Posts tagged neuroscience
Articles and news from the latest research reports.
Faulty stem cell regulation may contribute to cognitive deficits associated with Down syndrome
The learning and physical disabilities that affect people with Down syndrome may be due at least in part to defective stem cell regulation throughout the body, according to researchers at the Stanford University School of Medicine. The defects in stem cell growth and self-renewal observed by the researchers can be alleviated by reducing the expression of just one gene on chromosome 21, they found.
The finding marks the first time Down syndrome has been linked to stem cells, and addresses some long-standing mysteries about the disorder. Although the gene, called Usp16, is unlikely to be the only contributor to the disease, the finding raises the possibility of an eventual therapy based on reducing its expression.
“There appear to be defects in the stem cells in all the tissues that we tested, including the brain,” said Michael Clarke, MD, Stanford’s Karel H. and Avice N. Beekhuis Professor in Cancer Biology. The researchers conducted their studies in both mouse and human cells. “We believe Usp16 overexpression is a major contributor to the neurological deficits seen in Down syndrome.”
Clarke is the senior author of the research, published Sept. 11 in Nature. Postdoctoral scholar Maddalena Adorno, PhD, is the lead author.
“Conceptually, this study suggests that drug-based strategies to slow the rate of stem cell use could have profound effects on cognitive function, aging and risk for Alzheimer’s disease in people with Down syndrome,” said co-author Craig Garner, PhD, who is the co-director of Stanford’s Center for Research and Treatment of Down Syndrome and a professor of psychiatry and behavioral sciences.
Down syndrome, which is caused by an extra copy of chromosome 21, affects about 400,000 people in the United States and 6 million worldwide. It causes both physical and cognitive problems. While many of the physical issues, such as vulnerability to heart problems, can now be treated, no treatments exist for poor cognitive function.
The new study’s findings suggest answers to many long-standing mysteries about the condition, including why people with Down syndrome appear to age faster and exhibit early Alzheimer’s disease.
“This study is the first to provide a possible explanation for these tendencies,” said Garner. The fact that people with Down syndrome have three copies of chromosome 21 and the Usp16 gene “accelerates the rate at which stem cells are used during early development, which likely exhausts stem cell pools and impairs tissue regeneration in adults with Down syndrome. As a result, their brains age faster and are susceptible to early onset neurodegenerative disorders.”
The researchers didn’t confine their studies to laboratory mice. They also investigated the effect of Usp16 overexpression in human cells. Adorno and colleagues in the laboratory of co-author Samuel Cheshier, MD, assistant professor of neurosurgery, found that the presence of excess Usp16 caused skin cells from unaffected people to grow more slowly. Furthermore, neural progenitor cells (those self-renewing cellular factories responsible for the development and maintenance of many of the cell types in the brain) were less able to form balls of cells called neurospheres — a laboratory test that reflects the number and robustness of nerve stem cells in a culture. Conversely, reducing Usp16 expression in skin and nerve-progenitor cells from people with Down syndrome allowed the cells, which usually proliferate slowly, to assume normal growth patterns.
“This gene is clearly regulating processes that are central to aging in mice and humans,” said Clarke, “and stem cells are severely compromised. Reducing Usp16 expression gives an unambiguous rescue at the stem cell level. The fact that it’s also involved in this human disorder highlights how critical stem cells are to our well-being.”
Adorno and Clarke didn’t set out to study Down syndrome. Clarke’s past research has focused on how normal stem cells and cancer stem cells regenerate themselves, and Adorno was searching for genes that could inhibit a specific molecular pathway involved in the self-renewal of these cells. Understanding how normal stem cells regenerate themselves could help to repair tissue and organ damage from disease, and understanding how cancer stem cells maintain themselves could help explain why they are unusually resistant to chemotherapy or radiation therapy — often resulting in a patient’s relapse after seemingly successful treatment. Usp16 seemed to fit the bill; it plays a critical role in a self-renewal pathway previously identified by Clarke and his colleagues.
But Adorno and Clarke soon realized that Usp16 had another interesting property: in humans, it is found on chromosome 21.
They turned to Garner and Cheshier to help them evaluate a possible link to Down syndrome. Garner supplied two strains of mice commonly used to study the condition. One, Ts65Dn, has three copies of 132 genes found on human chromosome 21 — including Usp16. The second, Ts1Cje, has three copies of 79 genes from the chromosome, but only two copies of Usp16. Although both mice display some symptoms of the disorder, Ts65Dn more closely mimics the craniofacial structure and learning and memory disabilities seen in affected humans.
Colleagues in the Cheshier laboratory found that neural stem cells from the more-severely affected Ts65Dn mice were less able to self-renew and grow normally than were cells from the Ts1Cje mice. Reducing the expression of Usp16 in the cells from the Ts65Dn mice to more normal levels largely corrected these functional defects.
“We demonstrated that central nervous system stem cells in Down syndrome mice were defective in their ability to self-renew — the process by which stem cells regenerate themselves upon cell division. Blocking Usp16 expression in these cells restored this ability,” said Cheshier. “We hope in the future that correcting this Usp16 defect can lead to therapeutics that will ameliorate the central nervous system defects seen in patients with Down syndrome.”
Finally, the researchers created a new, Ts65Dn-derived mouse strain in which one of the three copies of Usp16 was mutated. This normalized the level of expression of that gene, without affecting the overexpression of the other 131 triplicated genes in these mice. Nerve progenitor cells from these mice were equally able as normal cells to form neurospheres. The researchers are now continuing their studies of these mice.
“We are really interested in learning how other genes in this chromosomal region may be affecting stem cell renewal,” said Clarke. “We also want to understand how much we’re able to rescue the neurological defect by normalizing the expression of Usp16 in this mouse model. How does this compare to what is happening in humans? We’re sure it plays some significant role.”
(Source: med.stanford.edu)
The eyes have it: Scientists reveal how organic mercury can interfere with vision
More than one billion people worldwide rely on fish as an important source of animal protein, states the United Nations Food and Agriculture Organization. And while fish provide slightly over 7 per cent of animal protein in North America, in Asia they represent about 23 per cent of consumption.
Humans consume low levels of methylmercury by eating fish and seafood. Methylmercury compounds specifically target the central nervous system, and among the many effects of their exposure are visual disturbances, which were previously thought to be solely due to methylmercury-induced damage to the brain visual cortex. However, after combining powerful synchrotron X-rays and methylmercury-poisoned zebrafish larvae, scientists have found that methylmercury may also directly affect vision by accumulating in the retinal photoreceptors, i.e. the cells that respond to light in our eyes.
(Image: A cross section of a zebrafish eye shows the localization of mercury in the outer segments of photoreceptor cells.)
Dr. Gosia Korbas, BioXAS staff scientist at the Canadian Light Source (CLS), says the results of this experiment show quite clearly that methylmercury localizes in the part of the photoreceptor cell called the outer segment, where the visual pigments that absorb light reside.
“There are many reports of people affected by methylmercury claiming a constricted field of vision or abnormal colour vision,” said Korbas. “Now we know that one of the reasons for their symptoms may be that methylmercury directly targets photoreceptors in the retina.”
Korbas and the team of researchers from the University of Saskatchewan including Profs. Graham George, Patrick Krone and Ingrid Pickering conducted their experiments using three X-ray fluorescence imaging beamlines (2-ID-D, 2-ID-E and 20-ID-B) at the Advanced Photon Source, Argonne National Laboratory near Chicago, US, as well as the scanning X-ray transmission beamline (STXM) at the Canadian Light Source in Saskatoon, Canada.
After exposing zebrafish larvae to methylmercury chloride in water, the team was able to obtain high-resolution maps of elemental distributions, and pinpoint the localization of mercury in the outer segments of photoreceptor cells in both the retina and pineal gland of zebrafish specimens. The results of the research were published in ACS Chemical Biology under the title “Methylmercury Targets Photoreceptor Outer Segments”.
Korbas said zebrafish are an excellent model for investigating the mechanisms of heavy metal toxicity in developing vertebrates. One of the reasons for that is their high degree of correlation with mammals. Recent studies have demonstrated that about 70 per cent of protein-coding human genes have their counterparts in zebrafish, and 84 per cent of genes linked to human diseases can be found in zebrafish.
“Researchers are studying the potential effects of low level chronic exposure to methylmercury, which is of global concern due to methylmercury presence in fish, but the message that I want to get across is that such exposures may negatively affect vision. Our study clearly shows that we need more research into the direct effects of methylmercury on the eye,” Korbas concluded.
(Source: lightsource.ca)
Fat Marker Predicts Cognitive Decline in People With HIV
Similarities found between HIV-associated brain damage and impairment from genetic fat-storage disease
Johns Hopkins scientists have found that levels of certain fats found in cerebral spinal fluid can predict which patients with HIV are more likely to become intellectually impaired.
The researchers believe that these fat markers reflect disease-associated changes in how the brain metabolizes these fat molecules. These changes disrupt the brain cells’ ability to regulate the activity of cells’ “garbage disposals” meant to degrade and flush the brain of molecular debris. In this case, too much cholesterol and a fat known as sphingomyelin build up in the lysosomes — the garbage disposals — backing up waste and leading to often debilitating cognitive declines.
As many as half of patients infected with HIV will develop some form of cognitive impairment, ranging from mild (trouble counting change or driving a car) to frank dementia (an inability to manage activities of every day life), but no tests have been available to predict which people were more likely to suffer cognitive losses.
“Every researcher of neurodegenerative disease is chasing biomarkers for the same reason: It’s better to identify problems before they strike,” says Norman J. Haughey, Ph.D., an associate professor in the departments of neurology and psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. He led the current study described online in the journal Neurology.
“It’s very hard to reverse brain damage after it starts,” he says. “Instead, we want to figure out who is likely to lose cognitive function and stop the damage before it happens.”
Haughey and his team analyzed 321 cerebral spinal fluid samples collected from seven test sites across the continental United States, Hawaii and Puerto Rico. The samples came from 291 HIV-positive participants and 30 HIV-negative subjects. The investigators found that early accumulations of a small number of these fat molecules could predict the probability of cognitive decline. As cognitive function declined in these patients, the number of different types of fat molecules that accumulated increased. The types of accumulating fat molecules in HIV were very similar to those that accumulate in inherited forms of a class of diseases called lysosomal storage disorders. This suggests that in some HIV-infected patients, the brain is retaining more of these fats, and this may disrupt the function of lysosomes.
Haughey says he believes some of these impairments in the metabolism of these fats found in people with HIV stems from the infection itself, while others may be linked to the lifesaving antiretroviral therapy taken by most people with HIV. The medications have been associated with elevated blood cholesterol and triglycerides, along with a host of other side effects. Those with HIV are now taking these drugs for decades and the complications from long-term use have not been well studied, he says.
The similarities between the metabolic disturbances in HIV-infected individuals and those apparent in lysosomal storage disorders are enabling Haughey and his team to collaborate with researchers who study genetic lysosomal storage diseases, and who are developing experimental treatments to clear the fat buildup. They are currently exploring dietary and pharmacological interventions designed to restore balance that could potentially restore brain metabolism in HIV-infected individuals, and in doing so could promote good brain health by ensuring the lysosomes function properly.
(Source: hopkinsmedicine.org)
New System Uses Nanodiamonds to Deliver Chemotherapy Directly to Brain Tumors
Researchers at UCLA’s Jonsson Comprehensive Cancer Center have developed a new drug delivery system using nanodiamonds (NDs) that allows for direct application of chemotherapy to brain tumors with fewer harmful side effects and better cancer-killing efficiency than existing treatments.
The study was a collaboration between Dean Ho, professor, division of oral biology and medicine, division of advanced prosthodontics, and department of bioengineering and co-director of the Weintraub Center for Reconstructive Biotechnology at UCLA School of Dentistry and colleagues from the Lurie Children’s Hospital of Chicago and Northwestern University Feinberg School of Medicine.
Glioblastoma is the most common and lethal type of brain tumor. Despite treatment with surgery, radiation and chemotherapy, median survival time of patients with glioblastoma is less than 1.5 years. This tumor is notoriously difficult to treat in part because chemotherapy drugs injected on their own often are unable to cross the blood-brain barrier, which is the system of protective blood vessels that surround the brain. Also, most drugs do not stay concentrated in the tumor tissue long enough to be effective.
The drug doxorubicin (DOX) is a common chemotherapy agent that is a promising treatment for a broad range of cancers, and served as a model drug for treatment of brain tumors when injected directly into the tumor. Ho’s team originally developed a strategy for strongly attaching DOX molecules to ND surfaces, creating a combined substance called ND-DOX.
Nanodiamonds can carry a broad range of drug compounds and prevent the ejection of drug molecules that are injected on their own by proteins found in cancer cells. Thus the ND-DOX stays in the tumor longer than DOX alone, exposing the tumor cells to the drug much longer without affecting the tissue surrounding the tumor.
Ho and colleagues hypothesized that glioblastoma might be efficiently treated with a nanodiamond-modified drug using a technique called convection enhanced delivery (CED), by which they injected ND-DOX directly into brain tumors in rodent models.
The researchers found that the ND-DOX levels in the tumor were retained for a duration far beyond that of DOX alone. The DOX was taken into the tumor and stayed in the tumor longer when attached to NDs. ND-DOX also increased programmed cell death (apoptosis) and decreased cell viability in glioma (brain cancer) cell lines.
Their results also showed for the first time that ND- DOX delivery limited the amount of DOX that was distributed outside the tumor and reduced toxic side effects while keeping the drug in the tumor longer and increasing tumor-killing efficiency for brain cancer treatment. Treatment was more effective and survival time increased significantly in rats treated with ND-DOX compared to those given unmodified DOX. Further research will expand the list of brain cancer chemotherapy drugs that can be attached to the ND surface to improve treatment and reduce side effects.
“Nanomaterials are promising vehicles for treating different types of cancer,” Ho said, “We’re looking for the drugs and situations where nanotechnology actually helps chemotherapy function better, making it easier on the patient and harder on the cancer.” Ho adds that a project of this scale has been successful due to the multi-disciplinary and proactive interactions between his team of bioengineers and outstanding clinical collaborators from Northwestern and Lurie Children’s Hospital.
Ho went on to say that the ND has many facets, almost like the surface of a soccer ball, and can bind to DOX very strongly and quickly. To have a nanoparticle that has translational significance it has to have as many benefits as possible engineered into one system as simply as possible. CED of ND-DOX offers a powerful treatment delivery system against these very difficult and deadly brain tumors.
The study appears in the advance online issue of the peer-reviewed journal Nanomedicine: Nanotechnology, Biology and Medicine.
(Source: newswise.com)
Multiple Sclerosis Appears to Originate in Different Part of Brain Than Long Believed
The search for the cause of multiple sclerosis, a debilitating disease that affects up to a half million people in the United States, has confounded researchers and medical professionals for generations. But Steven Schutzer, a physician and scientist at Rutgers New Jersey Medical School, has now found an important clue why progress has been slow – it appears that most research on the origins of MS has focused on the wrong part of the brain.
Look more to the gray matter, the new findings published in the journal PLOS ONE suggest, and less to the white. That change of approach could give physicians effective tools to treat MS far earlier than ever before.
Until recently, most MS research has focused on the brain’s white matter, which contains the nerve fibers. And for good reason: Symptoms of the disease, which include muscle weakness and vision loss, occur when there is deterioration of a fatty substance called myelin, which coats nerves contained in the white matter and acts as insulation for them. When myelin in the brain is degraded, apparently by the body’s own immune system, and the nerve fiber is exposed, transmission of nerve impulses can be slowed or interrupted. So when patients’ symptoms flare up, the white matter is where the action in the brain appears to be.
But Schutzer attacked the problem from a different direction. He is one of the first scientists to analyze patients’ cerebrospinal fluid (CSF) by taking full advantage of a combination of technologies called proteomics and high-resolution mass spectrometry. “Proteins present in the clear liquid that bathes the central nervous system can be a window to physical changes that accompany neurological disease,” says Schutzer, “and the latest mass spectrometry techniques allow us to see them as never before.” In this study, he used that novel approach to compare the cerebrospinal fluid of newly diagnosed MS patients with that of longer term patients, as well as fluid taken from people with no signs of neurological disease.
What Schutzer found startled one of his co-investigators, Patricia K. Coyle of Stony Brook University in New York, one of the leading MS clinicians and researchers in the country. The proteins in the CSF of the new MS patients suggested physiological disruptions not only in the white matter of the brain where the myelin damage eventually shows up. They also pointed to substantial disruptions in the gray matter, a different part of the brain that contains the axons and dendrites and synapses that transfer signals between nerves.
Several scientists had in fact hypothesized that there might be gray matter involvement in early MS, but the technology needed to test their theories did not yet exist. Schutzer’s analysis, which Coyle calls “exquisitely sensitive,” provides the solid physical evidence for the very first time. It includes a finding that nine specific proteins associated with gray matter were far more abundant in patients who had just suffered their first attack than in longer term MS patients or in the healthy controls. “This evidence indicates gray matter may be the critical initial target in MS rather than white matter,” says Coyle. “We may have been looking in the wrong area.”
According to Coyle, that realization presents exciting possibilities. One, she says, is that patients who suffer attacks that appear related to MS could have their cerebrospinal fluid tested quickly. If proteins that point to early MS are found, helpful therapy could begin at once, before the disease can progress further.
Coyle says Schutzer’s findings may also lead one day to more effective treatments for MS with far fewer side effects. Without specific knowledge of what causes multiple sclerosis, patients now need to take medications that can broadly weaken their immune systems. These drugs slow the body’s destruction of myelin in the brain, but also degrade the immune system’s ability to keep the body healthy in other ways. By suggesting an exciting new direction for MS research, Schutzer and his team may have set the stage for more targeted treatments that attack MS while preserving other important immune functions.
Schutzer sees an even broader future for the work he is now doing. He also has used advanced analysis of cerebrospinal fluid to identify physical markers for neurological ailments that include Lyme disease, in which he has been a world leader in research for many years, as well as chronic fatigue syndrome. He says, “When techniques are refined, more medical conditions are examined, and costs per patient come down, one day there could be a broad panel of tests through which patients and their doctors can get early evidence of a variety of disorders, and use that knowledge to treat them both more quickly and far more effectively than is possible now. “
Study Suggests Possibility of Selectively Erasing Unwanted Memories
The human brain is exquisitely adept at linking seemingly random details into a cohesive memory that can trigger myriad associations—some good, some not so good. For recovering addicts and individuals suffering from post-traumatic stress disorder (PTSD), unwanted memories can be devastating. Former meth addicts, for instance, report intense drug cravings triggered by associations with cigarettes, money, even gum (used to relieve dry mouth), pushing them back into the addiction they so desperately want to leave.
Now, for the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have been able to erase dangerous drug-associated memories in mice and rats without affecting other more benign memories.
The surprising discovery, published this week online ahead of print by the journal Biological Psychiatry, points to a clear and workable method to disrupt unwanted memories while leaving the rest intact.
“Our memories make us who we are, but some of these memories can make life very difficult,” said Courtney Miller, a TSRI assistant professor who led the research. “Not unlike in the movie Eternal Sunshine of the Spotless Mind, we’re looking for strategies to selectively eliminate evidence of past experiences related to drug abuse or a traumatic event. Our study shows we can do just that in mice — wipe out deeply engrained drug-related memories without harming other memories.”
Changing the Structure of Memory
To produce a memory, a lot has to happen, including the alteration of the structure of nerve cells via changes in the dendritic spines—small bulb-like structures that receive electrochemical signals from other neurons. Normally, these structural changes occur via actin, the protein that makes up the infrastructure of all cells.
In the new study, the scientists inhibited actin polymerization—the creation of large chainlike molecules—by blocking a molecular motor called myosin II in the brains of mice and rats during the maintenance phase of methamphetamine-related memory formation.
Behavioral tests showed the animals immediately and persistently lost memories associated with methamphetamine—with no other memories affected.
In the tests, animals were trained to associate the rewarding effects of methamphetamine with a rich context of visual, tactile and scent cues. When injected with the inhibitor many days later in their home environment, they later showed a complete lack of interest when they encountered drug-associated cues. At the same time, the response to other memories, such as food rewards, was unaffected.
While the scientists are not yet sure why powerful methamphetamine-related memories are also so fragile, they think the provocative findings could be related to the role of dopamine, a neurotransmitter involved in reward and pleasure centers in the brain and known to modify dendritic spines. Previous studies had shown dopamine is released during both learning and drug withdrawal. Miller adds, “We are focused on understanding what makes these memories different. The hope is that our strategies may be applicable to other harmful memories, such as those that perpetuate smoking or PTSD.”
(Source: scripps.edu)
Study creates new memories by directly changing the brain
Findings could prove helpful in understanding and resolving learning and memory disorders
By studying how memories are made, UC Irvine neurobiologists created new, specific memories by direct manipulation of the brain, which could prove key to understanding and potentially resolving learning and memory disorders.
Research led by senior author Norman M. Weinberger, a research professor of neurobiology & behavior at UC Irvine, and colleagues has shown that specific memories can be made by directly altering brain cells in the cerebral cortex, which produces the predicted specific memory. The researchers say this is the first evidence that memories can be created by direct cortical manipulation. Study results appeared in the August 29 issue of Neuroscience.
During the research, Weinberger and colleagues played a specific tone to test rodents then stimulated the nucleus basalis deep within their brains, releasing acetylcholine (ACh), a chemical involved in memory formation. This procedure increased the number of brain cells responding to the specific tone. The following day, the scientists played many sounds to the animals and found that their respiration spiked when they recognized the particular tone, showing that specific memory content was created by brain changes directly induced during the experiment. Created memories have the same features as natural memories including long-term retention.
"Disorders of learning and memory are a major issue facing many people and since we’ve found not only a way that the brain makes memories, but how to create new memories with specific content, our hope is that our research will pave the way to prevent or resolve this global issue," said Weinberger, who is also a fellow with the Center for the Neurobiology of Learning & Memory and the Center for Hearing Research at UC Irvine.
The creation of new memories by directly changing the cortex is the culmination of several years of research in Weinberger’s lab implicating the nucleus basalis and ACh in brain plasticity and specific memory formation. Previously, the authors had also shown that the strength of memory is controlled by the number of cells in the auditory cortex that process a sound.
Western scientists discover a novel opiate addiction switch in the brain
Neuroscientists at Western University (London, Canada) have made a remarkable new discovery revealing the underlying molecular process by which opiate addiction develops in the brain. Opiate addiction is largely controlled by the formation of powerful reward memories that link the pleasurable effects of opiate-class drugs to environmental triggers that induce drug craving in individuals addicted to opiates. The research is published in the September 11th issue of The Journal of Neuroscience.
The Addiction Research Group led by Steven Laviolette of the Schulich School of Medicine & Dentistry was able to identify how exposure to heroin induces a specific switch in a memory molecule in a region of the brain called the basolateral amygdala, which is involved importantly in controlling memories related to opiate addiction, withdrawal, and relapse. Using a rodent model of opiate addiction, Laviolette’s team found that the process of opiate addiction and withdrawal triggered a switch between two molecular pathways in the amygdala controlling how opiate addiction memories were formed. In the non-dependent state, they found that a molecule called extracellular signal-related kinase or “ERK” was recruited for early stage addiction memories. However, once opiate addiction had developed, the scientists observed a functional switch to a separate molecular memory pathway, controlled by a molecule called calmodulin-dependent kinase II or “CaMKII”.
“These findings will shed important new light on how the brain is altered by opiate drugs and provide exciting new targets for the development of novel pharmacotherapeutic treatments for individuals suffering from chronic opiate addiction,” says Laviolette, an associate professor in the Departments of Anatomy & Cell Biology, Psychiatry, and Psychology.
(Source: communications.uwo.ca)
Early-onset Parkinson’s disease linked to genetic deletion
Scientists at the Centre for Addiction and Mental Health (CAMH) and University Health Network (UHN) have found a new link between early-onset Parkinson’s disease and a piece of DNA missing from chromosome 22. The findings help shed new light on the molecular changes that lead to Parkinson’s disease.
The study appears online today in JAMA Neurology.
Among people aged 35 to 64 who were missing DNA from a specific part of chromosome 22, the research team found a marked increase in the number of cases of Parkinson’s disease, compared to expected rates of Parkinson’s disease in the general population from the same age group.
The deletion, which occurs when a person is born with about 50 genes missing on one chromosome 22, is associated with 22q11.2 deletion syndrome. People with this condition may have heart or other birth defects, learning or speech difficulties, and some develop schizophrenia. It occurs in an estimated 1 in 2,000 to 4,000 births, but is believed to be under-diagnosed.
“22q11.2 deletion syndrome has been fairly well studied in childhood and adolescence, but less is known about its effects as people age,” said Dr. Anne Bassett, Director of CAMH’s Clinical Genetics Research Program and Director of the Dalglish Family Hearts and Minds Clinic at UHN, the world’s first clinic dedicated to adults with 22q11.2 deletion syndrome. A few cases of patients with the syndrome who had Parkinson’s disease symptoms had been previously reported, which suggested that the two conditions might be linked.
Parkinson’s disease is one of the most common neurodegenerative disorders worldwide, typically affecting people over the age of 65. Earlier onset of Parkinson’s disease, before age 50, is rare and has been associated with several other genetic changes that are not on chromosome 22.
The researchers studied 159 adults with 22q11.2 deletion syndrome to discover how many had been clinically diagnosed with Parkinson’s disease. For three individuals with the deletion and Parkinson’s disease who were deceased, brain tissue was also examined.
“Through a post-mortem examination, we were able to show that all three patients had a loss of neurons that was typical of that seen in Parkinson’s disease. The examination also helped to show that the symptoms of Parkinson’s disease were not related to side effects of the medications commonly used to treat schizophrenia,” added Dr.Rasmus Kiehl, neuropathologist in UHN’s Laboratory Medicine Program, who co-authored the report with CAMH graduate student Nancy Butcher. The team also found that Parkinson’s disease in 22q11.2 deletion syndrome is associated with abnormal accumulations of protein called Lewy bodies in the brain in some, but not all cases, just as in another genetic form of Parkinson’s disease.
The findings highlight the complexity of clinical care when both Parkinson’s disease and 22q11.2 deletion syndrome are present. “Our results may inform best practices in the clinic in these cases,” said Dr. Bassett, Senior Scientist in CAMH’s Campbell Family Mental Health Research Institute.
Because patients with 22q11.2DS who have schizophrenia are often prescribed anti-psychotic medications, they may experience side-effects such as tremors and muscle stiffness, similar to symptoms of Parkinson’s disease.
As a result, the researchers found that anti-psychotic use delayed the diagnosis of Parkinson’s disease – and the opportunity for treatment – by up to 10 years.
For people with early-onset Parkinson’s disease, who also have other features that could indicate 22q11.2 deletion syndrome, clinical genetic testing for the deletion on chromosome 22 should be considered, the researchers suggest.
“Our discovery that the 22q11.2 deletion syndrome is associated with Parkinson’s disease is very exciting,” said Dr. Anthony Lang, Director of the Movement Disorders Program at the Krembil Neuroscience Centre of Toronto Western Hospital. “The varying pathology that we found is reminiscent of certain other genetic causes of Parkinson’s disease, and opens new directions to search for novel genes that could cause its more common form. Studies of patients with 22q11.2 deletion syndrome before they ever develop clinical features of Parkinson’s disease may not only provide important information on the effectiveness of screening methods for early detection of the disease, but also allow for future ‘neuroprotective treatments’ to be introduced at the ultimate time when they can have a chance to make an important impact on preventing the disease or slowing its course.”
“Most people with 22q11.2 deletion syndrome will not develop Parkinson’s disease,” emphasizes Dr. Bassett. “But it does occur at a rate higher than in the general population. We will now be on the look-out for this so we can provide the best care for patients.”
(Source: camh.ca)
Therapy Slows Onset and Progression of Lou Gehrig’s Disease
Studies of a therapy designed to treat amyotrophic lateral sclerosis (ALS) suggest that the treatment dramatically slows onset and progression of the deadly disease, one of the most common neuromuscular disorders in the world. The researchers, led by teams from The Research Institute at Nationwide Children’s Hospital and the Ludwig Institute at the University of California, San Diego, found a survival increase of up to 39 percent in animal models with a one-time treatment, a crucial step toward moving the therapy into human clinical trials.
The therapy reduces expression of a gene called SOD1, which in some cases of familial ALS has a mutation that weakens and kills nerve cells called motor neurons that control muscle movement. While many drug studies involve only one type of animal model, this effort included analysis in two different models treated before and after disease onset. The in-depth study could vault the drug into human clinical trials, said Brian Kaspar, PhD, a principal investigator in the Center for Gene Therapy at Nationwide Children’s and a senior author on the research, which was published online Sept. 6 in Molecular Therapy.
“We designed these rigorous studies using two different models of the disease with the experimenters blinded to the treatment and in two separate laboratories,” said Dr. Kaspar, who collaborated on the study with a team led by Don Cleveland, PhD, at the University of California, San Diego. “We were very pleased with the results, and found that the delivery approach was successful in a larger species, enabling us to initiate a clinical translational plan for this horrible disease.”
There currently is no cure for ALS, also called Lou Gehrig’s disease. The Centers for Disease Control and Prevention estimates there are about 5,000 new cases in the U.S. each year, mostly in people age 50 to 60. Although the exact cause of ALS is unknown, more than 170 mutations in the SOD1 gene have been found in many patients with familial ALS, which accounts for about 2 percent of all cases.
SOD1 provides instructions for making an enzyme called superoxide dismutase, which is found throughout the body and breaks down toxic molecules that can be damaging to cells. When mutated, the SOD1 gene yields a faulty version of the enzyme that is especially harmful to motor neurons. One of the mutations, which is found in about half of all familial ALS patients, is particularly devastating, with death usually coming within 18 months of diagnosis. SOD1 has also been implicated in other types of ALS, called sporadic ALS, which means the therapy could prove beneficial for larger numbers of patients suffering with this disease.
Earlier work by Dr. Kaspar and others found that they could halt production of the mutated enzyme by blocking SOD1 expression, which in turn, they suspected, would slow ALS progression. To test this hypothesis, the researchers would not only need to come up with an approach that would block the gene, but also figure out how to specifically target cells implicated in the disease, which include motor neurons and glial cells. What’s more, the therapy would preferably be administered noninvasively instead of direct delivery via burr holes drilled into the skull.
Dr. Kaspar’s team accomplished the second part of this challenge in 2009, when they discovered that adeno-associated virus serotype 9 (AAV9) could cross the blood-brain barrier, making it an ideal transport system for delivering genes and RNA interference strategies designed to treat disease.
In this new work, funded by the National Institutes of Health, the researchers blocked human SOD1, using a technology known as short hairpin RNA, or shRNA. These single strands of RNA are designed in the lab to seek out specific sequences found in the human SOD1 gene, latch onto them and block gene expression.
In one of the mouse models used in the study, ALS develops earlier and advances more quickly. In the other, the disease develops later and progresses more slowly. All of the mice received a single injection of AAV9-SOD1-shRNA before or after disease onset.
Results showed that in the rapid-disease-progressing model, mice treated before disease onset saw a 39 percent increase in survival compared to control treated mice. Strikingly, in mice treated at 21 days of age, disease progression was slowed by 66 percent. Perhaps more surprising was the finding that even after symptoms surfaced in these models, treatment still resulted in a 23 percent increase in survival and a 36 percent reduction in disease progression. In the slower-disease-onset model, treatment extended survival by 22 percent and delayed disease progression by 38 percent.
“The extension of survival is fantastic, and the fact that we delayed disease progression in both models when treated at disease onset is what drives our excitement to advance this work to human clinical trials,” said Kevin Foust, PhD, co-first author on the manuscript and an assistant professor in neurosciences at The Ohio State University College of Medicine.
In addition to the potential therapeutic benefit, the study also offers some interesting insights into the biological underpinnings of ALS. The role of motor neurons in ALS has been well documented, but this study also highlighted another key player—astrocytes, the most abundant cell type in the human brain and supporters of neuronal function.
“Recent work from our collaborator Dr. Cleveland has demonstrated that astrocytes and other types of glia are as important if not more important in ALS, as they really drive disease progression,” said Dr. Kaspar. “Indeed, in looking at data from mice, more than 50 percent of astrocytes were targeted throughout the spinal cord by this gene-delivery approach.”
Ideally, a therapy would hit motor neurons and astrocytes equally hard. The best way to do that is to deliver the drug directly into the cerebrospinal fluid (CSF), which would reduce the amount of SOD1 suppression in cells outside the brain and reduce immune system exposure to AAV9—elements that would add weight to an argument for studying the drug in humans.
Injections directly into CSF cannot be done easily in mice, so the team took the study a crucial step further by injecting AAV9-SOD1-shRNA into the CSF of healthy nonhuman primates. The results were just as the team hoped—the amount of gene expression dropped by as much as 90 percent in motor neurons and nearly 70 percent in astrocytes and no side effects were reported, laying the groundwork towards moving to human clinical trials.
“We have a vast amount of work to do to move this toward a clinical trial, but we’re encouraged by the results to date and our team at Nationwide Children’s and our outstanding collaborators are fully committed to making a difference in this disease,” Dr. Kaspar said.
The findings could impact other studies underway in Dr. Kaspar’s lab, including research on Spinal Muscular Atrophy, an often fatal genetic disease in infants and children that can cause profoundly weakened muscles in the arms and legs and respiratory failure.
“This research provides further proof of targeting motor neurons and glial cells throughout the entire spinal cord for treatment of Spinal Muscular Atrophy and other degenerative diseases of the brain and spinal cord, through a less invasive manner than direct injections,” said Dr. Kaspar, who also is an associate professor of pediatrics and neurosciences at The Ohio State University College of Medicine.
(Source: nationwidechildrens.org)