Posts tagged neurodegenerative diseases
Articles and news from the latest research reports.
Manipulating Memory in the Hippocampus
Protein modification may help control Alzheimer’s and epilepsy, TAU researchers find
In the brain, cell-to-cell communication is dependent on neurotransmitters, chemicals that aid the transfer of information between neurons. Several proteins have the ability to modify the production of these chemicals by either increasing or decreasing their amount, or promoting or preventing their secretion. One example is tomosyn, which hinders the secretion of neurotransmitters in abnormal amounts.
Dr. Boaz Barak of Tel Aviv University’s Sagol School of Neuroscience, in collaboration with Prof. Uri Ashery, used a method for modifying the levels of this protein in the mouse hippocampus — the region of the brain associated with learning and memory. It had a significant impact on the brain’s activity: Over-production of the protein led to a sharp decline in the ability to learn and memorize information, the researchers reported in the journal NeuroMolecular Medicine.
"This study demonstrates that it is possible to manipulate various processes and neural circuits in the brain," says Dr. Barak, a finding which may aid in the development of therapeutic procedures for epilepsy and neurodegenerative diseases such as Alzheimer’s. Slowing the transmission rate of information when the brain is overactive during epileptic seizures could have a beneficial effect, and readjusting the levels of tomosyn in an Alzheimer’s patient may help increase cognition and combat memory loss.
A maze of memory loss
The researchers teamed up with a laboratory at the National Institutes of Health (NIH) in Baltimore to create a virus which produces the tomosyn protein. In the lab, the virus was injected into the hippocampus region in mice. Then, in order to test the consequences, they performed a series of behavioral tests designed to measure functions like memory, cognitive ability, and motor skills.
In one experiment, called the Morris Water Maze, mice had to learn to navigate to, and remember, the location of a hidden platform placed inside a pool with opaque water. During the first five days of testing, researchers found that the test group with an over-production of tomosyn had a significant problem in learning and memorizing the location of the platform, compared to a control group that received a placebo injection. And when the platform was removed from the maze, the test group spent less time swimming around the area where the platform once was, indicating that they had no memory of its existence. In comparison, the control group of mice searched for the missing platform in its previous location for two or even three days after its removal, notes Dr. Barak.
These findings were further verified by measuring electrical activity in the brains of both the test group and the control group. In the test group, researchers found decreased levels of transmissions between neurons in the hippocampus, a physiological finding that may explain the results of the behavioral tests.
Correcting neuronal processes
In the future, Dr. Barak believes that the ability to modify proteins directly in the brain will allow for more control over brain activities and the correction of neurodegenerative processes, such as providing stricter regulation in neuronal activity for epileptic patients or stimulating neurotransmitters to help with learning and memory loss in Alzheimer’s patients. Indeed, a separate study conducted by the researchers demonstrates that mouse models for Alzheimer’s disease do have an over-production of tomosyn in the hippocampus region, so countering the production of this protein could have a beneficial effect.
Now Dr. Barak and Prof. Ashery are working towards a method for artificially decreasing levels of the protein, which they believe will have the opposite effect on the cognitive ability of the mice. “We hypothesize that with an under-production in tomosyn, the mice will show a marked improvement in their performance in behavioral testing,” he says.
(Source: aftau.org)
Little less protein may be answer in neurodegenerative disorders
In some neurodegenerative diseases, and specifically in a devastating inherited condition called spinocerebellar ataxia 1 (SCA1), the answer may not be an “all-or-nothing,” said a collaboration of researchers from Baylor College of Medicine, the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and the University of Minnesota in a report that appears online in the journal Nature. The problem might be solved with just a little less.
"If you can only decrease the levels of ataxin-1 (the protein involved in SCA1) by 20 percent, you can reduce many symptoms of the disease," said Dr. Huda Zoghbi, professor of molecular and human genetics and pediatrics at BCM and director of the Neurological Research Institute. She is also a Howard Hughes Medical Institute Investigator.
Her long-time colleague Dr. Harry Orr, director of the University of Minnesota Institute for Translational Neuroscience, echoed that sentiment: “Perhaps, if you decrease the levels of the protein, you will decrease the severity of the disease.” In this report, the laboratories of Zoghbi, Dr. Juan Botas, also of BCM and the Neurological Researcher Institute, Dr. Thomas Westbrook, assistant professor of molecular and human genetics at BCM, and Orr identified a molecular pathway in the cell (RAS/MAPK/MSK1) with components that can be modulated slightly to reduce the levels of defective ataxin-1, the protein that causes disease in patients with the disorder.
Spinocerebellar ataxia 1 occurs when the ataxin-1 gene is mutated, with three letters of the DNA alphabet repeating many, many times. The abnormal protein that results cannot fold correctly and piles up in the cell, eventually killing it. As with many neurodegenerative disorders, the process can take over a decade. A person usually does not develop symptoms of this form of ataxia until he or she is 30 years old or older. The person develops gait problems, eventually loses the ability to speak and function and dies. Zoghbi and Orr teamed to find the gene associated with the disorder in 1993. Their work on the disease has spanned 20 years.
Totally eliminating the protein would not work. Mice that lack the gene have problems with learning and memory, indicating that ataxin-1 plays a role in those activities. Reducing the levels of ataxin-1 does not cure the disease, but it can significantly delay onset.
A Collaborative Innovation Award from the Howard Hughes Medical Institute enabled Zoghbi to put together the team that could screen for the genes or the gene pathway that could be manipulated to result in less ataxin-1.
"Harry and I had studied the disease and we had animal models. Botas, professor of molecular and human genetics at BCM, had a fruit fly model and Dr. Westbrook had a nice technology that enabled us to monitor ataxin-1 levels."
They began with a screen for genes that could affect the levels of ataxin-1 produced in the cell, said Dr. Ismail Al-Ramahi, a postdoctoral fellow in the lab of Botas. Dr. Jeehye Park, a post-doctoral fellow in Zoghbi’s laboratory, and Al-Ramahi are co-first authors of the report. Park and her colleagues carried out the screen in human cell lines and Al-Ramahi and his colleagues carried out the screen in fruit flies (Drosophila melanogaster).
The screen in human cells focused on forms of enzymes called kinases because they are susceptible to the effects of drugs. Using a special technique called RNA silencing, they targeted each known human kinase. At the same, Botas and Al-Ramahi screened kinase genes in fruit flies with a form of SCA1. When the two laboratories compared results, they found 10 genes in common that when inhibited could reduce the levels of ataxin-1 as well as the toxicity associated with it. The genes were part of the RAS/MAPK/MSKI signaling cascade within the cell.
Then the researchers focused on one protein in this pathway called MSK1 and found that when its levels were decreased in mice that were laboratory models of SCA1, the levels of ataxin-1 dropped and the animals improved. That was the final experiment that proved that reducing levels of the protein could stave off the disease.
"We want to look for more pathways," said Zoghbi. If they find more pathways, they may be able to reduce toxicity. "If you have a pain and you take acetaminophen all the time, you have a risk of toxicity. Similarly, if you took a nonsteroidal anti-inflammatory all the time, you would have another toxicity. If you alternate between them, there is less toxicity. If we hit only one pathway with a big inhibition, we risk some toxicity. If we find two or three pathways and hit each only a little, the rest of the body should not be hurt. Each little hit should help us reduce ataxin-1 by a respectable amount."
"I think what is novel about this paper is the integration of the screen in cells that was done in Huda’s lab and the screen in fruit flies done in our lab to look for targets for genes about which we knew nothing ahead of time," said Botas.
While the finding in spinocerebellar ataxia 1 is exciting, its potential application in other diseases is even more provocative.
"Now that we know that it works with ataxin-1, we can revisit many proteins whose levels drive neurodegeneration in sporadic and inherited diseases such as Alzheimer’s, Parkinson’s, Huntington’s and other neurological disorders," said Zoghbi. "This is a pilot study and the results from it are as important as a new pathway in neurodegenerative disease research."
"These are diseases that take a long time to develop," said Park. "Most Alzheimer’s occurs after the age of 85. If we could delay it until age 95, that would be very helpful."
"This is getting us really close, not only for SCA1, but I think it’s going to be a guidepost for work on a lot of other neurodegenerative diseases," said Orr. "It sets us a beautiful research strategy to get at that goal."
(Source: bcm.edu)
The value of copper has risen dramatically in the 21st century as many a thief can tell you, but in addition to the thermal and electrical properties that make it such a hot commodity metal, copper has chemical properties that make it essential to a healthy brain. Working at the interface of chemistry and neuroscience, Berkeley Lab chemist Christopher Chang and his research group at UC Berkeley have developed a series of fluorescent probes for molecular imaging of copper in the brain. Speaking at the recent national meeting of the American Chemical Society in New Orleans, he described the challenges of creating and applying live-cell and live-animal copper imaging probes and explained the importance of meeting these challenges.
“The human brain is a unique biological system, possessing unparalleled biological complexity in a compact space,” Chang said. “Although it accounts for only two-percent of total body mass, it consumes 20-percent of the oxygen taken in through respiration. As a consequence of its high demand for oxygen and oxidative metabolism, the brain has among the highest levels of copper, as well as iron and zinc in the body.”
Neuron and glia cells in the brain both require copper for the basic respiratory and antioxidant enzymes cytochrome c oxidase and superoxide dismutase. Copper is also necessary for brain-specific enzymes that control neurotransmitters, such as dopamine, as well as neuropeptides and dietary amines. Disruption of copper oxidation in the brain has been linked to several neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Menkes’ and Wilson’s.
“The complex relationships between copper status and various stages of health and disease have been difficult to determine in part because of a lack of methods for monitoring dynamic changes in copper pools in whole living organisms,” Chang said. “We’ve been designing fluorescent probes that can map the movement of copper in live cells, tissue or even model organisms, such as mice and zebrafish.”
Their first success was Coppersensor-3 (CS3), a small-molecule fluorescent probe that can be used to image labile copper pools in living cells at endogenous, basal levels. They used CS3 in conjunction with synchrotron-based X-ray fluorescence microscopy (XRFM) to discover that neuronal cells move significant pools of copper upon activation and that these copper movements are dependent on calcium signaling.
“This was the first established link between mobile copper and major cell signaling pathways,” Chang said. “Being able to map transient copper movements after neuronal depolarization revealed how neural activity triggers copper mobility, and enabled us to create a model for calcium/copper crosstalk in neurons.”
The CS3 probe was followed by Mitochondrial Coppersensor-1 (Mito-CS1), a fluorescent sensor that can selectively target mitochondria and detect basal and labile copper pools in living cells. Mitochondria, the organelles that generate most of the chemical energy used by cells, are important reservoirs for copper. By allowing direct, real-time visualization of exchangeable mitochondrial copper pools, the Mito-CS1 probe enabled Chang and his colleagues to discover that cells maintain copper homeostasis in mitochondria even in situations of copper deficiency and metabolic malfunctions.
“This work illustrated the importance of regulating copper stores in mitochondria,” Chang said.
The latest copper probe from Chang’s group is Coppersensor 790 (CS790), a fluorescent sensor that features near-infrared excitation and emission capabilities, ideal for penetrating thicker biological specimens. CS790 can be used to monitor fluctuations in exchangeable copper stores under basal conditions, as well as under copper overload or deficiency conditions. Chang and his group are using CS790 to study a mouse model of Wilson’s disease, a genetic disorder characterized by an accumulation of excess copper.
“The in vivo fluorescence detection of copper provided by CS790 and our other fluorescent probes is opening up unique opportunities to explore the roles that copper plays in the healthy physiology of the brain, as well as in the development and progression copper-related diseases,” Chang said.
Researchers identify genetic suspects in sporadic Lou Gehrig’s disease
Researchers at the Stanford University School of Medicine have identified mutations in several new genes that might be associated with the development of spontaneously occurring cases of the neurodegenerative disease known as amyotrophic lateral sclerosis, or ALS. Also known as Lou Gehrig’s disease, the progressive, fatal condition, in which the motor neurons that control movement and breathing gradually cease to function, has no cure.
Although researchers know of some mutations associated with inherited forms of ALS, the majority of patients have no family history of the disease, and there are few clues as to its cause. The Stanford researchers compared the DNA sequences of 47 patients who have the spontaneous form of the disease, known as sporadic ALS, with those of their unaffected parents. The goal was to identify new mutations that were present in the patient but not in either parent that may have contributed to disease development.
Several suspects are mutations in genes that encode chromatin regulators — cellular proteins that govern how DNA is packed into the nucleus of a cell and how it is accessed when genes are expressed. Protein members of one these chromatin-regulatory complexes have recently been shown to play roles in normal development and some forms of cancer.
"The more we know about the genetic causes of the disorder, the greater insight we will have as to possible therapeutic targets," said Aaron Gitler, PhD, associate professor of genetics. "Until now, researchers have primarily relied upon large families with many cases of inherited ALS and attempted to pinpoint genetic regions that seem to occur only in patients. But more than 90 percent of ALS cases are sporadic, and many of the genes involved in these cases are unknown."
Gitler is the senior author of the study, published online May 26 in Nature Neuroscience. Postdoctoral scholar Alessandra Chesi, PhD, is the lead author. Gitler and Chesi collaborated with members of the laboratory of Gerald Crabtree, MD, professor of developmental biology and of pathology. Crabtree, a Howard Hughes Medical Institute investigator, is also a co-author of the study.
Chesi and Gitler combined deductive reasoning with recent advances in sequencing technology to conduct the work, which relied on the availability of genetic samples from not only ALS patients, but also the patients’ unaffected parents. Such trios can be difficult to obtain for diseases like sporadic ALS that strike well into adulthood when a patient’s parents may no longer be alive. Gitler and Chesi collaborated with researchers from Emory University and Johns Hopkins University to collect these samples.
The researchers compared the sequences of a portion of the genome called the exome, which directly contributes to the amino acid sequences of all the proteins in a cell. (Many genes contain intervening, non-protein-coding regions of DNA called introns that are removed prior to protein production.) Mutations found only in the patient’s exome, but not in that of his or her parents’, were viewed as potential disease-associated candidates - particularly if they affected the composition or structure of the resulting protein made from that gene.
Focusing on just the exome, which is about 1 percent of the total amount of DNA in each human cell, vastly reduced the total amount of DNA that needed to be sequenced and allowed the researchers to achieve relatively high coverage (or repeated sequencing to ensure accuracy) of each sample.
"We wanted to find novel changes in the patients," Chesi said. "These represent a class of mutations called de novo mutations that likely occurred during the production of the parents’ reproductive cells." As a result, these mutations would be carried in all the cells of patients, but not in their parents or siblings.
Using the exome sequencing technique, the researchers identified 25 de novo mutations in the ALS patients. Of these, five are known to be in genes involved in the regulation of the tightly packed form of DNA called chromatin — a proportion that is much higher than would have been expected by chance, according to Chesi.
Furthermore, one of the five chromatin regulatory proteins, SS18L1, is a member of a neuron-specific complex called nBAF, which has long been studied in Crabtree’s laboratory. This complex is strongly expressed in the brain and spinal cord, and affects the ability of the neurons to form branching structures called dendrites that are essential to nerve signaling.
"We found that, in one sporadic ALS case, the last nine amino acids of this protein are missing," Gitler said. "I knew that Gerald Crabtree’s lab had been investigating SS18L1, so I asked him about it. In fact, they had already identified these amino acids as being very important to the function of the protein."
When the researchers expressed the mutant SS18L1 in motor neurons isolated from mouse embryos, they found the neurons were unable to extend and grow new dendrites as robustly as normal neurons in response to stimuli. They also showed that SS18L1 appears to physically interact with another protein known to be involved in cases of familial, or inherited, ALS.
Although the results are intriguing, the researchers caution that more work is necessary to conclusively prove whether and how mutations in SS18L1 contribute to sporadic cases of ALS. But now they have an idea of where to look in other patients, without requiring the existence of patient and parent trios. They are planning to sequence SS18L1 and other candidates in an additional few thousand sporadic ALS cases.
"This is the first systematic analysis of ALS triads for the presence of de novo mutations," Chesi said. "Now we have a list of candidate genes we can pursue. We haven’t proven that these mutations cause ALS, but we’ve shown, at least in the context of SS18L1, that the mutation carried by some patients is damaging to the protein and affects the ability of mouse motor neurons to form dendrites."
(Source: med.stanford.edu)
A pan-European study: signs of motor disorders can appear years before disease manifestation
It is known that signs of neurological disorders such as Alzheimer’s and Huntington’s disease can appear years before the disease becomes manifest; these signs take the form of subtle changes in the brain and behavior of individuals affected. For the first time, an international group of researchers led by the DZNE and the Bonn University Hospital has proven the existence of such signatures for motor disorders belonging to the group of “spinocerebellar ataxias”. The scientists report these findings in the current online edition of “The Lancet Neurology”. This pan-European study could open up new possibilities of early diagnosis and smooth the way for treatments which tackle diseases before the patient’s nervous system is irreparably damaged.
“Spinocerebellar ataxias” comprise a group of genetic diseases of the cerebellum and other parts of the brain. Persons affected only have limited control of their muscles. They also suffer from balance disorders and impaired speech. The symptoms originate from mutations in the patient’s genetic make-up. These cause nerve cells to become damaged and to die off. Such genetic defects are comparatively rare: it is estimated that about 3,000 people in Germany are affected.
It is known that there are various subtypes of these neurodegenerative diseases. The age at which the symptoms manifest consequently fluctuates between about 30 and 50. “Our aim was to find out whether specific signs can be recognized before a disease becomes obvious,” says project leader Prof. Thomas Klockgether, Director for Clinical Research at the DZNE and Director of the Clinic for Neurology at Bonn University Hospital.
Pan-European cooperation
The study, which involved 14 research centers in all, focused on the four most common forms of spinocerebellar ataxia. These account for more than half of all cases. More than 250 siblings and children of patients throughout Europe declared their willingness to participate in appropriate tests. These individuals had no obvious symptoms of ataxia. However, about half of them had inherited the genetic defects which invariably cause the disease to manifest in the long term.
With the aid of a mathematical model that considered the genetic mutations and their effects, the scientists were able to estimate the time remaining until the disease could be expected to manifest. In the test group, this “time to onset” varied from 2 to 24 years. These and all other test results remained anonymous: the data was not known to the test subjects, neither could the researchers assign it to specific participants. The same applied to individuals whose DNA turned out to be inconspicuous. “People in families with cases of ataxia usually have not taken a genetic test and they don’t want to know any results. This kind of information has to be treated very carefully for ethical reasons,” emphasizes Klockgether.
Extensive tests
The study participants made themselves available for various examinations including standardized tests of muscular coordination. These included measuring the time needed by the subjects to walk a specific distance. Another series of experiments involved inserting small pins into the holes of a board and taking them back out as quickly as possible. Yet another test measured how often the participants could repeat a certain sequence of syllables in ten seconds. “The tests were designed in such a way that they would provide significant information but still be easy to perform,” says Klockgether. “Tests like these can be performed anywhere without need for special technology.”
Technically complex methods were also used: all study participants were tested for the genetic defects relevant to ataxia. At some of the research centers involved in the study, it was also possible to examine the subjects with the aid of magnetic resonance imaging (MRI). This enabled researchers to measure the total brain volume as well as the dimensions of individual parts of the brain in about a third of the subjects.
Notable findings
In two of the four types of ataxia investigated, the scientists found signs of impending disease. “We found a loss in brain volume, particularly shrinkage in the area of the cerebellum and brain stem. These subjects also had subtle difficulties with coordination,” Klockgether summarizes the results. “This means that manifestations of this kind can be measured years before the disease is likely to become obvious.”
The findings for the other two types of ataxia were less conclusive. “I assume that there are indications also for these types of the disease. However, this subgroup of participants was relatively small. It is therefore difficult to make statistically reliable statements about these subjects,” says the Bonn-based researcher.
In his view, the study results testify to the modern-day view of neurodegenerative processes: “Neurodegeneration doesn’t begin when the symptoms surface. Rather, it is a stealthy disease which starts developing years or even decades beforehand.”
Klockgether believes that this gradual development offers certain opportunities: “If we intervened in this process by appropriate treatments and at a sufficiently early stage, it might be possible to slow down or even stop the disease process.”
More investigations planned
The current results will be the basis for long-term investigations. A new series of tests with the same group of individuals has already started; further tests are scheduled every two years. The scientists intend to monitor the study participants for as long as possible.
(Source: dzne.de)
Reducing caloric intake delays nerve cell loss
Activating an enzyme known to play a role in the anti-aging benefits of calorie restriction delays the loss of brain cells and preserves cognitive function in mice, according to a study published in the May 22 issue of The Journal of Neuroscience. The findings could one day guide researchers to discover drug alternatives that slow the progress of age-associated impairments in the brain.
Previous studies have shown that reducing calorie consumption extends the lifespan of a variety of species and decreases the brain changes that often accompany aging and neurodegenerative diseases such as Alzheimer’s. There is also evidence that caloric restriction activates an enzyme called Sirtuin 1 (SIRT1), which studies suggest offers some protection against age-associated impairments in the brain.
In the current study, Li-Huei Tsai — director of the Picower Institute for Learning and Memory and Picower Professor of Neuroscience at MIT — along with postdoc Johannes Gräff and others at MIT tested whether reducing caloric intake would delay the onset of nerve cell loss that is common in neurodegenerative disease, and if so, whether SIRT1 activation was driving this effect. The group not only confirmed that caloric restriction delays nerve cell loss, but also found that a drug that activates SIRT1 produces the same effects.
“There has been great interest in finding compounds that mimic the benefits of caloric restriction that could be used to delay the onset of age-associated problems and/or diseases,” says Dr. Luigi Puglielli, who studies aging at the University of Wisconsin, Madison, and was not involved in this study. “If proven safe for humans, this study suggests such a drug could be used as a preventive tool to delay the onset of neurodegeneration associated with several diseases that affect the aging brain.”
In the study, Tsai’s team first decreased the normal diets of mice genetically engineered to rapidly undergo changes in the brain associated with neurodegeneration by 30 percent. Following three months on the diet, the mice completed several learning and memory tests. “We not only observed a delay in the onset of neurodegeneration in the calorie-restricted mice, but the animals were spared the learning and memory deficits of mice that did not consume reduced-calorie diets,” Tsai says.
Curious if they could recreate the benefits of caloric restriction without changing the animals’ diets, the scientists gave a separate group of mice a drug that activates SIRT1. Similar to what the researchers found in the mice exposed to reduced-calorie diets, the mice that received the drug had less cell loss and better cellular connectivity than the mice that did not receive the drug. Additionally, the mice that received the drug treatment performed as well as normal mice in learning and memory tests.
“The question now is whether this type of treatment will work in other animal models, whether it’s safe for use over time, and whether it only temporarily slows down the progression of neurodegeneration or stops it altogether,” Tsai says.
Deep brain stimulation: a fix when the drugs don’t work
Neurological disorders can have a devastating impact on the lives of sufferers and their families.
Symptoms of these disorders differ extensively – from motor dysfunction in Parkinson’s disease, memory loss in Alzheimer’s disease to inescapable cravings in drug addiction.
Drug treatments are often ineffective in these disorders. But what if there was a way to simply switch off a devastating tremor, or boost a fading memory?
Recent advances using Deep Brain Stimulation (DBS) in selective brain regions have provided therapeutic benefits and have allowed those affected by these neurological disorders freedom from their symptoms, in absence of an existing cure.
A pacemaker for the brain
Artificial cardiac pacemakers are typically associated with controlling and resynchronising heartbeats by electrical stimulation of the heart muscle.
In a similar manner, DBS sends electrical impulses to specific parts of the brain that control discrete functions. This stimulation evokes control over the neural activity within these regions.
Prior to switching on the electrical stimulation, electrodes are surgically implanted within precise brain regions to control a specific function.
The neurosurgery is conducted under local anaesthetic to maintain consciousness in the patient. This ensures that the electrode does not damage critical brain regions.
The brain itself has no pain receptors so does not require anaesthetic.
Following recovery from surgery the electrodes are activated and the current calibrated by a neurologist to determine the optimal stimulation parameters.
The patient can then control whether the electrodes are on or off by a remote battery-powered device.
Turning off tremors
Perhaps the most documented success of DBS is in the control of tremors and motor coordination in Parkinson’s disease.
This is caused by the degeneration of neurons in an area of the brain called the substantia nigra. These neurons secrete the neurotransmitter dopamine.
Deterioration of these neurons reduces the amount of dopamine available to be released in a brain area involved in movement, the basal ganglia.
Drug therapy for Parkinson’s disease involves the use of levodopa (L-DOPA), a form of dopamine that can cross the blood brain barrier and then be synthesised into dopamine.
The administration of L-DOPA temporarily reduces the motor symptoms by increasing dopamine concentrations in the brain. However, side effects of this treatment include nausea and disordered movement.
DBS has been shown to provide relief from the motoric symptoms of Parkinson’s disease and essential tremors.
For the treatment of Parkinson’s disease electrodes are implanted into regions of the basal ganglia – the subthalamic nucleus or globus pallidus, to restore control of movement.
These are regions innervated by the deteriorating substantia nigra, therefore the DBS boosts stimulation to these areas.
Patients can then switch on the electrodes, stimulating these brain regions to enhance control of movement and diminish tremors.
Restoring fading memories
Recently, DBS has been used to diminish memory deficits associated with Alzheimer’s disease, a progressive and terminal form of dementia.
The pathologies associated with Alzheimer’s disease involve the formation of amyloid plaques and neurofibrillary tangles within the brain leading to dysfunction and death of neurons.
Brain regions primarily affected include the temporal lobes, containing important memory structures including the hippocampus.
Recent clinical trials with DBS involve the implantation of electrodes within the fornix – a structure connecting the left and right hippocampi together.
By stimulating neural activity within the hippocampi via the fornix, memory deficits associated with Alzheimer’s disease can be improved, enhancing the daily functioning of patients and slowing the progression of cognitive decline.
Deactivating addiction
Another use of DBS is in the treatment of substance abuse and drug addiction. Substance-related addictions constitute the most frequently occurring psychiatric disease category and patients are prone to relapse following rehabilitative treatment.
Persistent drug use leads to long term changes in the brain’s reward system.
Understanding of the reward systems affected in addiction has created a range of treatment options that directly target dysregulated brain circuits in order to normalise functionality.
One of the key reward regions in the brain is the nucleus accumbens and this has been used as a DBS target to control addiction.
Translational animal research has indicated that stimulation of the nucleus accumbens decreases drug seeking in models of addiction. Clinical studies have shown improved abstinence in both heroin addicts and alcoholics.
Studies have extended the use of DBS to potentially restore control of maladaptive eating behaviours such as compulsive binge eating.
In a recent study, binge eating of a high fat food in mice was decreased by DBS of the nucleus accumbens. This is the first study demonstrating that DBS can control maladaptive eating behaviours and may be a potential therapeutic tool in obesity.
Despite its therapeutic use for more than a decade, the neural mechanism of DBS is still not yet fully understood.
The remedial effect is proposed to involve modulation of the dopamine system – and this seems particularly relevant in the context of Parkinson’s disease and addiction.
DBS potentially has effects on the functional activity of other interconnected brain systems. While it can provide therapeutic relief from symptoms of neurological diseases, it does not treat the underlying pathology.
But it provides both effective and rapid intervention from the effects of debilitating illnesses, restoring activity in deteriorating brain regions and aids understanding of the brain circuits involved in these disorders.
Gene Involved in Neurodegeneration Keeps Clock Running
Northwestern University scientists have shown a gene involved in neurodegenerative disease also plays a critical role in the proper function of the circadian clock.
In a study of the common fruit fly, the researchers found the gene, called Ataxin-2, keeps the clock responsible for sleeping and waking on a 24-hour rhythm. Without the gene, the rhythm of the fruit fly’s sleep-wake cycle is disturbed, making waking up on a regular schedule difficult for the fly.
The discovery is particularly interesting because mutations in the human Ataxin-2 gene are known to cause a rare disorder called spinocerebellar ataxia (SCA) and also contribute to amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. People with SCA suffer from sleep abnormalities before other symptoms of the disease appear.
This study linking the Ataxin-2 gene with abnormalities in the sleep-wake cycle could help pinpoint what is causing these neurodegenerative diseases as well as provide a deeper understanding of the human sleep-wake cycle.
The findings will be published May 17 in the journal Science. Ravi Allada, M.D., professor of neurobiology in the Weinberg College of Arts and Sciences, and Chunghun Lim, a postdoctoral fellow in his lab, are authors of the paper.
Period (per) is a well-studied gene in fruit flies that encodes a protein, called PER, which regulates circadian rhythm. Allada and Lim discovered that Ataxin-2 helps activate translation of PER RNA into PER protein, a key step in making the circadian clock run properly.
“It’s possible that Ataxin-2’s function as an activator of protein translation may be central to understanding how, when you mutate the gene and disrupt its function, it may be causing or contributing to diseases such as ALS or spinocerebellar ataxia,” Allada said.
The fruit fly Drosophila melanogaster is a model organism for scientists studying the sleep-wake cycle because the fly’s genes are highly conserved with the genes of humans.
“I like to say that flies sleep similarly to humans, except flies don’t use pillows,” said Allada, who also is associate director for Northwestern’s Center for Sleep and Circadian Biology. The biological timing mechanism for all animals comes from a common ancestor hundreds of millions of years ago.
Ataxin-2 is the second gene in a little more than two years that Northwestern researchers have identified as a core gear of the circadian clock, and the two genes play similar roles.
Allada, Lim and colleagues in 2011 reported their discovery of a gene, which they dubbed “twenty-four,” that plays a role in translating the PER protein, keeping the sleep-wake cycle on a 24-hour rhythm.
Allada and Lim wanted to better understand how twenty-four works, so they looked at proteins that associate with twenty-four. They found the twenty-four protein sticking to ATAXIN-2 and decided to investigate further. In their experiments, reported in Science, Allada and Lim discovered the Ataxin-2 and twenty-four genes appear to be partners in PER protein translation.
“We’ve really started to define a pathway that regulates the circadian clock and seems to be especially important in a specific group of neurons that governs the fly’s morning wake-up,” Allada said. “We saw that the molecular and behavioral consequences of losing Ataxin-2 are nearly the same as losing twenty-four.”
As is the case in a mutation of the twenty-four gene, when the Ataxin-2 gene is not present, very little PER protein is found in the circadian pacemaker neurons of the brain, and the fly’s sleep-wake rhythm is disturbed.
Scientists develop drug that slows Alzheimer’s in mice
A drug developed by scientists at the Salk Institute for Biological Studies, known as J147, reverses memory deficits and slows Alzheimer’s disease in aged mice following short-term treatment. The findings, published May 14 in the journal Alzheimer’s Research and Therapy, may pave the way to a new treatment for Alzheimer’s disease in humans.
"J147 is an exciting new compound because it really has strong potential to be an Alzheimer’s disease therapeutic by slowing disease progression and reversing memory deficits following short-term treatment," says lead study author Marguerite Prior, a research associate in Salk’s Cellular Neurobiology Laboratory.
Despite years of research, there are no disease-modifying drugs for Alzheimer’s. Current FDA-approved medications, including Aricept, Razadyne and Exelon, offer only fleeting short-term benefits for Alzheimer’s patients, but they do nothing to slow the steady, irreversible decline of brain function that erases a person’s memory and ability to think clearly.
According to the Alzheimer’s Association, more than 5 million Americans are living with Alzheimer’s disease, the sixth leading cause of death in the country and the only one among the top 10 that cannot be prevented, cured or even slowed.
J147 was developed at Salk in the laboratory of David Schubert, a professor in the Cellular Neurobiology Laboratory. He and his colleagues bucked the trend within the pharmaceutical industry, which has focused on the biological pathways involved in the formation of amyloid plaques, the dense deposits of protein that characterize the disease. Instead, the Salk team used living neurons grown in laboratory dishes to test whether their new synthetic compounds, which are based upon natural products derived from plants, were effective at protecting brain cells against several pathologies associated with brain aging. From the test results of each chemical iteration of the lead compound, they were able to alter their chemical structures to make them much more potent. Although J147 appears to be safe in mice, the next step will require clinical trials to determine whether the compound will prove safe and effective in humans.
"Alzheimer’s disease research has traditionally focused on a single target, the amyloid pathway," says Schubert, "but unfortunately drugs that have been developed through this pathway have not been successful in clinical trials. Our approach is based on the pathologies associated with old age-the greatest risk factor for Alzheimer’s and other neurodegenerative diseases-rather than only the specificities of the disease."
To test the efficacy of J147 in a much more rigorous preclinical Alzheimer’s model, the Salk team treated mice using a therapeutic strategy that they say more accurately reflects the human symptomatic stage of Alzheimer’s. Administered in the food of 20-month-old genetically engineered mice, at a stage when Alzheimer’s pathology is advanced, J147 rescued severe memory loss, reduced soluble levels of amyloid, and increased neurotrophic factors essential for memory, after only three months of treatment.
In a different experiment, the scientists tested J147 directly against Aricept, the most widely prescribed Alzheimer’s drug, and found that it performed as well or better in several memory tests.
"In addition to yielding an exceptionally promising therapeutic, both the strategy of using mice with existing disease and the drug discovery process based upon aging are what make the study interesting and exciting," says Schubert, "because it more closely resembles what happens in humans, who have advanced pathology when diagnosis occurs and treatment begins." Most studies test drugs before pathology is present, which is preventive rather than therapeutic and may be the reason drugs don’t transfer from animal studies to humans.
Prior and her colleagues say that several cellular processes known to be associated with Alzheimer’s pathology are affected by J147, including an increase in a protein called brain-derived neurotrophic factor (BDNF), which protects neurons from toxic insults, helps new neurons grow and connect with other brain cells, and is involved in memory formation. Postmortem studies show lower than normal levels of BDNF in the brains of people with Alzheimer’s.
Because of its broad ability to protect nerve cells, the researchers believe that J147 may also be effective for treating other neurological disorders, such as Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS), as well as stroke, although their study did not directly explore the drug’s efficacy as a therapy for those diseases.
The Salk researchers say that J147, with its memory enhancing and neuroprotective properties, along with its safety and availability as an oral medication, would make an “ideal candidate” for Alzheimer’s disease clinical trials. They are currently seeking funding for such a trial.
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)