Posts tagged parkinson's disease
Articles and news from the latest research reports.
Artificial Sweetener a Potential Treatment for Parkinson’s Disease
TAU researcher says mannitol could prevent aggregation of toxic proteins in the brain
Mannitol, a sugar alcohol produced by fungi, bacteria, and algae, is a common component of sugar-free gum and candy. The sweetener is also used in the medical field — it’s approved by the FDA as a diuretic to flush out excess fluids and used during surgery as a substance that opens the blood/brain barrier to ease the passage of other drugs.
Now Profs. Ehud Gazit and Daniel Segal of Tel Aviv University’s Department of Molecular Microbiology and Biotechnology and the Sagol School of Neuroscience, along with their colleague Dr. Ronit Shaltiel-Karyo and PhD candidate Moran Frenkel-Pinter, have found that mannitol also prevents clumps of the protein α-synuclein from forming in the brain — a process that is characteristic of Parkinson’s disease.
These results, published in the Journal of Biological Chemistry and presented at the Drosophila Conference in Washington, DC in April, suggest that this artificial sweetener could be a novel therapy for the treatment of Parkinson’s and other neurodegenerative diseases. The research was funded by a grant from the Parkinson’s Disease Foundation and supported in part by the Lord Alliance Family Trust.
Seeing a significant difference
After identifying the structural characteristics that facilitate the development of clumps of α-synuclein, the researchers began to hunt for a compound that could inhibit the proteins’ ability to bind together. In the lab, they found that mannitol was among the most effective agents in preventing aggregation of the protein in test tubes. The benefit of this substance is that it is already approved for use in a variety of clinical interventions, Prof. Segal says.
Next, to test the capabilities of mannitol in the living brain, the researchers turned to transgenic fruit flies engineered to carry the human gene for α-synuclein. To study fly movement, they used a test called the “climbing assay,” in which the ability of flies to climb the walls of a test tube indicates their locomotive capability. In the initial experimental period, 72 percent of normal flies were able to climb up the test tube, compared to only 38 percent of the genetically-altered flies.
The researchers then added mannitol to the food of the genetically-altered flies for a period of 27 days and repeated the experiment. This time, 70 percent of the mutated flies could climb up the test tube. In addition, the researchers observed a 70 percent reduction in aggregates of α-synuclein in mutated flies that had been fed mannitol, compared to those that had not.
These findings were confirmed by a second study which measured the impact of mannitol on mice engineered to produce human α-synuclein, developed by Dr. Eliezer Masliah of the University of San Diego. After four months, the researchers found that the mice injected with mannitol also showed a dramatic reduction of α-synuclein in the brain.
Delivering therapeutic compounds to the brain
The researchers now plan to re-examine the structure of the mannitol compound and introduce modifications to optimize its effectiveness. Further experiments on animal models, including behavioral testing, whose disease development mimics more closely the development of Parkinson’s in humans is needed, Prof. Segal says.
For the time being, mannitol may be used in combination with other medications that have been developed to treat Parkinson’s but which have proven ineffective in breaking through the blood/brain barrier, says Prof. Segal. These medications may be able to “piggy-back” on mannitol’s ability to open this barrier into the brain.
Although the results look promising, it is still not advisable for Parkinson’s patients to begin ingesting mannitol in large quantities, Prof. Segal cautions. More testing must be done to determine dosages that would be both effective and safe.
(Source: aftau.org)
Study finds brain-imaging technique can help diagnose movement disorders
A new University of Florida study suggests a promising brain-imaging technique has the potential to improve diagnoses for the millions of people with movement disorders such as Parkinson’s disease.
Utilizing the diffusion tensor imaging technique, as it is known, could allow clinicians to assess people earlier, leading to improved treatment interventions and therapies for patients.
The three-year study looked at 72 patients, each with a clinically defined movement disorder diagnosis. Using a technique called diffusion tensor imaging, the researchers successfully separated the patients into disorder groups with a high degree of accuracy.
The study is being published in the journal Movement Disorders.
“The purpose of this study is to identify markers in the brain that differentiate movement disorders which have clinical symptoms that overlap, making [the disorders] difficult to distinguish,” said David Vaillancourt, associate professor in the department of applied physiology and kinesiology and the study’s principal investigator.
“No other imaging, cerebrospinal fluid or blood marker has been this successful at differentiating these disorders,” he said. “The results are very promising.”
Movement disorders such as Parkinson’s disease, essential tremor, multiple system atrophy and progressive supranuclear palsy exhibit similar symptoms in the early stages, which can make it challenging to assign a specific diagnosis. Often, the original diagnosis changes as the disease progresses, Vaillancourt said.
Diffusion tensor imaging, known as DTI, is a non-invasive method that examines the diffusion of water molecules within the brain and can identify key areas that have been affected as a result of damage to gray matter and white matter in the brain. Vaillancourt and his team measured areas of the basal ganglia and cerebellum in individuals, and used a statistical approach to predict group classification. By asking different questions within the data and comparing different groups to one another, they were able to show distinct separation among disorders.
“Our goal was to use these measures to accurately predict the original disease classification,” Vaillancourt said. “The idea being that if a new patient came in with an unknown diagnosis, you might be able to apply this algorithm to that individual.
He compared the process to a cholesterol test.
“If you have high cholesterol, it raises your chances of developing heart disease in the future,” he said. “There are tests like those that give a probability or likelihood scenario of a particular disease group. We’re going a step further and trying to utilize information to predict the classification of specific tremor and Parkinsonian diseases.”
(Source: news.ufl.edu)
PD-Like Sleep and Motor Problems Observed in α-Synuclein Mutant Mice
The presence of Lewy bodies in nerve cells, formed by intracellular deposits of the protein α-synuclein, is a characteristic pathologic feature of Parkinson’s Disease (PD). In the quest for an animal model of PD that mimics motor and non-motor symptoms of human PD, scientists have developed strains of mice that overexpress α-synuclein. By studying a strain of mice bred to overexpress α-synuclein via the Thy-1 promoter, scientists have found these mice develop many of the age-related progressive motor symptoms of PD and demonstrate changes in sleep and anxiety. Their results are published in the latest issue of Journal of Parkinson’s Disease.
PD is the second most common neurodegenerative disorder in the United States, affecting approximately one million Americans and five million people worldwide. Its prevalence is projected to double by 2030. The most obvious symptoms are movement-related, such as involuntary shaking and muscle stiffness; non-motor symptoms, such as increases in anxiety and sleep disturbances, can appear prior to the onset of motor symptoms. Although the drug levodopa can relieve some symptoms, there is no cure – intensifying the pressure to find an animal model that can help clarify the pathological processes underlying human PD and find new medications to treat the pathology and/or relieve symptoms.
Investigators at the National Institute on Aging compared wild type mice with specially bred mice that were transgenic for the A53T mutation of the human α-synuclein (SNCA) gene under the control of a human thymus cell antigen 1, theta (THY-1) promoter. As the mice aged, their motor performance on a rotarod test (which measures how long the mouse can remain on a rotating rod) became impaired and the length of their strides were significantly shorter than the wild type control mice.
The study also found that SNCA mice displayed fragmented nighttime activity patterns compared to wild type controls and appeared to have a reduced overall sleep time. “Despite the prevalence of abnormal sleep patterns in PD, very few studies to date have outlined sleep disturbances in animal models of PD,” says Sarah M. Rothman, PhD, a researcher with the National Institute on Aging, in Baltimore, MD.
Many PD patients typically show an increase in anxiety and depression, and in this respect the SNCA mouse model did not replicate the human condition. SNCA mice displayed an early and significant decrease in anxiety-like behavior that persisted throughout their lifespan, as shown by both open field and elevated plus maze tests (in which mice have the choice of spending time in open or closed arms of a maze). Other rodent models that utilize changes in expression of α-synuclein have also reported lower anxiety levels. The authors suggest that higher levels of serotonin found in the hypothalamus of the SNCA mice may be associated with the reduced anxiety observed.
The authors say it is important to remember that the SNCA “model utilizes the presence of a mutation that only occurs very rarely in PD. While all PD patients display α-synuclein pathology, they do not all express the mutated form of the protein,” says Dr. Rothman.
(Source: alphagalileo.org)
New technique for deep brain stimulation surgery proves accurate and safe
Surgery has been used for Parkinson’s disease and familial tremors, and also shows promise for other disorders
The surgeon who more than two decades ago pioneered deep brain stimulation surgery in the United States to treat people with Parkinson’s disease and other movement disorders has now developed a new way to perform the surgery — which allows for more accurate placement of the brain electrodes and likely is safer for patients.
The success and safety of the new surgical technique could have broad implications for deep brain stimulation, or DBS, surgery into the future, as it may increasingly be used to help with a wide range of medical issues beyond Parkinson’s disease and familial tremors.
The new surgery also offers another distinct advantage: patients are asleep during the surgery, rather than being awake under local anesthesia to help surgeons determine placement of the electrodes as happens with the traditional DBS surgery.
A study detailing the new surgical technique is being published in the June 2013 edition of the Journal of Neurosurgery, and has been published online at the journal’s website.
"I think this will be how DBS surgery will be done in most cases going forward," said Kim Burchiel, M.D., F.A.C.S., chair of neurological surgery at Oregon Health & Science University and the lead author of the Journal of Neurosurgery article. “This surgery allows for extremely accurate placement of the electrodes and it’s safer. Plus patients don’t need to be awake during this surgery — which will mean many more patients who can be helped by this surgery will now be willing to consider it.”
DBS surgery was first developed in France in 1987. Burchiel was the first surgeon in North America to perform the surgery, as part of a Food and Drug Administration-approved clinical trial in 1991.
The FDA approved the surgery for “essential tremor” in 1997 and for tremors associated with Parkinson’s disease in 2002. The surgery has been performed tens of thousands of times over the last decade or so in the United States, most often for familial tremor and Parkinson’s disease. Burchiel and his team at OHSU have performed the surgery more than 750 times.
The surgery involves implanting very thin wire electrodes in the brain, connected to something like a pacemaker implanted in the chest. The system then stimulates the brain to often significantly reduce the tremors.
For most of the last two decades, the DBS patient was required to be awake during surgery, to allow surgeons to determine through monitoring the patient’s symptoms and getting other conscious patient feedback whether the electrodes were placed in the right spots in the brain.
But the traditional form of the surgery had drawbacks. Many patients who might have benefitted weren’t willing to undergo the sometimes 4 to 6 hour surgery while awake. There also is a small chance of hemorrhaging in the brain as the surgeon places or moves the electrodes to the right spot in the brain.
The new technique uses advances in brain imaging in recent years to place the electrodes more safely, and more accurately, than in traditional DBS surgery. The surgical team uses CT scanning during the surgery itself, along with an MRI of the patient’s brain before the surgery, to precisely place the electrodes in the brain, while better ensuring no hemorrhaging or complications from the insertion of the electrode.
The Journal of Neurosurgery article reported on 60 patients who had the surgery at OHSU over an 18-month period beginning in early 2011.
"What our results say is that it’s safe, that we had no hemorrhaging or complications at all — and the accuracy of the electrode placement is the best ever reported," Burchiel said.
Burchiel and his team have done another 140 or so surgeries with the new procedure since enrollment in the study ended. OHSU was the first center to pioneer the new DBS procedure, but other surgical teams across the U.S. are learning the technique at OHSU, and bringing it back to their own centers.
The positive results with the new DBS technique could have ramifications as medical researchers nationwide continue to explore possible new uses for DBS surgery. DBS surgery has shown promising results in clinical trials with some Alzheimer’s patients, with some forms of depression and even with obesity.
If the early promising results for these conditions are confirmed, the number of people who might be candidates for DBS surgery could expand greatly, Burchiel said.
The length of the new surgery for the 60 patients involved in the study was slightly longer than traditional DBS surgery. But as Burchiel and his team have developed the new surgical technique, the new DBS surgeries are usually much shorter, often taking half the time of the more traditional approach. Given that, and that the electrodes are placed more accurately and the surgery is cheaper to perform, the new DBS surgery likely will be the technique most surgeons will use in coming years, Burchiel said.
DBS surgery often helps significantly reduce tremors in patients with familial tremor and tremors and other symptoms in Parkinson’s disease. A parallel study is ongoing at OHSU to assess how symptoms of the patients have improved since their DBS surgery using this new method.
(Image: Dr Frank Gaillard)
Proteins in migration
In Parkinson’s disease, the protein “alpha-synuclein” aggregates and accumulates within neurons. Specific areas of the brain become progressively affected as the disease develops and advances. The mechanism underlying this pathological progression is poorly understood but could result from spreading of the protein (or abnormal forms of it) along nerve projections connecting lower to upper brain regions. Scientists at the German Center for Neurodegenerative Diseases (DZNE) in Bonn have developed a novel experimental model that reproduces for the first time this pattern of alpha-synuclein brain spreading and provides important clues on the mechanisms underlying this pathological process. They triggered the production of human alpha-synuclein in the lower rat brain and were able to trace the spreading of this protein toward higher brain regions. The new experimental paradigm could promote the development of ways to halt or slow down disease development in humans. The research team headed by Prof. Donato Di Monte presents these results in the scientific journal “EMBO Molecular Medicine”.
Parkinson’s disease is a disorder of the nervous system. It typically manifests itself with motor disturbances, such as an uncontrollable trembling of the limbs, as well as non-motor symptoms, including sleep disorders and depression.
At the present, no cure exists for Parkinson’s disease, although symptomatic intervention, including treatment with dopamine agonists, can alleviate patients’ motor impairment. Parkinson’s is the second most common neurodegenerative disorder, after Alzheimer’s disease; it is estimated that 100,000 to 300,000 patients are affected by Parkinson’s disease in Germany alone.
In a small percentage of cases, Parkinson’s disease is due to genetic abnormalities carried within families. For the vast majority of patients, however, the cause of the disease remains unknown; the development of this sporadic form of the disease is likely promoted by both environmental and genetic risk factors. An intriguing characteristic of the brain of patients with sporadic Parkinson’s disease is the progressive accumulation of intraneuronal inclusions that were first described by a German neurologist, Friedrich Lewy, and are therefore called Lewy bodies.
“A major discovery in the late 90’s was that Lewy bodies are formed when the protein alpha-synuclein becomes aggregated,” says Di Monte. “Since then, it was also found that aggregates of alpha-synuclein are progressively accumulated within the patients’ brains during the course of the disease”.
Pathology studies from human brains show that the deposits usually start forming in the lower part of the brain, in an area named “medulla oblongata”. In subsequent disease stages, alpha-synuclein aggregates are observed in progressively higher (more rostral) brain regions, including the midbrain and cortical areas.
“This spreading appears to follow a typical pattern based on anatomical connections between regions of the brain,” says the neuroscientist. “For this reason, it has been hypothesized that alpha-synuclein or abnormal forms of it can be transferred between two interconnected neurons and hence migrate throughout the brain. But until now, there was no way of targeting the medulla oblongata to reproduce this spreading of alpha-synuclein in the laboratory. It is also unclear what conditions could trigger the inter-neuronal passage of the protein or its aggregates. We have now developed a new experimental paradigm which enables investigations on these fundamental issues.”
From the neck into the brain
The researchers’ concept is based on reproducing alpha-synuclein spreading in rats: for this, they transferred the blueprint of the human form of alpha-synuclein into the rat brain. The blueprint was transported by specifically engineered viral particles that the scientists injected into nerve fibres in the neck of the animals. The genetic code for the protein passed along these fibres into the medulla oblongata, where transfected rat neurons began producing high quantities of human alpha-synuclein.
“We have good reasons to believe that the medulla oblongata is a primary site of early disease development. This is why we wanted to activate production of alpha-synuclein specifically in this part of the brain. The medulla oblongata is difficult to reach via surgical procedures. For this reason, we injected the viral particles into the vagus nerve. This is a long nerve stretching from the abdomen via the neck to the medulla oblongata. The nerve consequently served as an entrance into the brain and, in particular, the medulla oblongata,” Di Monte explains.
A migrating protein
The researchers monitored the production and localization of human alpha-synuclein in rats’ brains over a period of four and a half months after injection of the viral particles. As predicted, the exogenous protein was synthesized only within neurons of the medulla oblongata connected to the vagus nerve. Starting at two months, however, human alpha-synuclein was observed also in brain areas more and more distant from the medulla oblongata. Caudo-rostral spreading involved inter-neuronal passage of the protein along specific nerve tracts and was accompanied by morphological alterations (such as swellings) of the neuronal projections taking up human alpha-synuclein.
The study, sponsored in part by the Blanche A. Paul Foundation, bears a number of critical implications. It reproduces a pattern of protein propagation that resembles the progressive spreading of pathological alpha-synuclein in Parkinson’s disease. As importantly, the process of protein transmission was triggered by overproduction of alpha-synuclein within a specific brain region.
“Overproduction of alpha-synuclein accompanies a variety of conditions, such as aging, neuronal injury or genetic polymorphisms, that could promote the development of Parkinson’s disease.” concludes Di Monte. “Thus, our results suggest a mechanistic link between disease risk factors, enhanced levels of alpha-synuclein, spreading of the protein and its pathological accumulation.”
Insight into the early stages of Parkinson’s
The new model mimics events that likely occur in the early stages of alpha-synuclein pathology in the absence of overt behavioural (in rats) or clinical (in patients) manifestations. “It will therefore become a valuable tool to investigate early mechanisms of disease pathogenesis that could be targeted for therapeutic intervention. Early intervention would have a greater probability to prevent or halt the spreading of pathology and progression of the disease,” says Di Monte.
(Source: dzne.de)
Common Food Supplement Fights Degenerative Brain Disorders
Nutritional supplement delays advancement of Parkinson’s and Familial Dysautonomia, TAU researchers discover
Widely available in pharmacies and health stores, phosphatidylserine is a natural food supplement produced from beef, oysters, and soy. Proven to improve cognition and slow memory loss, it’s a popular treatment for older people experiencing memory impairment. Now a team headed by Prof. Gil Ast and Dr. Ron Bochner of Tel Aviv University’s Department of Human Molecular Genetics has discovered that the same supplement improves the functioning of genes involved in degenerative brain disorders, including Parkinson’s disease and Familial Dysautonomia (FD).
In FD, a rare genetic disorder that impacts the nervous system and appears almost exclusively in the Ashkenazi Jewish population, a genetic mutation prevents the brain from manufacturing healthy IKAP proteins — which likely have a hand in cell migration and aiding connections between nerves — leading to the early degeneration of neurons. When the supplement was applied to cells taken from FD patients, the gene function improved and an elevation in the level of IKAP protein was observed, reports Prof. Ast. These results were replicated in a second experiment which involved administering the supplement orally to mouse populations with FD.
The findings, which have been published in the journal Human Molecular Genetics, are very encouraging, says Prof. Ast. “That we see such an effect on the brain — the most important organ in relation to this disease — shows that the supplement can pass through the blood-brain barrier even when administered orally, and accumulate in sufficient amounts in the brain.”
Slowing the death of nerve cells
Already approved for use as a supplement by the FDA, phosphatidylserine contains a molecule essential for transmitting signals between nerve cells in the brain. Prof. Ast and his fellow researchers decided to test whether the same chemical, which is naturally synthesized in the body and known to boost memory capability, could impact the genetic mutation which leads to FD.
Researchers applied a supplement derived from oysters, provided by the Israeli company Enzymotec, to cells collected from FD patients. Noticing a robust effect on the gene, including a jump in the production of healthy IKAP proteins, they then tested the same supplement on mouse models of FD, engineered with the same genetic mutation that causes the disease in humans.
The mice received the supplement orally, every two days for a period of three months. Researchers then conducted extensive genetic testing to assess the results of the treatment. “We found a significant increase of the protein in all the tissues of the body,” reports Prof. Ast, including an eight-fold increase in the liver and 1.5-fold increase in the brain. “While the food supplement does not manufacture new nerve cells, it probably delays the death of existing ones,” he adds.
Therapeutic potential for Parkinson’s
That the supplement is able to improve conditions in the brain, even when given orally, is a significant finding, notes Prof. Ast. Most medications enter the body through the blood stream, but are incapable of breaking through the barrier between the blood and the brain.
In addition, the researchers say the supplement’s positive effects extend beyond the production of IKAP. Not only did phosphatidylserine impact the gene associated with FD, but it also altered the level of a total of 2400 other genes — hundreds of which have been connected to Parkinson’s disease in previous studies.
The researchers believe that the supplement may have a beneficial impact on a number of degenerative diseases of the brain, concludes Prof. Ast, including a major potential for the development of new medications which would help tens of millions of people worldwide suffering from these devastating diseases.
(Source: aftau.org)
Cancer Drug Prevents Build-up of Toxic Brain Protein
Researchers at Georgetown University Medical Center have used tiny doses of a leukemia drug to halt accumulation of toxic proteins linked to Parkinson’s disease in the brains of mice. This finding provides the basis to plan a clinical trial in humans to study the effects.
They say their study, published online May 10 in Human Molecular Genetics, offers a unique and exciting strategy to treat neurodegenerative diseases that feature abnormal buildup of proteins in Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Huntington disease and Lewy body dementia, among others.
“This drug, in very low doses, turns on the garbage disposal machinery inside neurons to clear toxic proteins from the cell. By clearing intracellular proteins, the drug prevents their accumulation in pathological inclusions called Lewy bodies and/or tangles, and also prevents amyloid secretion into the extracellular space between neurons, so proteins do not form toxic clumps or plaques in the brain,” says the study’s senior investigator, neuroscientist Charbel E-H Moussa, MB, PhD. Moussa heads the laboratory of dementia and Parkinsonism at Georgetown.
When the drug, nilotinib, is used to treat chronic myelogenous leukemia (CML), it forces cancer cells into autophagy — a biological process that leads to death of tumor cells in cancer.
“The doses used to treat CML are high enough that the drug pushes cells to chew up their own internal organelles, causing self-cannibalization and cell death,” Moussa says. “We reasoned that small doses — for these mice, an equivalent to one percent of the dose used in humans — would turn on just enough autophagy in neurons that the cells would clear malfunctioning proteins, and nothing else.”
Moussa, who has long sought a way to force neurons to clean up their garbage, came up with the idea of using cancer drugs that push autophagy in tumors to help diseased brains. “No one has tried anything like this before,” he says.
Moussa, and his two co-authors — graduate student Michaeline Hebron and Irina Lonskaya, PhD, a postdoctoral researcher in Moussa’s lab — searched for cancer drugs that can cross the blood-brain barrier. They discovered two candidates — nilotinib and bosutinib, which is also approved to treat CML. This study discusses experiments with nilotinib, but Moussa says that use of bosutinib is also beneficial.
The mice used in this study over-express alpha-Synuclein, the protein that builds up in Lewy bodies in Parkinson’s disease and dementia patients and which is found in many other neurodegenerative diseases. The animals were given one milligram of nilotinib every two days. (By contrast, the FDA approved use of up to 1,000 milligrams of nilotinib once a day for CML patients.)
“We successfully tested this for several diseases models that have an accumulation of intracellular protein,” Moussa says. “It gets rid of alpha synuclein and tau in a number of movement disorders, such as Parkinson’s disease as well as Lewy body dementia.”
The team also showed that movement and functionality in the treated mice was greatly improved, compared with untreated mice.
In order for such a therapy to be as successful as possible in patients, the agent would need to be used early in neurodegenerative diseases, Moussa hypothesizes. Later use might retard further extracellular plaque formation and accumulation of intracellular proteins in inclusions such as Lewy bodies.
Moussa is planning a phase II clinical trial in participants who have been diagnosed with disorders that feature build-up of alpha Synuclein, including Lewy body dementia, Parkinson’s disease, progressive supranuclear palsy (PSP) and multiple system atrophy (MSA).
(Source: explore.georgetown.edu)
Boosting ‘cellular garbage disposal’ can delay the aging process
UCLA life scientists have identified a gene previously implicated in Parkinson’s disease that can delay the onset of aging and extend the healthy life span of fruit flies. The research, they say, could have important implications for aging and disease in humans.
The gene, called parkin, serves at least two vital functions: It marks damaged proteins so that cells can discard them before they become toxic, and it is believed to play a key role in the removal of damaged mitochondria from cells.
"Aging is a major risk factor for the development and progression of many neurodegenerative diseases," said David Walker, an associate professor of integrative biology and physiology at UCLA and senior author of the research. "We think that our findings shed light on the molecular mechanisms that connect these processes."
In the research, published today in the early online edition of the journal Proceedings of the National Academy of Sciences, Walker and his colleagues show that parkin can modulate the aging process in fruit flies, which typically live less than two months. The researchers increased parkin levels in the cells of the flies and found that this extended their life span by more than 25 percent, compared with a control group that did not receive additional parkin.
"In the control group, the flies are all dead by Day 50," Walker said. "In the group with parkin overexpressed, almost half of the population is still alive after 50 days. We have manipulated only one of their roughly 15,000 genes, and yet the consequences for the organism are profound."
"Just by increasing the levels of parkin, they live substantially longer while remaining healthy, active and fertile," said Anil Rana, a postdoctoral scholar in Walker’s laboratory and lead author of the research. "That is what we want to achieve in aging research — not only to increase their life span but to increase their health span as well."
Treatments to increase parkin expression may delay the onset and progression of Parkinson’s disease and other age-related diseases, the biologists believe. (If parkin sounds related to Parkinson’s, it is. While the vast majority of people with the disease get it in older age, some who are born with a mutation in the parkin gene develop early-onset, Parkinson’s-like symptoms.)
"Our research may be telling us that parkin could be an important therapeutic target for neurodegenerative diseases and perhaps other diseases of aging," Walker said. "Instead of studying the diseases of aging one by one — Parkinson’s disease, Alzheimer’s disease, cancer, stroke, cardiovascular disease, diabetes — we believe it may be possible to intervene in the aging process and delay the onset of many of these diseases. We are not there yet, and it can, of course, take many years, but that is our goal."
'The garbage men in our cells go on strike'
To function properly, proteins must fold correctly, and they fold in complex ways. As we age, our cells accumulate damaged or misfolded proteins. When proteins fold incorrectly, the cellular machinery can sometimes repair them. When it cannot, parkin enables cells to discard the damaged proteins, said Walker, a member of UCLA’s Molecular Biology Institute.
"If a protein is damaged beyond repair, the cell can recognize that and eliminate the protein before it becomes toxic," he said. "Think of it like a cellular garbage disposal. Parkin helps to mark damaged proteins for disposal. It’s like parkin places a sticker on the damaged protein that says ‘Degrade Me,’ and then the cell gets rid of this protein. That process seems to decline with age. As we get older, the garbage men in our cells go on strike. Overexpressed parkin seems to tell them to get back to work."
Rana focused on the effects of increased parkin activity at the cellular and tissue levels. Do flies with increased parkin show fewer damaged proteins at an advanced age? “The remarkable finding is yes, indeed,” Walker said.
Parkin has recently been shown to perform a similarly important function with regard to mitochondria, the tiny power generators in cells that control cell growth and tell cells when to live and die. Mitochandria become less efficient and less active as we age, and the loss of mitochondrial activity has been implicated in Alzheimer’s, Parkinson’s and other neurodegenerative diseases, as well as in the aging process, Walker said.
Parkin appears to degrade the damaged mitochondria, perhaps by marking or changing their outer membrane structure, in effect telling the cell, “This is damaged and potentially toxic. Get rid of it.”
If parkin is good, is more parkin even better?
While the researchers found that increased parkin can extend the life of fruit flies, Rana also discovered that too much parkin can have the opposite effect — it becomes toxic to the flies. When he quadrupled the normal amount of parkin, the fruit flies lived substantially longer, but when he increased the amount by a factor of 30, the flies died sooner.
"If you bombard the cell with too much parkin, it could start eliminating healthy proteins," Rana said.
In the lower doses, however, the scientists found no adverse effects. Walker believes the fruit fly is a good model for studying aging in humans — who also have the parkin gene — because scientists know all of the fruit fly’s genes and can switch individual genes on and off.
Previous research has shown that fruit flies die sooner when you remove parkin, Walker noted.
Walker and Rana do not know what the optimal amount of parkin would be in humans.
While the biologists increased parkin activity in every cell in the fruit fly, Rana also conducted an experiment in which he increased parkin expression only in the nervous system. That, too, was sufficient to make the flies live longer.
"This tells us that parkin is neuroprotective during aging," Walker said. "However, the beneficial effects of parkin are greater — twice as large — when we increased its expression everywhere."
"We were excited about this research from the beginning but did not know then that the life span increase would be this impressive," Rana said.
The image that accompanies this news release shows clumps or aggregates of damaged proteins in an aged brain from a normal fly (left panel) and an age-matched brain with increased neuronal parkin levels (right panel). As can be seen, increasing parkin levels in the aging brain reduces the accumulation of aggregated proteins.
Scientists have found that this kind of protein aggregation occurs in mammals as well, including humans, Rana said.
"Imagine the damage the accumulation of protein trash is doing to the cell," Walker said. "With increased Parkin, the trash has been collected. Without it, the garbage that should be discarded is accumulating in the cells."
Study Shows How Parkinson’s Disease Protein Acts like a Virus
A protein known to be a key player in the development of Parkinson’s disease is able to enter and harm cells in the same way that viruses do, according to a Loyola University Chicago Stritch School of Medicine study.
The protein is called alpha-synuclein. The study shows how, once inside a neuron, alpha synuclein breaks out of lysosomes, the digestive compartments of the cell. This is similar to how a cold virus enters a cell during infection. The finding eventually could lead to the development of new therapies to delay the onset of Parkinson’s disease or halt or slow its progression, researchers said.
The study by virologist Edward Campbell, PhD, and colleagues, was published April 25, 2013 in the journal PLOS ONE.
Alpha-synuclein plays a role in the normal functioning of healthy neurons. But in Parkinson’s disease patients, the protein turns bad, aggregating into clumps that lead to the death of neurons in the area of the brain responsible for motor control. Previous studies have shown that these protein aggregates can enter and harm cells. Campbell and colleagues showed how alpha synuclein can bust out of lysosomes, small structures that collectively serve as the cell’s digestive system. The rupture of these bubble-like structures, known as vesicles, releases enzymes that are toxic to the rest of the cell.
“The release of lysosomal enzymes is sensed as a ‘danger signal’ by cells, since similar ruptures are often induced by invading bacteria or viruses,” said Chris Wiethoff, a collaborator on the study. “Lysosomes are often described as ‘suicide bags’ because when they are ruptured by viruses or bacteria, they induce oxidative stress that often leads to the death of the affected cell.”
In a viral or bacterial infection, the deaths of such infected cells may overall be a good thing for the infected individual. But in Parkinson’s disease, this same protective mechanism may lead to the death of neurons and enhance the spread of alpha-synuclein between cells in the brain, Campbell said. “This might explain the progressive nature of Parkinson’s disease. More affected cells leads to the spread of more toxic alpha-synuclein aggregates in the brain,” Campbell said. “This is very similar to what happens in a spreading viral infection.”
Campbell stressed that these studies need to be followed up and confirmed in other models of Parkinson’s disease. “Using cultured cells, we have made some exciting observations. However, we need to understand how lysosomal rupture is affecting disease progression in animal models of Parkinson’s disease and, ultimately, the brains of people affected by Parkinson’s disease. Can we interfere with the ability of alpha-synuclein to rupture lysosomes in these settings? And will that have a positive effect on disease progression? These are the questions we are excited to be asking next.”
Jeffrey H. Kordower, PhD, professor of neurological sciences, professor of neurosurgery and director of the Research Center for Brain Repair at Rush University Medical Center, said the study “is an important finding by a group of investigators who are beginning to make their impact in the field of Parkinson’s disease. This paper adds to the growing concept that alpha-synuclein, a main culprit in the cause of Parkinson’s disease, can transfer from cell to cell. This paper elegantly puts a mechanism behind such a transfer. The findings will help shape the direction of Parkinson’s disease research for years to come.”
Missing link in Parkinson’s disease found
Researchers at Washington University School of Medicine in St. Louis have described a missing link in understanding how damage to the body’s cellular power plants leads to Parkinson’s disease and, perhaps surprisingly, to some forms of heart failure.
These cellular power plants are called mitochondria. They manufacture the energy the cell requires to perform its many duties. And while heart and brain tissue may seem entirely different in form and function, one vital characteristic they share is a massive need for fuel.
Working in mouse and fruit fly hearts, the researchers found that a protein known as mitofusin 2 (Mfn2) is the long-sought missing link in the chain of events that control mitochondrial quality.
The findings are reported April 26 in the journal Science.
The new discovery in heart cells provides some explanation for the long known epidemiologic link between Parkinson’s disease and heart failure.
“If you have Parkinson’s disease, you have a more than two-fold increased risk of developing heart failure and a 50 percent higher risk of dying from heart failure,” says senior author Gerald W. Dorn II, MD, the Philip and Sima K. Needleman Professor of Medicine. “This suggested they are somehow related, and now we have identified a fundamental mechanism that links the two.”
Heart muscle cells and neurons in the brain have huge numbers of mitochondria that must be tightly monitored. If bad mitochondria are allowed to build up, not only do they stop making fuel, they begin consuming it and produce molecules that damage the cell. This damage eventually can lead to Parkinson’s or heart failure, depending on the organ affected. Most of the time, quality-control systems in a healthy cell make sure damaged or dysfunctional mitochondria are identified and removed.
Over the past 15 years, scientists have described much of this quality-control system. Both the beginning and end of the chain of events are well understood. And since 2006, scientists have been working to identify the mysterious middle section of the chain – the part that allows the internal environment of sick mitochondria to communicate to the rest of the cell that it needs to be destroyed.
“This was a big question,” Dorn says. “Scientists would draw the middle part of the chain as a black box. How do these self-destruct signals inside the mitochondria communicate with proteins far away in the surrounding cell that orchestrate the actual destruction?”
“To my knowledge, no one has connected an Mfn2 mutation to Parkinson’s disease,” Dorn says. “And until recently, I don’t think anybody would have looked. This isn’t what Mfn2 is supposed to do.”
Mitofusin 2 is known for its role in fusing mitochondria together, so they might exchange mitochondrial DNA in a primitive form of sexual reproduction.
“Mitofusins look like little Velcro loops,” Dorn says. “They help fuse together the outer membranes of mitochondria. Mitofusins 1 and 2 do pretty much the same thing in terms of mitochondrial fusion. What we have done is describe an entirely new function for Mfn2.”
The mitochondrial quality-control system begins with what Dorn calls a “dead man’s switch.”
“If the mitochondria are alive, they have to do work to keep the switch depressed to prevent their own self-destruction,” Dorn says.
Specifically, mitochondria work to import a molecule called PINK. Then they work to destroy it. When mitochondria get sick, they can’t destroy PINK and its levels begin to rise. Then comes the missing link that Dorn and his colleague Yun Chen, PhD, senior scientist, identified. Once PINK levels get high enough, they make a chemical change to Mfn2, which sits on the surface of mitochondria. This chemical change is called phosphorylation. Phosphorylated Mfn2 on the surface of the mitochondria can then bind with a molecule called Parkin that floats around in the surrounding cell.
Once Parkin binds to Mfn2 on sick mitochondria, Parkin labels the mitochondria for destruction. The labels then attract special compartments in the cell that “eat” and destroy the sick mitochondria. As long as all links in the quality-control system work properly, the cells’ damaged power plants are removed, clearing the way for healthy ones.
“But if you have a mutation in PINK, you get Parkinson’s disease,” Dorn says. “And if you have a mutation in Parkin, you get Parkinson’s disease. About 10 percent of Parkinson’s disease is attributed to these or other mutations that have been identified.”
According to Dorn, the discovery of Mfn2’s relationship to PINK and Parkin opens the doors to a new genetic form of Parkinson’s disease. And it may help improve diagnosis for both Parkinson’s disease and heart failure.
“I think researchers will look closely at inherited Parkinson’s cases that are not explained by known mutations,” Dorn says. “They will look for loss of function mutations in Mfn2, and I think they are likely to find some.”
Similarly, as a cardiologist, Dorn and his colleagues already have detected mutations in Mfn2 that appear to explain certain familial forms of heart failure, the gradual deterioration of heart muscle that impairs blood flow to the body. He speculates that looking for mutations in PINK and Parkin might be worthwhile in heart failure as well.
“In this case, the heart has informed us about Parkinson’s disease, but we may have also described a Parkinson’s disease analogy in the heart,” he says. “This entire process of mitochondrial quality control is a relatively small field for heart specialists, but interest is growing.”