Posts Tagged Genetics

How Drugs for Schizophrenia Sow Seeds of Resistance


How Drugs for Schizophrenia Sow Seeds of ResistanceA new study has identified why certain drugs have mixed success in treating schizophrenia; effective at first, but with chronic administration becoming less and less so.

In the study, reported online in the journal Nature Neuroscience, scientists investigated the external genetic reasons (called epigenetic factors) that cause treatment-resistance to atypical antipsychotic drugs.

Use of antipsychotic drugs is the standard of care for schizophrenia. Researchers at Mount Sinai School of Medicine report that 30 percent of individuals with schizophrenia do not respond to currently available treatments.

Researchers discovered that, over time, an enzyme in the brains of schizophrenic patients, analyzed at autopsy, begins to compensate for the prolonged chemical changes caused by antipsychotics, resulting in reduced efficacy of the drugs.

“These results are groundbreaking because they show that drug resistance may be caused by the very medications prescribed to treat schizophrenia, when administered chronically,” said Javier Gonzalez-Maeso, Ph.D., lead investigator on the study.

Researchers found that an enzyme called HDAC2 was highly expressed in the brain of mice chronically treated with antipsychotic drugs, resulting in lower expression of the receptor called mGlu2 and a recurrence of psychotic symptoms. A similar finding was observed in the postmortem brains of schizophrenic patients.

In response, the research team administered a chemical called suberoylanilide hydroxamic acid (SAHA), which inhibits the entire family of HDACs. This treatment prevented the detrimental effect of the antipsychotic called clozapine on mGlu2 expression, and also improved the therapeutic effects of atypical antipsychotics in mouse models.

Previous research conducted by the team showed that chronic treatment with the antipsychotic clozapine causes repression of mGlu2 expression in the frontal cortex of mice, a brain area key to cognition and perception.

The researchers hypothesized that this effect of clozapine on mGlu2 may play a crucial role in restraining the therapeutic effects of antipsychotic drugs.

“We had previously found that chronic antipsychotic drug administration causes biochemical changes in the brain that may limit the therapeutic effects of these drugs,”said Gonzalez-Maeso. “We wanted to identify the molecular mechanism responsible for this biochemical change, and explore it as a new target for new drugs that enhance the therapeutic efficacy of antipsychotic drugs.”

Mitsumasa Kurita, Ph.D., a postdoctoral fellow at Mount Sinai and the lead author of the study, said, “We found that atypical antipsychotic drugs trigger an increase of HDAC2 in the frontal cortex of individuals with schizophrenia, which then reduces the presence of mGlu2, and thereby limits the efficacy of these drugs.”

As a result of these findings, Gonzalez-Maeso’s team is now developing compounds that specifically inhibit HDAC2 as adjunctive treatments to antipsychotics.

Source:The Mount Sinai Hospital/Mount Sinai School of Medicine

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Gene Related to Autism Behavior ID’d in Mice Study


Gene Related to Autism Behavior ID'd in Mice StudyIn a new mouse study, University of California, Davis, researchers have found that a defective gene is responsible for brain changes that lead to the disrupted social behavior that accompanies autism.

Investigators believe the discovery could lead to the development of medications to treat the condition.

Prior research had determined that the gene is defective in children with autism, but its effect on neurons in the brain was not known.

The new studies in mice show that abnormal action of just this one gene disrupted energy use in neurons. The harmful changes were coupled with antisocial and prolonged repetitive behavior — traits found in autism.

The research is published in the scientific journal PLoS ONE.

“A number of genes and environmental factors have been shown to be involved in autism, but this study points to a mechanism — how one gene defect may trigger this type of neurological behavior,” said study senior author Cecilia Giulivi, Ph.D.

“Once you understand the mechanism, that opens the way for developing drugs to treat the condition,” she said.

The defective gene appears to disrupt neurons’ use of energy, Giulivi said, the critical process that relies on the cell’s molecular energy factories called mitochondria.

In the research, a gene called pten was modififed in the mice so that neurons lacked the normal amount of pten’s protein. The scientists detected malfunctioning mitochondria in the mice as early as 4 to 6 weeks after birth.

By 20 to 29 weeks, DNA damage in the mitochondria and disruption of their function had increased dramatically.

At this time, the mice began to avoid contact with their litter mates and engage in repetitive grooming behavior. Mice without the single gene change exhibited neither the mitochondria malfunctions nor the behavioral problems.

The antisocial behavior was most pronounced in the mice at an age comparable in humans to the early teenage years – a period in which schizophrenia and other behavioral disorders become most apparent, Giulivi said.

The research showed that, when defective, pten’s protein interacts with the protein of a second gene known as p53 to dampen energy production in neurons.

The interaction causes severe stress that leads to a spike in harmful mitochondrial DNA changes and abnormal levels of energy production in the cerebellum and hippocampus — brain regions critical for social behavior and cognition.

Investigators report that pten mutations previously have been linked to Alzheimer’s disease as well as a spectrum of autism disorders.

The new research shows that when pten protein was insufficient, its interaction with p53 triggered deficiencies and defects in other proteins that also have been found in patients with learning disabilities including autism.

Source: University of California – Davis Health System

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Stress, Depression Reduce Brain Volume Thanks to Genetic ‘Switch’


Stress, Depression Reduce Brain Volume Thanks to Genetic 'Switch' Scientists have known that stress and depression can cause the brain to retract or lose volume, a condition associated with both emotional and cognitive impairment. Now, a new study discovers why this occurs.

Yale scientists have found that the deactivation of a single genetic switch can instigate a cascading loss of brain connections in humans and depression in animal models.

Researchers say the genetic switch, known as a transcription factor, represses the expression of several genes that are necessary for the formation of synaptic connections between brain cells. The loss of connections, in turn, can contribute to loss of brain mass in the prefrontal cortex, say the scientists.

“We wanted to test the idea that stress causes a loss of brain synapses in humans,” said senior author Ronald Duman, Ph.D. “We show that circuits normally involved in emotion, as well as cognition, are disrupted when this single transcription factor is activated.”

In the study, the research team analyzed tissue of depressed and non-depressed patients donated from a brain bank and looked for different patterns of gene activation.

The brains of patients who had been depressed exhibited lower levels of expression in genes that are required for the function and structure of brain synapses.

Lead author and postdoctoral researcher H.J. Kang, Ph.D., discovered that at least five of these genes could be regulated by a single transcription factor called GATA1.

When the transcription factor was activated in animal models, rodents exhibited depressive-like symptoms, suggesting GATA1 plays a role not only in the loss of connections between neurons but also in symptoms of depression.

This finding of genetic variations in GATA1 may help researchers identify people at high risk for major depression or sensitivity to stress.

“We hope that by enhancing synaptic connections, either with novel medications or behavioral therapy, we can develop more effective antidepressant therapies,” Duman said.

Source: Yale University

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Fragile X, Down Syndrome Involve Similar Pathways


Mental disabilities stemming from Fragile X and Down syndrome involve similar molecular pathways, according to a new study published in The EMBO Journal.

Both disorders are characterized by problems with the processes that regulate the way nerve cells develop dendritic spines—the small protrusions on the surface of nerve cells that are vital for communication in the brain.

“We have shown for the first time that some of the proteins altered in Fragile X and Down syndromes are common molecular triggers of intellectual disability in both disorders,” said Kyung-Tai Min, a professor at Indiana University and the Ulsan National Institute of Science and Technology in Korea.

“Specifically, two proteins interact with each other in a way that limits the formation of spines or protrusions on the surface of dendrites.”

“These outgrowths of the cell are essential for the formation of new contacts with other nerve cells and for the successful transmission of nerve signals. When the spines are impaired, information transfer is impeded and mental retardation takes hold,” he said.

Two of the most common genetic causes of intellectual disability are Fragile X and Down syndromes.

Fragile X syndrome is triggered by a single gene mutation that prevents the production of a protein needed for proper neural development (Fragile X mental retardation protein). For Down syndrome to occur, all or a part of a third copy of chromosome 21 must be present.

Although each syndrome is due to a separate genetic difference, the researchers identified a shared molecular pathway in mice that triggers intellectual disability in both disorders.

Down syndrome mice models have difficulties with memory and brain function, and the development of the heart is often compromised, symptoms that are also observed in humans with Down syndrome.

“We believe these experiments provide an important step forward in understanding the multiple roles of DSCR1 in neurons and in identifying a molecular interaction that is closely linked to intellectual disability for both syndromes,” said Min.

Source:  The EMBO Journal

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Genetic Link Found to Rapid Weight Gain from Antipsychotic Meds


Genetic Link Found to Rapid Weight Gain from Antipsychotic MedsScientists have discovered two genetic variants associated with substantial, rapid weight gain occurring in nearly half of patients treated with antipsychotic medications.

The results from two studies from the Centre for Addiction and Mental Health in Canada could eventually be used to identify which patients have the variations, enabling doctors to choose strategies to prevent this serious side effect and offer more personalized treatment, the researchers note.

“Weight gain occurs in up to 40 percent of patients taking medications called second-generation or atypical antipsychotics, which are used because they’re effective in controlling the major symptoms of schizophrenia,” said Dr. James Kennedy, senior author of the study.

The weight gain can lead to obesity, type 2 diabetes, heart problems and a shortened life span, he noted.

“Identifying genetic risks leading to these side effects will help us prescribe more effectively,” said Kennedy. Currently, the center screens for two other genetic variations that affect patients’ responses to psychiatric medications.

Each study identified a different variation near the melanocortin-4 receptor (MC4R) gene, which is known to be linked to obesity.

In the latest study, people carrying two copies of a variant gained about three times as much weight as those with one or no copies, after six to 12 weeks of treatment with atypical antipsychotics.

The study had four patient groups: Two from the U.S., one in Germany, and one from a larger European study. Three of the four groups had never taken atypical antipsychotics.

Different groups were treated with drugs such as olanzapine, risperidone, aripiprazole or quetiapine, and compliance was monitored to ensure the treatment regime was followed, the researchers said. Weight and other metabolic-related measures were taken at the start and during treatment.

“The weight gain was associated with this genetic variation in all these groups, which included pediatric patients with severe behavior or mood problems, and patients with schizophrenia experiencing a first episode or who did not respond to other antipsychotic treatments,” noted researcher Dr. Daniel Müller.

“The results from our genetic analysis combined with this diverse set of patients provide compelling evidence for the role of this MC4R variant. Our research group has discovered other gene variants associated with antipsychotic-induced weight gain in the past, but this one appears to be the most compelling finding thus far.”

The gene’s role in antipsychotic-induced weight gain was identified in a study published earlier this year in The Pharmacogenomics Journal. Researchers
found a different variation on MC4R that was linked to the side effect.

For both studies, CAMH researchers did genotyping experiments to identify the single changes to the sequence of the MC4R gene — known as single nucleotide polymorphisms (SNPs) — related to the drug-induced weight gain side effect.

The MC4R gene encodes a receptor involved in the brain pathways regulating weight, appetite and satiety. “We don’t know exactly how the atypical antipsychotics disrupt this pathway, or how this variation affects the receptor,” said Müller. “We need further studies to validate this result and eventually turn this into a clinical application.”

The recent study is published online in the Archives of General Psychiatry.

Source: The Centre for Addiction and Mental Health (CAMH)

DNA photo by shutterstock.

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Mice Study Shows Overactive Immune System Contributes to Autism


Mice Study Shows Overactive Immune System Contributes to Autism  A new study suggests that changes in an overactive immune system can contribute to autism-like behaviors in mice.

The study from the California Institute of Technology (Caltech) also found that, in some cases, this activation can be related to what a developing fetus experiences in the womb.

“We have long suspected that the immune system plays a role in the development of autism spectrum disorder,” said Dr. Paul Patterson, the Anne P. and Benjamin F. Biaggini Professor of Biological Sciences at Caltech, who led the work.

“In our studies of a mouse model based on an environmental risk factor for autism, we find that the immune system of the mother is a key factor in the eventual abnormal behaviors in the offspring.”

The first step was establishing a mouse model that tied the autism-related behaviors to immune changes, he said.

Several large studies — including one that involved tracking the medical history of every person born in Denmark between 1980 and 2005 — found a correlation between viral infection during the first trimester of a mother’s pregnancy and a higher risk for autism in her child. As part of the new study, researchers injected pregnant mouse mothers with a viral mimic that triggered the same type of immune response a viral infection would.

“In mice, this single insult to the mother translates into autism-related behavioral abnormalities and neuropathologies in the offspring,” said Elaine Hsiao, a graduate student in Patterson’s lab and lead author of the paper.

The team found that the offspring exhibit the core behavioral symptoms associated with autism spectrum disorder, including repetitive or stereotyped behaviors, decreased social interactions, and impaired communication.

In mice, this translates to such behaviors as compulsively burying marbles placed in their cage, excessively self-grooming, choosing to spend time alone or with a toy rather than interacting with a new mouse, or vocalizing ultrasonically less often or in an altered way compared to typical mice.

Next, the researchers studied the immune system of the offspring of mothers that had been infected and found that they displayed a number of immune changes.

Some of those changes parallel those seen in people with autism, including decreased levels of regulatory T cells, which play a role in suppressing the immune response, the researchers said.

Taken together, the observed alterations add up to an immune system in overdrive, which promotes inflammation.

“Remarkably, we saw these immune abnormalities in both young and adult offspring of immune-activated mothers,” Hsiao said. “This tells us that a prenatal challenge can result in long-term consequences for health and development.”

The researchers were then able to test whether the offspring’s immune problems contribute to their autism-related behaviors. In a test of this hypothesis, the researchers gave the affected mice a bone-marrow transplant from typical mice.

The normal stem cells in the transplanted bone marrow not only replenished the immune system of the mice, but altered their autism-like behavior, the researchers report.

The researchers note that because the work was conducted in mice, the results cannot be readily extrapolated to humans, and they do not suggest that bone-marrow transplants should be considered as a treatment for autism.

They also have yet to establish whether it was the infusion of stem cells or the bone-marrow transplant procedure itself — complete with irradiation — that corrected the behaviors.

However, the results do suggest that immune irregularities in children could be an important target for innovative immune manipulations in addressing the behaviors associated with autism, said Patterson. By correcting these immune problems, it might be possible to ameliorate some of the classic developmental delays seen in autism, he noted.

The results appear in a paper in the Proceedings of the National Academy of Sciences (PNAS).

Source: California Institute of Technology

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Behavioral, Cognitive Challenges Define Fetal Alcohol Exposure


Behavioral and Cognitive Challenges Define Fetal Alcohol ExposureNew research suggests the only sign of fetal alcohol exposure may be signs of abnormal intellectual or behavioral development.

Researchers at the National Institutes of Health have discovered that the facial features classically attributed to fetal alcohol syndrome do not develop in a majority of children.

Rather, nervous system abnormalities in children may manifest as challenged intellect and behavioral development, including language delays, hyperactivity, attention deficits or intellectual delays. Researchers define deficits or abnormalities as functional neurologic impairments.

In the study, authors documented an abnormality in one of these areas in about 44 percent of children whose mothers drank four or more drinks per day during pregnancy.

In contrast, abnormal facial features were present in about 17 percent of alcohol exposed children.

Fetal alcohol syndrome refers to a pattern of birth defects found in children of mothers who consumed alcohol during pregnancy.

These involve a characteristic pattern of facial abnormalities, growth retardation, and brain damage.

Neurological and physical differences seen in children exposed to alcohol prenatally — but who do not have the full pattern of birth defects seen in fetal alcohol syndrome — are classified as fetal alcohol spectrum disorders.

“Our concern is that in the absence of the distinctive facial features, health care providers evaluating children with any of these functional neurological impairments might miss their history of fetal alcohol exposure,” said Devon Kuehn, M.D.

“As a result, children might not be referred for appropriate treatment and services.”

The study may be found online in Alcoholism: Clinical and Experimental Research.

The research was conducted as part of a long-term study of heavy drinking in pregnancy known as the NICHD–University of Chile Alcohol in Pregnancy Study.

The investigation began by researchers asking over 9000 women at a community health clinic in Santiago, Chile about their alcohol use during pregnancy.

They found 101 pregnant women, who had four or more drinks per day during their pregnancies and matched them with 101 women having similar characteristics but who consumed no alcohol when they were pregnant.

After these women gave birth, the researchers evaluated the infants’ health and conducted regular assessments of their physical, intellectual and emotional development through age 8.

The researchers documented that children exposed to alcohol presented an increased risk of:

  • Abnormal facial features (16 percent);
  • Delayed growth (14 percent);
  • Cognitive delays (including intellectual) (29 percent);
  • Language delays (18 percent);
  • Hyperactivity (25 percent).

Some of the women with heavy drinking habits also engaged in binge drinking (5 or more drinks at a time). Even though these women already had high levels of alcohol consumption, the researchers found that this habit increased the likelihood of poor outcomes for their children.

Source: NIH/National Institute of Child Health and Human Development

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