Posts tagged psychology

July 2nd, 2012

Using a mouse model of autism, researchers at the University of Cincinnati (UC) and Cincinnati Children’s Hospital Medical Center have successfully treated an autism spectrum disorder characterized by severe cognitive impairment.

The research team, led by Joe Clark, PhD, a professor of neurology at UC, reports its findings online July 2, 2012, in the Journal of Clinical Investigation, a publication of the American Society for Clinical Investigation.

The disorder, creatine transporter deficiency (CTD) is caused by a mutation in the creatine transporter protein that results in deficient energy metabolism in the brain. Linked to the X chromosome, CTD affects boys most severely; women are carriers and pass it on to their sons.

Using cyclocreatine, researchers successfully treated an autism spectrum disorder known as creatine transporter deficiency in a mouse model of autism.

The brains of boys with CTD do not function normally, resulting in severe speech deficits, developmental delay, seizures and profound mental retardation. CTD is estimated to currently affect about 50,000 boys in the United States and is the second-most common cause of X-linked mental retardation after Fragile X syndrome.

Following CTD’s discovery at UC in 2000, researchers at UC and Cincinnati Children’s led by Clark discovered a method to treat it with cyclocreatine—also known as CincY, and pronounced cinci-why—a creatine analogue originally developed as an adjunct to cancer treatment. They then treated genetically engineered mice as an animal model of the human disease.

“CincY successfully entered the brain and reversed the mental retardation-like symptoms in the mice, with benefits seen in nine weeks of treatment,” says Clark, adding that no harmful effects to the mice were observed in the study. “Treated mice exhibited a profound improvement in cognitive abilities, including recognition of novel objects, spatial learning and memory.”

As a repurposed drug (originally developed for another therapy), CincY has already been through part of the U.S. Food and Drug Administration (FDA) approval process. It is taken orally as a pill or powder.

UC’s Office of Entrepreneurial Affairs and Technology Commercialization has reached agreement with Lumos Pharma, a privately held Austin, Texas, startup company based on UC technology, to develop and commercialize CincY. Lumos Pharma was created with technology licensed from UC’s Office of Entrepreneurial Affairs and Technology Commercialization. Its CEO is Rick Hawkins, a 30-year biotech industry veteran. Jon Saxe is its chairman.

“It has taken many years to get here and I am happy that our efforts have led to this translational effort to make a therapy available to those afflicted with CTD,” says Clark. “We look forward with commitment and hope to the day when those patients will benefit from our work.”

The collaboration gained momentum when Lumos Pharma submitted a proposal based on Clark’s technology to the National Institutes of Health and was selected as a drug development project partner by the National Center for Advancing Translational Sciences’ Therapeutics for Rare and Neglected Diseases (TRND) program. Under TRND’s collaborative operational model, project partners form joint project teams with TRND and receive in-kind support from TRND drug development scientists, laboratory and contract resources.

Lumos Pharma plans to initiate a TRND-supported preclinical development plan, with TRND support continuing through the filing of an Investigational New Drug (IND) application with the FDA prior to beginning a clinical trial. Such a trial would be about three years away, Clark says.

Source: Neuroscience News

ScienceDaily (July 2, 2012) — Deleting a single gene in the cerebellum of mice can cause key autistic-like symptoms, researchers have found. They also discovered that rapamycin, a commonly used immunosuppressant drug, prevented these symptoms.

The deleted gene is associated with Tuberous Sclerosis Complex (TSC), a rare genetic condition. Since nearly 50 percent of all people with TSC develop autism, the researchers believe their findings will help us better understand the condition’s development.

"We are trying to find out if there are specific circuits in the brain that lead to autism-spectrum disorders in people with TSC," said Mustafa Sahin, Harvard Medical School associate professor of neurology at Boston Children’s Hospital and senior author on the paper. "And knowing that deleting the genes associated with TSC in the cerebellum leads to autistic symptoms is a vital step in figuring out that circuitry."

This is the first time researchers have identified a molecular component for the cerebellum’s role in autism. “What is so remarkable is that loss of this gene in a particular cell type in the cerebellum was sufficient to cause the autistic-like behaviors,” said Peter Tsai, HMS instructor of neurology and the first author of this particular study.

These findings were published online July 1 in Nature.

TSC is a genetic disease caused by mutations in either one of two genes, TSC1 and TSC2. Patients develop benign tumors in various organs in the body, including the brain, kidneys and heart, and often suffer from seizures, delayed development and behavioral problems.

Researchers have known that there was a link between TSC genes and autism, and have even identified the cerebellum as the key area where autism and related conditions develop.

In both cases, deleting this gene caused the three main signs of autistic-like behaviors:

• Abnormal social interactions. The mice spent less time with each other and more with inanimate objects, compared to controls.
• Repetitive behaviors. The mice spent extended amounts of time pursuing one activity or with one particular object far more than normal.
• Abnormal communication. Ultrasonic vocalizations, the communication technique among rodents, were highly distressed.

The researchers also tested learning. “These mice were able to learn new things normally,” said Tsai, “but they had trouble with ‘reversal learning,’ or re-learning what they had learned when their environment changed.”

Tsai and colleagues tested this by training the mice to swim a particular path in which a platform where they could rest was set up on one side of the pool. When the researchers moved the platform to the other side of the pool, the mice had greater difficulty than the control mice re-learning to swim to the other side.

"These changes in behavior indicate that the TSC1 gene in Purkinje cells, and by extension, the cerebellum, are a part of the circuitry for autism disorders,” emphasized Sahin.

The researchers also found that the drug rapamycin averted the effects of the deleted gene. Administering the drug to the mice during development prevented the formation of autistic-like behaviors.

Currently, Sahin is the sponsor-principal investigator for an ongoing Phase II clinical trial to test the efficacy of everolimus, a compound in the same family as rapamycin, in improving neurocognition in children with TSC. The trial will be open for enrollment until December 2013.

"Our next step will be to see how the abnormalities in Purkinje cells affect autism-like development. We don’t know how generalizable our current findings are, but understanding mechanisms beyond TSC genes might be useful to autism," said Tsai.

Source: Science Daily

ScienceDaily (July 2, 2012) — New research led by Patrick F. Sullivan, MD, FRANZCP, a medical geneticist at the University of North Carolina School of Medicine, points to an increased risk of autism spectrum disorders (ASDs) among individuals whose parents or siblings have been diagnosed with schizophrenia or bipolar disorder.

The findings were based on a case-control study using population registers in Sweden and Israel, and the degree to which these three disorders share a basis in causation “has important implications for clinicians, researchers and those affected by the disorders,” according to a report of the research published online July 2, 2012 in the Archives of General Psychiatry.

"The results were very consistent in large samples from several different countries and lead us to believe that autism and schizophrenia are more similar than we had thought," said Dr. Sullivan, professor in the department of genetics and director of psychiatric genomics at UNC.

Sullivan and colleagues found that the presence of schizophrenia in parents was associated with an almost three times increased risk for ASD in groups from both Stockholm and all of Sweden.

Schizophrenia in a sibling also was associated with roughly two and a half times the risk for autism in the Swedish national group and a 12 times greater risk in a sample of Israeli military conscripts. The authors speculate that the latter finding from Israel resulted from individuals with earlier onset schizophrenia, “which has a higher sibling recurrence.”

Bipolar disorder showed a similar pattern of association but of a lesser magnitude, study results indicate.

"Our findings suggest that ASD, schizophrenia and bipolar disorder share etiologic risk factors," the authors state. "We suggest that future research could usefully attempt to discern risk factors common to these disorders."

Source: Science Daily

By Sabrina Richards | July 2, 2012

Scientists find that declining DNA methylation in mouse neurons may cause age-related memory deficits.

An elderly man
Flickr, BLEU MAN

Research is increasingly connecting changes in epigenetic regulation of gene expression  to the aging process. Many studies demonstrate that DNA methylation declines with age. Now, new research published yesterday (July 1) in Nature Neuroscience links DNA methylation with brain aging. Researchers show that levels of an enzyme that attaches methyl groups to cytosine nucleotides throughout the genome is linked to cognitive decline, and that its overexpression can restore performance of aging mice on memory-related tasks.

“We already know normal aging is associated with cognitive decline, but this paper links that with expression a specific DNA methyltransferase,” said Yuan Gao, an epigeneticist at the Lieber Institute for Brain Development in Maryland, who did not participate in the study. The current work also builds on other studies demonstrating that proper regulation of methylation in brain cells is critical to memory formation. Previous studies have suggested a connection between loss of DNA methylation and Alzheimer’s disease, said Gao, suggesting that if researchers could “restore [methyltransferase] activity and cure or delay dementia, it would make a nice model” for developing drugs to tackle age-related cognitive diseases.

DNA methylation, wherein a methyl group is attached to a cytosine next to a guanosine, is one form of epigenetic regulation that can modulate how available genes are to the cell’s transcription machinery, and thus how highly expressed they are. Scientists already appreciate how differences in epigenetic regulation can affect development of diseases like cancer, without need for gene mutations. Studies are also accumulating that correlate declining methylation with aging, although the mechanism remains unclear.

Classically, DNA methylation is considered a repressive modification, but that view is beginning to change, suggesting a more nuanced role for methylation in gene regulation, explained senior author Hilmar Bading of the University of Heidelberg. The twist in Bading’s current research is that the methyltransferase his group focuses on, Dnmt3a2, may be working to enable gene transcription, rather than repress it.

This gene-activating role may stem from methylation that blocks repressors, rather than activators, explained Trygve Tollesfbol, who investigates the role of epigenetics in cancer and aging at the University of Alabama, who did not participate in the research. Whether methylation is located in the promoter or body of the gene can also determine whether it inhibits or enhances transcription, explained Guoping Fan, who studies epigenetic regulation of neuron development at the University of California, Los Angeles.

Bading’s group identified Dnmt3a2 when looking for genes that are upregulated by neuronal activity. Knowing that DNA methylation decreases with age, first author Ana Oliviera compared Dnmt3a2 expression in 3-month-old and 18-month-old mice, and found lower levels of Dnmt3a2 in the older mice. Furthermore, learning tasks designed to stimulate hippocampus neurons failed to upregulate Dnmt3a2 expression in old mice as robustly as in young mice.

Theorizing that reduced Dnmt3a2-dependent DNA methylation contributed to older mice’s poorer performance on learning and memory tasks, the scientists used an adeno-associated virus to supplement Dnmt3a2 expression in their hippocampal neurons. Boosting its expression enhanced both brain methylation in the older mice, and their ability to learn. Conversely, when the researchers used short hairpin RNA to knockdown Dnmt3a2 expression in young mice, their performance on learning and memory tests worsened.

“I think Dnmt3a2 has a basic gating function,” said Bading. Neurons need to turn genes on and off quickly in response to changing stimulation. Bading hypothesizes that Dnmt3a2-dependent methylation helps keep genes—like brain-derived neurotrophic factor (BDNF) and Arc, both regulated by Dnmt3a2 and both involved in responses to signaling changes—receptive to changing stimulation, putting “the genome in the right state for being inducible,” Bading said. Genes like BDNF shouldn’t be transcribed all the time, but it may be that without Dnmt3a2-dependent methylation, “the door is closed” neurons can’t express them when they need to.

This could set up a vicious cycle, Bading explained, because Dnmt3a2 is also induced by neuronal activity. Less Dnmt3a2 would result in less expression of methylation-dependent genes, possibly including Dnmt3a2 itself, and the effect would worsen over time. “It would take many years to add up, but aging takes years,” Bading noted.

Methylation is unlikely to be the only epigenetic factor in aging, said Tollefsbol, who anticipates similar investigations into other DNA and histone modifications. BDNF itself has already been linked to histone acetylation and brain aging. “A good paper like this raises more questions than it answers,” Tollefsbol noted. “DNA methylation is probably only about a half or third of the [epigenetics and aging] equation.”

Source: TheScientist

ScienceDaily (July 1, 2012) — When people have similar injuries, why do some end up with chronic pain while others recover and are pain free? The first longitudinal brain imaging study to track participants with a new back injury has found the chronic pain is all in their heads — quite literally.

(Credit: © drubig-photo / Fotolia)

A new Northwestern Medicine study shows for the first time that chronic pain develops the more two sections of the brain — related to emotional and motivational behavior — talk to each other. The more they communicate, the greater the chance a patient will develop chronic pain.

The finding provides a new direction for developing therapies to treat intractable pain, which affects 30 to 40 million adults in the United States.

Researchers were able to predict, with 85 percent accuracy at the beginning of the study, which participants would go on to develop chronic pain based on the level of interaction between the frontal cortex and the nucleus accumbens.

The study is published in the journal Nature Neuroscience.

"For the first time we can explain why people who may have the exact same initial pain either go on to recover or develop chronic pain," said A. Vania Apakarian, senior author of the paper and professor of physiology at Northwestern University Feinberg School of Medicine.

"The injury by itself is not enough to explain the ongoing pain. It has to do with the injury combined with the state of the brain. This finding is the culmination of 10 years of our research."

The more emotionally the brain reacts to the initial injury, the more likely the pain will persist after the injury has healed. “It may be that these sections of the brain are more excited to begin with in certain individuals, or there may be genetic and environmental influences that predispose these brain regions to interact at an excitable level,” Apkarian said.

The nucleus accumbens is an important center for teaching the rest of the brain how to evaluate and react to the outside world, Apkarian noted, and this brain region may use the pain signal to teach the rest of the brain to develop chronic pain.

"Now we hope to develop new therapies for treatment based on this finding," Apkarian added.

Chronic pain participants in the study also lost gray matter density, which is likely linked to fewer synaptic connections or neuronal and glial shrinkage, Apkarian said. Brain synapses are essential for communication between neurons.

"Chronic pain is one of the most expensive health care conditions in the U. S. yet there still is not a scientifically validated therapy for this condition," Apkarian said. Chronic pain costs an estimated $600 billion a year, according to a 2011 National Academy of Sciences report. Back pain is the most prevalent chronic pain condition.

A total of 40 participants who had an episode of back pain that lasted four to 16 weeks — but with no prior history of back pain — were studied. All subjects were diagnosed with back pain by a clinician. Brain scans were conducted on each participant at study entry and for three more visits during one year.

Source: Science Daily

June 29, 2012

Scientists at Arizona State University have discovered that honey bees may teach us about basic connections between taste perception and metabolic disorders in humans.

Honey bees may help scientists understand how food-related behaviors interact with internal metabolism and how to manipulate those behaviors to control metabolic disorders. Photo by: Christofer Bang

By experimenting with honey bee genetics, researchers have identified connections between sugar sensitivity, diabetic physiology and carbohydrate metabolism. Bees and humans may partially share these connections.

In a study published in the open-access journal PLoS Genetics (Public Library of Science), Gro Amdam, an associate professor, and Ying Wang, a research scientist, in the School of Life Sciences in ASU’s College of Liberal Arts and Sciences, explain how for the first time, they’ve successfully inactivated two genes in the bees’ “master regulator” module that controls food-related behaviors. By doing so, researchers discovered a possible molecular link between sweet taste perception and the state of internal energy.

“A bee’s sensitivity to sugar reveals her attitude towards food, how old the bee is when she starts searching for nectar and pollen, and which kind of food she prefers to collect,” said Wang, the lead author of the paper. “By suppressing these two ‘master’ genes, we discovered that bees can become more sensitive to sweet taste. But interestingly, those bees also had very high blood sugar levels, and low levels of insulin, much like people who have Type 1 diabetes.”

In Amdam’s honey bee lab at ASU, scientists suppressed two genes including vitellogenin, which is similar to a human gene called apolipoprotein B, and ultraspiracle, which partners with an insect hormone that has some functions in common with the human thyroid hormone. The team is the first in the world to accomplish this double gene-suppressing technique. Researchers used this method to understand how the master regulator works.

“Now, if one can use the bees to understand how taste perception and metabolic syndromes are connected, it’s a very useful tool,” said Amdam, who also has a honey bee laboratory at the Norwegian University of Life Sciences. “Most of what we know about deficits in human perceptions is from people who are very sick or have had a brain trauma. We know shockingly little about people in this area.”

The researchers are now considering how, exactly, the bees’ sweet taste was enhanced by the experiment. The most metabolically active tissue of the bee, called the fat body, may hold the key. The fat body is similar to the liver and abdominal fat in humans, in that it helps store nutrients and create energy.

Amdam explains that taste perception evolved as a survival mechanism, for bees as well as for people. For example, bitter foods may be poisonous or sweet taste may signal foods rich in calories for energy. For all animals, taste perception must communicate properly with one’s internal energetic state to control food intake and maintain normal life functions. Without this, poorly functioning taste perception can contribute to unhealthy eating behaviors and metabolic diseases, such as diabetes and obesity.

“From this study, we realized we can take advantage of honey bees in understanding how food-related behaviors interact with internal metabolism, as well as how to manipulate these food-related behaviors in order to control metabolic disorders,” added Amdam.

Provided by Arizona State University

Source: PHYS.ORG

June 29th, 2012

Researchers shed light on molecular cause of childhood’s worst conditions as first step toward developing more effective treatments.

A research team led by Seattle Children’s Research Institute has discovered new gene mutations associated with markedly enlarged brain size, or megalencephaly.  Mutations in three genes, AKT3, PIK3R2 and PIK3CA, were also found to be associated with a constellation of disorders including cancer, hydrocephalus, epilepsy, autism, vascular anomalies and skin growth disorders.  The study, “De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes,” was published online June 24 in Nature Genetics.

The discovery offers several important lessons and hope for the future in medicine.  First, the research team discovered additional proof that the genetic make-up of a person is not completely determined at the moment of conception.  Researchers previously recognized that genetic changes may occur after conception, but this was believed to be quite rare.  Second, discovery of the genetic causes of these human diseases, including developmental disorders, may also lead directly to new possibilities for treatment.

Researchers discovered new gene mutations associated with markedly enlarged brain size, or megalencephaly. Mutations in three genes, AKT3, PIK3R2 and PIK3CA, were also found to be associated with a constellation of disorders including cancer, hydrocephalus, epilepsy, autism, vascular anomalies and skin growth disorders. Image adapted from an image by Dr. Laughlin Dawes of an 18 month old with demyelinating disorder.

AKT3, PIK3R2 and PIK3CA are present in all humans, but mutations in the genes are what lead to conditions including megalencephaly, cancer and other disorders.  PIK3CA is a known cancer-related gene, and appears able to make cancer more aggressive.  Scientists at Boston Children’s Hospital recently published similar findings related to PIK3CA and a rare condition known as CLOVES syndrome in the American Journal of Human Genetics.

Physician researcher James Olson, MD, PhD, a pediatric cancer expert at Seattle Children’s and Fred Hutchinson Cancer Research Center who was not affiliated with the study, acknowledged the two decades-worth of work that led to the findings.  “This study represents ideal integration of clinical medicine and cutting-edge genomics,” he said.  “I hope and believe that the research will establish a foundation for successfully using drugs that were originally developed to treat cancer in a way that helps normalize intellectual and physical development of affected children.  The team ‘knocked it out of the park’ by deep sequencing exceptionally rare familial cases and unrelated cases to identify the culprit pathway.”  The genes— AKT3, PIK3R2 and PIK3CA—all encode core components of the phosphatidylinositol-3-kinase (P13K)/AKT pathway, the “culprit pathway” referenced by Olson.

The research provides a first, critical step in solving the mystery behind chronic childhood conditions and diseases.  At the bedside, children with these conditions could see new treatments in the next decade.  “This is a huge finding that provides not only new insight for certain brain malformations, but also, and more importantly, provides clues for what to look for in less severe cases and in conditions that affect many children,” said William Dobyns, MD, a geneticist at Seattle Children’s Research Institute.  “Kids with cancer, for example, do not have a brain malformation, but they may have subtle growth features that haven’t yet been identified.  Physicians and researchers can now take an additional look at these genes in the search for underlying causes and answers.”

Researchers at Seattle Children’s Research Institute will now delve more deeply into the findings, with an aim to uncover even more about the potential medical implications for children.  “Based on what we’ve found, we believe that we can eventually reduce the burden of and need for surgery for kids with hydrocephalus and change the way we treat other conditions, including cancer, autism and epilepsy,” said  Jean-Baptiste Rivière, PhD, at Seattle Children’s Research Institute.  “This research truly helps advance the concept of personalized medicine.”

Drs. Dobyns, Rivière and team made this discovery through exome sequencing, a strategy used to selectively sequence the coding regions of the genome as an inexpensive but effective alternative to whole genome sequencing.  An exome is the most functionally relevant part of a genome, and is most likely to contribute to the phenotype, or observed traits and characteristics, of an organism.

Source: Neuroscience News

ScienceDaily (June 29, 2012) — Cognitive skills such as learning and memory diminish with age in everyone, and the drop-off is steepest in Alzheimer’s disease. Texas scientists seeking a way to prevent this decline reported exciting results this week with a drug that has Polynesian roots.

Easter Island statues. (Credit: © Celsius / Fotolia)

The researchers, appointed in the School of Medicine at The University of Texas Health Science Center San Antonio, added rapamycin to the diet of healthy mice throughout the rodents’ life span. Rapamycin, a bacterial product first isolated from soil on Easter Island, enhanced learning and memory in young mice and improved these faculties in old mice, the study showed.

"We made the young ones learn, and remember what they learned, better than what is normal," said Veronica Galvan, Ph.D., assistant professor of physiology at the Barshop Institute for Longevity and Aging Studies, part of the UT Health Science Center. "Among the older mice, the ones fed with a diet including rapamycin actually showed an improvement, negating the normal decline that you see in these functions with age."

The drug also lowered anxiety and depressive-like behavior in the mice, Dr. Galvan said. Anxiety and depression are factors that impair human cognitive performance. Lead author Jonathan Halloran conducted scientifically reliable tests to accurately measure these cognitive components in the rodents.

Venturing into the open

Mice are burrowers that prefer tunnels with walls. To observe behavior, Halloran used an elevated maze of tunnels that led to a catwalk. “All of a sudden the mice are in open space,” Halloran said. “It’s pretty far from the floor for their size, sort of like if a person is hiking and suddenly the trail gets steep. It’s pretty far down and not so comfortable.”

Mice with less anxiety were more curious to explore the catwalk. “We observed that the mice fed with a diet containing rapamycin spent significantly more time out in the open arms of the catwalk than the animals fed with a regular diet,” Halloran said.

The second test measured depressive-like behavior in the rodents. Mice do not like to be held by their tails, which is the way they are moved from cage to cage. Inevitably they struggle to find a way out. “So we can measure how much and how often they struggle as a measure of the motivation they have to get out of an uncomfortable situation,” Dr. Galvan said.

Rapamycin acts like an antidepressant

Some mice barely struggle to get free, but if an antidepressant is administered they struggle a lot more. This behavior is very sensitive to the action of antidepressants and is a reliable measure of whether a drug is acting like an antidepressant, Dr. Galvan said.

"We found rapamycin acts like an antidepressant — it increases the time the mice are trying to get out of the situation," she said. "They don’t give up; they struggle more."

The reductions of anxiety and depressive-like behavior in rapamycin-treated mice held true for all ages tested, from 4 months of age (college age in human years) to 12 months old (the equivalent of middle age) to 25 months old (advanced age).

Feel-good chemicals elevated

The researchers measured levels of three “happy, feel-good” neurotransmitters: serotonin, dopamine and norepinephrine. All were significantly augmented in the midbrains of mice treated with rapamycin. “This is super-interesting, something we are going to pursue in the lab,” Dr. Galvan said.

Dr. Galvan and her team published research in 2010 showing that rapamycin rescues learning and memory in mice with Alzheimer’s-like deficits. The elevation of the three neurotransmitters, which are chemical messengers in the brain, may explain how rapamycin accomplished this, Dr. Galvan said.

Rapamycin is an antifungal agent administered to transplant patients to prevent organ rejection. The drug is named for Rapa Nui, the Polynesian title for Easter Island. This island, 2,000 miles from any population centers, is the famed site of nearly 900 mysterious monolithic statues.

Source: Science Daily

ScienceDaily (June 28, 2012) — Johns Hopkins researchers, working with an international consortium, say they have generated stem cells from skin cells from a person with a severe, early-onset form of Huntington’s disease (HD), and turned them into neurons that degenerate just like those affected by the fatal inherited disorder.

By creating “HD in a dish,” the researchers say they have taken a major step forward in efforts to better understand what disables and kills the cells in people with HD, and to test the effects of potential drug therapies on cells that are otherwise locked deep in the brain.

Although the autosomal dominant gene mutation responsible for HD was identified in 1993, there is no cure. No treatments are available even to slow its progression.

The research, published in the journal Cell Stem Cell, is the work of a Huntington’s Disease iPSC Consortium, including scientists from the Johns Hopkins University School of Medicine in Baltimore, Cedars-Sinai Medical Center in Los Angeles and the University of California, Irvine, as well as six other groups. The consortium studied several other HD cell lines and control cell lines in order to make sure results were consistent and reproducible in different labs.

The general midlife onset and progressive brain damage of HD are especially cruel, slowly causing jerky, twitch-like movements, lack of muscle control, psychiatric disorders and dementia, and — eventually — death. In some cases (as in the patient who donated the material for the cells made at Johns Hopkins), the disease can strike earlier, even in childhood.

"Having these cells will allow us to screen for therapeutics in a way we haven’t been able to before in Huntington’s disease," saysChristopher A. Ross, M.D., Ph.D., a professor of psychiatry and behavioral sciences, neurology, pharmacology and neuroscience at the Johns Hopkins University School of Medicine and one of the study’s lead researchers. "For the first time, we will be able to study how drugs work on human HD neurons and hopefully take those findings directly to the clinic."

Ross and his team, as well as other collaborators at Johns Hopkins and Emory University, are already testing small molecules for the ability to block HD iPSC degeneration.These small molecules have the potential to be developed into novel drugs for HD.

The ability to generate from stem cells the same neurons found in Huntington’s disease may also have implications for similar research in other neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

To conduct their experiment, Ross took a skin biopsy from a patient with very early onset HD.When seen by Ross at the HD Center at Hopkins, the patient was just seven years old. She had a very severe form of the disease, which rarely appears in childhood, and of the mutation that causes it. Using cells from a patient with a more rapidly progressing form of the disease gave Ross’ team the best tools with which to replicate HD in a way that is applicable to patients with all forms of HD.

Her skin cells were grown in culture and then reprogrammed by the lab of Hongjun Song, Ph.D., a professor at Johns Hopkins’ Institute for Cell Engineering, into induced pluripotent stem cells. A second cell line was generated in an identical fashion in Dr. Ross’s lab from someone without HD. Simultaneously, other HD and control iPS cell lines were generated as part of the NINDS funded HD iPS cell consortium.

Scientists at Johns Hopkins and other consortium labs converted those cells into generic neurons and then into medium spiny neurons, a process that took three months. What they found was that the medium spiny neurons deriving from HD cells behaved just as they expected medium spiny neurons from an HD patient would. They showed rapid degeneration when cultured in the lab using basic culture medium without extensive supporting nutrients. By contrast, control cell lines did not show neuronal degeneration.

"These HD cells acted just as we were hoping," says Ross, director of the Baltimore Huntington’s Disease Center. "A lot of people said, ‘You’ll never be able to get a model in a dish of a human neurodegenerative disease like this.’ Now, we have them where we can really study and manipulate them, and try to cure them of this horrible disease. The fact that we are able to do this at all still amazes us."

Specifically, the damage caused by HD is due to a mutation in the huntingtin gene (HTT), which leads to the production of an abnormal and toxic version of the huntingtin protein. Although all of the cells in a person with HD contain the mutation, HD mainly targets the medium spiny neurons in the striatum, part of the brain’s basal ganglia that coordinates movement, thought and emotion. The ability to work directly with human medium spiny neurons is the best way, researchers believe, to determine why these specific cells are susceptible to cell stress and degeneration and, in turn, to help find a way to halt progression of HD.

Much HD research is conducted in mice. And while mouse models have been helpful in understanding some aspects of the disease, researchers say nothing compares with being able to study actual human neurons affected by HD.

For years, scientists have been excited about the prospect of making breakthroughs in curing disease through the use of stem cells, which have the remarkable potential to develop into many different cell types. In the form of embryonic stem cells, they do so naturally during gestation and early life. In recent years, researchers have been able to produce induced pluripotent stem cells (iPSCs), which are adult cells (like the skin cells used in Ross’s experiments) that have been genetically reprogrammed back to the most primitive state. In this state, under the right circumstances, they can then develop into most or all of the 200 cell types in the human body.

Source: Science Daily