Neuroscience
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Two proteins previously found to contribute to ALS, also known as Lou Gehrig’s disease, have divergent roles. But a new study, led by researchers at the Department of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine, shows that a common pathway links them.
The discovery reveals a small set of target genes that could be used to measure the health of motor neurons, and provides a useful tool for development of new pharmaceuticals to treat the devastating disorder, which currently has no treatment or cure.
Funded in part by the National Institutes of Health and the California Institute for Regenerative Medicine (CIRM), the study will be published in the advance online edition of Nature Neuroscience on September 30.
ALS is an adult-onset neurodegenerative disorder characterized by premature degeneration of motor neurons, resulting in a progressive, fatal paralysis in patients.
The two proteins that contribute to the disease – FUS/TLS and TDP-43 – bind to ribonucleic acid (RNA), intermediate molecules that translate genetic information from DNA to proteins. In normal cells, both TDP-43 and FUS/TLS are found in the nucleus where they help maintain proper levels of RNA. In the majority of ALS patients, however, these proteins instead accumulate in the cell’s cytoplasm – the liquid that separates the nucleus from the outer membrane, and thus are excluded from the nucleus, which prevents them from performing their normal duties.
Since the proteins are in the wrong location in the cell, they are unable to perform their normal function, according to the study’s lead authors, Kasey R. Hutt, Clotilde Lagier-Tourenne and Magdalini Polymenidou. “In diseased motor neurons where TDP-43 is cleared from the nucleus and forms cytoplasmic aggregates,” the authors wrote, “we saw lower protein levels of three genes regulated by TDP-43 and FUS/TLS. We predicted that this, based on our mouse studies, and found the same results in neurons derived from human embryonic stem cells.”
In 2011, this team of UC San Diego scientists discovered that more than one-third of the genes in the brains of mice are direct targets of TDP-43, affecting the functions of these genes. In the new study, they compared the impact of the FUS/TLS protein to that of TDP-43, hoping to find a large target overlap.
“Surprisingly, instead we saw a relatively small overlap, and the common RNA targets genes contained exceptionally long introns, or non-coding segments. The set is comprised of genes that are important for synapse function,” said principal investigator Gene Yeo, PhD, assistant professor in the Department of Cellular and Molecular Medicine and the Institute for Genomic Medicine at UC San Diego and a visiting professor at the Molecular Engineering Laboratory in Singapore. “Loss of this common overlapping set of genes is evidence of a common pathway that appears to contribute to motor neuron degeneration.”
In an effort to understand the normal function of these two RNA binding proteins, the scientists knocked down the proteins in brains of mice to mimic nuclear clearance, using antisense oligonucleotide technology developed in collaboration with ISIS Pharmaceuticals. The study resulted in a list of genes that are up or down regulated, and the researchers duplicated the findings in human cells.
“If we can somehow rescue the genes from down regulation, or being decreased by these proteins, it could point to a drug target for ALS to slow or halt degeneration of the motor neurons,” said Yeo.
These proteins also look to be a central component in other neurodegenerative conditions. For example, accumulating abnormal TDP-43 and FUS/TLS in neuronal cytoplasm has been documented in frontotemporal lobar dementia, a neurological disorder that has been shown to be genetically and clinically linked to ALS, and which is the second most frequent cause of dementia after Alzheimer’s disease.
Using the new science of optogenetics, scientists can activate or shut down neural pathways, altering behavior and heralding a true cure for psychiatric disease.
Stopped at a red light on his drive home from work, Karl Deisseroth contemplates one of his patients, a woman with depression so entrenched that she had been unresponsive to drugs and electroshock therapy for years. The red turns to green and Deisseroth accelerates, navigating roads and intersections with one part of his mind while another part considers a very different set of pathways that also can be regulated by a system of lights. In his lab at Stanford University’s Clark Center, Deisseroth is developing a remarkable way to switch brain cells off and on by exposing them to targeted green, yellow, or blue flashes. With that ability, he is learning how to regulate the flow of information in the brain.
Deisseroth’s technique, known broadly as optogenetics, could bring new hope to his most desperate patients. In a series of provocative experiments, he has already cured the symptoms of psychiatric disease in mice. Optogenetics also shows promise for defeating drug addiction. When Deisseroth exposed a set of test mice to cocaine and then flipped a switch, pulsing bright yellow light into their brains, the expected rush of euphoria—the prelude to addiction—was instantly blocked. Almost miraculously, they were immune to the cocaine high; the mice left the drug den as uninterested as if they had never been exposed.
Most people know the frustration of having a word on the “tip of your tongue” that they simply can’t remember. But that passing nuisance can be an everyday occurrence for someone with aphasia, a communication disorder caused by a stroke or other brain damage that impairs the ability to process language.
About 1 million Americans — roughly one in every 250 — are affected by aphasia, which can also impact reading and writing skills. But how they acquire the problem and how long they’ll endure it differ from person to person, explained Ellayne Ganzfried, a speech-language pathologist and executive director of the National Aphasia Association.
"No two people with aphasia are alike because everyone’s brain responds to the injury in a different way," Ganzfried said. "About half of people who have aphasia recover quickly, within the first few days. If the symptoms of aphasia last longer than two or three months, a complete recovery is unlikely … [though] some people continue to improve over a period of years and even decades."
Strokes are the most common cause, followed by head injuries, tumors, migraines or other neurological issues. Depending on the damage to the brain regions controlling language, which are typically in the left hemisphere, the resulting aphasia can be broken into four broad categories:
"Processing language requires the collaboration of lots of different parts or systems of the brain," explained Karen Riedel, director of speech-language pathology at the Rusk Institute of Rehabilitation Medicine at NYU Langone Medical Center in New York City. "The whole brain ‘talks’ — the whole brain has something to do with the use of language."
Because of this, a variety of therapies are used to help people regain as much speech and language as possible. But regardless of the injury, people with aphasia have the best chances for recovery when language therapy begins immediately, Riedel said.
Because aphasia is so variable, a therapy that helps one person might not help another, she noted. Tried-and-true techniques include melodic intonation therapy, which uses melody and rhythm to help improve the ability to retrieve words, and constraint-induced therapy, which forces people to use speech over other communication methods.
But technology, Riedel said, has introduced new language-improvement techniques into the mix over the last few years that are both exciting and fun. Several apps available for iPhone or iPad involve synthetic speech that helps engage those with aphasia in yet another realm of communication.
"Our patients have much more access to different kinds of programs that are computer-based," she said. "There’s always something new around the corner."
What remains a constant concern, however, is the misunderstanding many people have of those with language difficulties and how to treat them, Ganzfried and Riedel agreed.
"Many people with aphasia will become socially isolated because of their communication difficulties, which can lead to depression," Ganzfried said. "There are also many misconceptions about aphasia, including that the person is mentally unstable or under the influence of drugs or alcohol. It’s also extremely frustrating. Imagine knowing what you want to say in your head but you can’t get the words out."
Researchers at Brigham and Women’s Hospital have found that melatonin supplementation significantly improved sleep in hypertensive patients taking beta-blockers
Over 20 million people in the United States take beta-blockers, a medication commonly prescribed for cardiovascular issues, anxiety, hypertension and more. Many of these same people also have trouble sleeping, a side effect possibly related to the fact that these medications suppress night-time melatonin production. Researchers at Brigham and Women’s Hospital (BWH) have found that melatonin supplementation significantly improved sleep in hypertensive patients taking beta-blockers.
The study will be electronically published on September 28, 2012 and will be published in the October print issue of SLEEP (Title: A mechanism for upper airway stability during slow wave sleep).
"Beta-blockers have long been associated with sleep disturbances, yet until now, there have been no clinical studies that tested whether melatonin supplementation can improve sleep in these patients," explained Frank Scheer, PhD, MSc, an associate neuroscientist at BWH, and principal investigator on this study. "We found that melatonin supplements significantly improved sleep."
The research team analyzed 16 hypertensive patients who regularly took beta-blockers as treatment for their hypertension. The study participants were given either a melatonin supplement or placebo to take each night before bed. To avoid bias, neither the participants nor the researchers knew which pill they were taking. During the three week study, the participants spent two separate four-day visits in lab. While in the lab, the researchers assessed the participants’ sleep patterns and found a 37-minute increase in the amount of sleep in the participants who received the melatonin supplement compared to those who received placebo. They also found an eight percent improvement of sleep efficiency and a 41 minute increase in the time spent in Stage 2 sleep, without a decrease in slow wave sleep or REM sleep.
"Over the course of three weeks, none of the study participants taking the melatonin showed any of the adverse effects that are often observed with other, classic sleep aids. There were also no signs of ‘rebound insomnia’ after the participants stopped taking the drug," explained Scheer, who is also an assistant professor of Medicine at Harvard Medical School. "In fact, melatonin had a positive carry-over effect on sleep even after the participants had stopped taking the drug."
The researchers caution that while this data is promising for hypertensive patients taking beta-blockers, more research is needed to determine whether patients taking beta-blockers for causes other than hypertension could also benefit from melatonin supplementation.
In what could be a breakthrough in the treatment of deadly brain tumors, a team of researchers from Barrow Neurological Institute and Arizona State University has discovered that the immune system reacts differently to different types of brain tissue, shedding light on why cancerous brain tumors are so difficult to treat.
The large, two-part study, led by Barrow research fellow Sergiy Kushchayev, MD under the guidance of Dr. Mark Preul, Director of Neurosurgery Research, was published in the Sept. 14 issue of Cancer Management and Research
The study explores the effects of immunotherapy on malignant gliomas, cancerous brain tumors that typically have a poor prognosis.
What the researchers discovered was that immune cells of the brain and of the blood exhibit massive rearrangements when interacting with a malignant glioma under treatment. Essentially, the study demonstrates that the complex immune system reacts differently in different brain tissues and different regions of the brain, including tumors.
"This is the first time that researchers have conducted a regional tissue study of the brain and a malignant glioma to show that these immune cells do not aggregate or behave in the same way in their respective areas of the brain," says Dr. Preul. "This means that effective treatment in one area of the brain may not be effective in another area. In fact, it could even cause other regions of the tumor to become worse."
The results of the study provide important insight into why clinical trials involving immunotherapies on glioma patients may not be working.
Scientists may be one step closer to predicting the uncertain course of relapsing-remitting multiple sclerosis (MS), a disease that can lay dormant for months or years, thanks to the discovery of a unique genetic marker. The marker, detailed by researchers in the August edition of The Journal of Immunology, is the first of its kind to be directly linked to MS.
The study, supported by funding from both the National Institutes of Health (NIH) and the Ohio State Center for Clinical and Translational Science (CCTS) was conducted by a team of scientists with The Ohio State University using blood samples from patients with MS, as well as mouse models. Researchers uncovered the molecule miR-29, while working to identify a biomarker in the blood that could indicate if a patient had an ongoing inflammatory response, such as MS.
“Our research was inspired by the knowledge gap that existed between microRNA and MS, as well as the unpredictable nature of MS,” said Kristen Smith, Ph.D., principal investigator, who received a “mentorship grant” to conduct the study alongside senior scientists at The Ohio State University Wexner Medical Center. “By identifying a unique marker associated with MS, we hope to inspire a relatively noninvasive test that could identify and predict the course of the disease, helping clinicians tailor therapies to disease progression.”
Source: newswise
Different anti-aging treatments work together and add years of life
The combination of two neuroprotective therapies, voluntary physical exercise, and the daily intake of melatonin has been shown to have a synergistic effect against brain deterioration in rodents with three different mutations of Alzheimer’s disease.
A study carried out by a group of researchers from the Barcelona Biomedical Research Institute (IIBB), in collaboration with the University of Granada and the Autonomous University of Barcelona, shows the combined effect of neuroprotective therapies against Alzheimer’s in mice.
Daily voluntary exercise and daily intake of melatonin, both of which are known for the effects they have in regulating circadian rhythm, show a synergistic effect against brain deterioration in the 3xTg-AD mouse, which has three mutations of Alzheimer’s disease.
"For years we have known that the combination of different anti-aging therapies such as physical exercise, a Mediterranean diet, and not smoking adds years to one’s life," Coral Sanfeliu, from the IIBB, explains to SINC. "Now it seems that melatonin, the sleep hormone, also has important anti-aging effects".
The experts analysed the combined effect of sport and melatonin in 3xTg-AD mice which were experiencing an initial phase of Alzheimer’s and presented learning difficulties and changes in behaviour such as anxiety and apathy.
The mice were divided into one control group and three other groups which would undergo different treatments: exercise –unrestricted use of a running wheel–, melatonin –a dose equivalent to 10 mg per kg of body weight–, and a combination of melatonin and voluntary physical exercise. In addition, a reference group of mice were included which presented no mutations of the disease.
"After six months, the state of the mice undergoing treatment was closer to that of the mice with no mutations than to their own initial pathological state. From this we can say that the disease has significantly regressed," Sanfeliu states.
The results, which were published in the journal Neurobiology of Aging, show a general improvement in behaviour, learning, and memory with the three treatments.
These procedures also protected the brain tissue from oxidative stress and provided good levels of protection from excesses of amyloid beta peptide and hyperphosphorylated TAU protein caused by the mutations. In the case of the mitochondria, the combined effect resulted in an increase in the analysed indicators of improved performance which were not observed independently.