMRI), and measured connections between areas of the brain that are involved in reward prediction using a technique called Diffusor Tensor Imaging (DTI).
The findings reveal that the older adults who performed best in the gambling game before drug treatment had greater integrity of their dopamine pathways. Older adults who performed poorly before drug treatment were not able to adequately signal reward expectation in the brain – this was corrected by L-DOPA and their performance improved on the drug.
Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, said: “This careful investigation into the subtle cognitive changes that take place as we age offers important insights into what may happen at both a functional and anatomical level in older people who have problems with making decisions. That the team were able to reverse these changes by manipulating dopamine levels offers the hope of therapeutic approaches that could allow older people to function more effectively in the wider community.”
(Source: eurekalert.org)
Peptides helping researchers in search for Parkinson’s disease treatment
Australian researchers have taken the first step in using bioactive peptides as the building blocks to help ‘build a new brain’ to treat degenerative brain disease.
Deakin University biomedical scientist Dr Richard Williams is working in a team with Dr David Nisbet from the Australian National University and Dr Clare Parish at the Florey Neuroscience Institute to develop a way to repair the damaged parts of the brain that cause Parkinson’s disease.
Parkinson’s disease develops when the brain cells (or neurons) that produce the chemical dopamine die or are damaged. Dopamine neurons produce a lubricant that helps the brain transmit signals to the body that control muscles and movement. When these cells die or are damaged the result is the shaking and muscle stiffness that are among the common symptoms of the disease.
"We are looking at a way of helping the brain to regenerate the dead or damaged cells that transport dopamine throughout the body," Dr Williams said. "Peptides help the body heal itself, providing many positive benefits for health, particularly in regenerative medicine; this is why the sports people were using them to recover more quickly in the current doping scandal."
Peptides are both the building blocks and the messengers of the body; the team has used them to mimic the normal brain environment and provide the chemical signals needed to help the brain function.
"Peptides stick together like Lego blocks, so in the first stage of the project we have been able to make a three dimensional material or tissue scaffold that provides the networks cells need to grow; but the peptides also carry instructions in the form of chemical signals which tell the cells to grow into new neurons," Dr Williams explained.
"Importantly, this material has the same consistency as the brain, does not cause chronic inflammation and is non-toxic to the body.
"Our aim is to use this scaffold material to support the patient’s own stem cells that could be turned into dopamine neurons and implanted back into the brain. We expect that when implanted the material and stem cells would be accepted by the brain as normal tissue and grow to replace the damaged or dead cells."
While the research is not yet complete, Dr Williams is excited by the possibilities this work offers to the treatment of degenerative conditions.
"It is no secret that we are living longer, and with this we are seeing an increase in many conditions that come about because of ageing such Parkinson’s. By developing biomaterials, like the ones we are working on, it could be possible to help the body to regenerate and provide an improved quality of life to the older members of our community," he said.
"This work can also be adapted to other parts of the body which struggle to repair themselves, such as new cartilage for joints, muscle and heart cells, bones and teeth. Ultimately, it will be like taking your car to the garage to have new parts fitted to replace the worn out ones."
The results of the first stage of this Australian Research Council funded project will be published in the international journal Soft Matter.
Breaking down the Parkinson’s pathway
The key hallmark of Parkinson’s disease is a slowdown of movement caused by a cutoff in the supply of dopamine to the brain region responsible for coordinating movement. While scientists have understood this general process for many years, the exact details of how this happens are still murky.
“We know the neurotransmitter, we know roughly the pathways in the brain that are being affected, but when you come right down to it and ask what exactly is the sequence of events that occurs in the brain, that gets a little tougher,” says Ann Graybiel, an MIT Institute Professor and member of MIT’s McGovern Institute for Brain Research.
A new study from Graybiel’s lab offers insight into some of the precise impairments caused by the loss of dopamine in brain cells affected by Parkinson’s disease. The findings, which appear in the March 12 online edition of the Journal of Neuroscience, could help researchers not only better understand the disease, but also develop more targeted treatments.
The neurons responsible for coordinating movement are located in a part of the brain called the striatum, which receives information from two major sources — the neocortex and a tiny region known as the substantia nigra. The cortex relays sensory information as well as plans for future action, while the substantia nigra sends dopamine that helps to coordinate all of the cortical input.
“This dopamine somehow modulates the circuit interactions in such a way that we don’t move too much, we don’t move too little, we don’t move too fast or too slow, and we don’t get overly repetitive in the movements that we make. We’re just right,” Graybiel says.
Parkinson’s disease develops when the neurons connecting the substantia nigra to the striatum die, cutting off a critical dopamine source; in a process that is not entirely understood, too little dopamine translates to difficulty initiating movement. Most Parkinson’s patients receive L-dopa, which can substitute for the lost dopamine. However, the effects usually wear off after five to 10 years, and complications appear.
New Effort to Identify Parkinson’s Biomarkers
Last month, the National Institutes of Health announced a new collaborative initiative that aims to accelerate the search for biomarkers — changes in the body that can be used to predict, diagnose or monitor a disease — in Parkinson’s disease, in part by improving collaboration among researchers and helping patients get involved in clinical studies. As part of this program, launched by the National Institute of Neurological Disorders and Stroke (NINDS), part of the NIH, Clemens Scherzer, MD, a neurologist and researcher at Brigham and Women’s Hospital (BWH), was awarded $2.6 million over five years to work on the development of biomarkers and facilitate NINDS-wide access to one of the largest data and biospecimens bank in the world for Parkinson’s available at BWH. This NINIDS initiative is highlighted in an editorial in the March issue of Lancet Neurology.
"There is a critical gap in the research that leads to lack of treatment for diseases like Parkinson’s," said Scherzer. "Biomarkers are desperately needed to make clinical trials more efficient, less expensive and to monitor disease and treatment response. We are hopeful that this initiative will fast track new discoveries in this area."
According to Scherzer, most of our knowledge of the human brain is based on the analysis of just 1.5 percent of the human genome that encodes proteins. The first part of Scherzer’s project will examine the function of the remaining 98.5 percent of the genome that, so far, has been unexplored in the human brain. While this remainder had been previously dismissed as “junk”, it is now becoming clearer that parts of it actively regulate cell biology. Scherzer and colleagues believe that “dark matter” RNA transcribed from stretches of so called “junk” DNA is active in brain cells and contributes to the complexity of normal dopamine neurons and, when corrupted, Parkinson’s disease.
"This offers a potentially ground breaking opportunity for biomarker development. Initially, the team will search for these RNAs associated in brain tissue of individuals at earliest stages of the disease. Then, this team will look for related biomarkers in the bloodstream and cerebrospinal fluid in both healthy brains and those with Parkinson’s," Scherzer said.
Scherzer’s lab has been spearheading biomarker research in this field since 2004 and the team already has 2,000 patients enrolled and being followed in a longitudinal study with rich clinical data and one of the largest biobanks in the world for Parkinson’s tissue with support from the Harvard NeuroDiscovery Center. The biobank was designed as an incubator for Parkinson’s research and until now was chiefly available for research collaborations within the Harvard-affiliated community. As part of this new project, this vast resource will be open to all NIH-funded investigators.
"Our ultimate goal is to personalize treatment for our patients with Parkinson’s." said Scherzer. "By opening up this vast collection of specimens, we are exploding the resources that are available to NIH-funded investigators looking at this disease. We hope to harness the power of collaboration to speed up biomarkers discovery."
(Source: brighamandwomens.org)