Posts tagged genetics

ScienceDaily (Mar. 8, 2012) — A new study in Science suggests that thrill-seeking is not limited to humans and other vertebrates. Some honey bees, too, are more likely than others to seek adventure. The brains of these novelty-seeking bees exhibit distinct patterns of gene activity in molecular pathways known to be associated with thrill-seeking in humans, researchers report.

A new study in Science suggests that thrill-seeking is not limited to humans and other vertebrates. Some honey bees, too, are more likely than others to seek adventure. (Credit: L. Brian Stauffer)

The findings offer a new window on the inner life of the honey bee hive, which once was viewed as a highly regimented colony of seemingly interchangeable workers taking on a few specific roles (nurse or forager, for example) to serve their queen. Now it appears that individual honey bees actually differ in their desire or willingness to perform particular tasks, said University of Illinois entomology professor and Institute for Genomic Biology director

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ScienceDaily (Mar. 8, 2012) — UT Southwestern Medical Center investigators have identified a genetic manipulation that increases the development of neurons in the brain during aging and enhances the effect of antidepressant drugs.

UT Southwestern Medical Center investigators have identified a genetic manipulation that increases the development of neurons in the brain during aging and enhances the effect of antidepressant drugs. (Credit: © rolffimages / Fotolia)

The research finds that deleting the Nf1 gene in mice results in long-lasting improvements in neurogenesis, which in turn makes those in the test group more sensitive to the effects of antidepressants.

"The significant implication of this work is that enhancing neurogenesis sensitizes mice to antidepressants — meaning they needed lower doses of the drugs to affect ‘mood’ — and also appears to have anti-depressive and anti-anxiety effects of its own that continue over time," said Dr. Luis Parada, director of the Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration and senior author of the study published in The Journal of Neuroscience.

Just as in people, mice produce new neurons throughout adulthood, although the rate declines with age and stress, said Dr. Parada, chairman of developmental biology at UT Southwestern. Studies have shown that learning, exercise, electroconvulsive therapy and some antidepressants can increase neurogenesis. The steps in the process are well known but the cellular mechanisms behind those steps are not.

"In neurogenesis, stem cells in the brain’s hippocampus give rise to neuronal precursor cells that eventually become young neurons, which continue on to become full-fledged neurons that integrate into the brain’s synapses," said Dr. Parada, an elected member of the National Academy of Sciences, its Institute of Medicine, and the American Academy of Arts and Sciences.

The researchers used a sophisticated process to delete the gene that codes for the Nf1 protein only in the brains of mice, while production in other tissues continued normally. After showing that mice lacking Nf1 protein in the brain had greater neurogenesis than controls, the researchers administered behavioral tests designed to mimic situations that would spark a subdued mood or anxiety, such as observing grooming behavior in response to a small splash of sugar water.

The researchers found that the test group mice formed more neurons over time compared to controls, and that young mice lacking the Nf1 protein required much lower amounts of anti-depressants to counteract the effects of stress. Behavioral differences between the groups persisted at three months, six months and nine months. “Older mice lacking the protein responded as if they had been taking antidepressants all their lives,” said Dr. Parada.

"In summary, this work suggests that activating neural precursor cells could directly improve depression- and anxiety-like behaviors, and it provides a proof-of-principle regarding the feasibility of regulating behavior via direct manipulation of adult neurogenesis," Dr. Parada said.

Dr. Parada’s laboratory has published a series of studies that link the Nf1 gene — best known for mutations that cause tumors to grow around nerves — to wide-ranging effects in several major tissues. For instance, in one study researchers identified ways that the body’s immune system promotes the growth of tumors, and in another study, they described how loss of the Nf1 protein in the circulatory system leads to hypertension and congenital heart disease.

Source: Science Daily

Article Date: 02 Mar 2012 - 1:00 PST

Scientists from Seattle Children’s Research Institute and the University of Washington, in collaboration with the Genomic Disorders Group Nijmegen in the Netherlands, have identified two new genes that cause Baraitser-Winter syndrome, a rare brain malformation that is characterized by droopy eyelids and intellectual disabilities.

“This new discovery brings the total number of genes identified with this type of brain defect to eight,” said William Dobyns, MD, a geneticist at Seattle Children’s Research Institute. Identification of the additional genes associated with the syndrome make it possible for researchers to learn more about brain development. The study, “De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome,” was published online in Nature Genetics.

The brain defect found in Baraitser-Winter syndrome is a smooth brain malformation or “lissencephaly,” as whole or parts of the surface of the brain appear smooth in scans of patients with the disorder. Previous studies by Dr. Dobyns and other scientists identified six genes that cause the smooth brain malformation, accounting for approximately 80% of affected children. Physicians and researchers worldwide have identified to date approximately 20 individuals with Baraitser-Winter syndrome.

While the condition is rare, Dr. Dobyns said the team’s findings have broad scientific implications. “Actins, or the proteins encoded by the ACTB and ACTG1 genes, are among the most important proteins in the function of individual cells,” he said. “Actins are critical for cell division, cell movement, internal movement of cellular components, cell-to-cell contact, signaling and cell shape,” said Dr. Dobyns, who is also a University of Washington professor of pediatrics. “The defects we found occur in the only two actin genes that are expressed in most cells,” he said. Gene expression is akin to a “menu” for conditions like embryo development or healing from an injury. The correct combination of genes must be expressed at the right time to allow proper development. Abnormal expression of genes can lead to a defect or malformation.

“Birth defects associated with these two genes also seem to be quite severe,” said Dr. Dobyns. “Children and people with these genes have short stature, an atypical facial appearance, birth defects of the eye, and the smooth brain malformation along with moderate mental retardation and epilepsy. Hearing loss occurs and can be progressive,” he said.

Dr. Dobyns is a renowned researcher whose life-long work has been to try to identify the causes of children’s developmental brain disorders such as Baraitser-Winter syndrome. He discovered the first known chromosome abnormality associated with lissencephaly (Miller-Dieker syndrome) while still in training in child neurology at Texas Children’s Hospital in 1983. That research led, 10 years later, to the discovery by Dobyns and others of the first lissencephaly gene known as LIS1.

Source: Medical News Today  

ScienceDaily (Mar. 1, 2012) — Down syndrome (DS) is the most common genetic disorder in live born children arising as a consequence of a chromosomal abnormality. It occurs as a result of having three copies of chromosome 21, instead of the usual two. It causes substantial physical and behavioral abnormalities, including life-long cognitive dysfunction that can range from mild to severe but which further deteriorates as individuals with DS age.

It is not currently possible to effectively treat the cognitive impairments associated with DS. However, these deficits are an increasing focus of research. In this issue of Biological Psychiatry, researchers at Stanford University, led by Dr. Ahmad Salehi, have published a review which highlights potential strategies for the treatment of these cognitive deficits.

The authors focus on insights emerging from animal models of Down syndrome and outline the structural abnormalities in the DS brain. They also discuss studies that have linked the over-expression of the amyloid precursor protein gene, called APP, to the degeneration of neurons in mice. These findings have led to the development of therapeutic treatments in mice, which now must be tested in humans.

"For more than a decade, we have been working on identifying a strategy to treat cognitive disabilities in our Down syndrome mouse models," said Dr. Salehi. "Considering the research and results with mouse models as an indication of success of a strategy in humans, we are ever closer to finding ways to at least partially restore cognitive function in children and adults with Down syndrome."

Interestingly, this research is also providing insights into Alzheimer’s disease (AD), the archetypal disorder of late life. All adults with Down syndrome develop AD pathology by age 40, and there are some remarkable similarities in the brain degeneration and cognitive dysfunction of individuals with DS and those with AD.

The leading AD hypothesis posits that it is caused by increasingly elevated levels of amyloid-related proteins, which are toxic to nerve cells in the brain. These same proteins also accumulate in the brains of people with DS because they are made by the APP gene, which is located on chromosome 21. Individuals with AD don’t have the extra chromosome, of course; rather, it is mutations in APP that appear to cause the brain degeneration associated with AD.

Dr. John Krystal, editor of Biological Psychiatry, commented: “The convergence of research on Down syndrome and Alzheimer’s disease highlights a central point that cannot be overstated. When we understand the fundamental biology of the brain, important new conceptual bridges emerge that guide new treatment approaches.”

Salehi added, “In the near future, we may very likely look back with the perspective that Down syndrome represents an example of how families of affected individuals came together and by supporting basic research, changed the course of a disorder that was considered untreatable for more than a century.”

Source: Science Daily

ScienceDaily (Feb. 29, 2012) — A repression of gene activity in the brain appears to be an early event affecting people with Alzheimer’s disease, researchers funded by the National Institutes of Health have found. In mouse models of Alzheimer’s disease, this epigenetic blockade and its effects on memory were treatable.

In a mouse model of Alzheimer’s disease (right), HDAC2 levels in the hippocampus are higher than in the normal mouse hippocampus (left). Credit: (Credit: Dr. Li-Huei Tsai, MIT)

"These findings provide a glimpse of the brain shutting down the ability to form new memories gene by gene in Alzheimer’s disease, and offer hope that we may be able to counteract this process," said Roderick Corriveau, Ph.D., a program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the research.

The study was led by Li-Huei Tsai, Ph.D., who is director of The Picower Institute for Learning and Memory at the Massachusetts Institute of Technology and an investigator at the Howard Hughes Medical Institute. It was published online February 29 in Nature.

Dr. Tsai and her team found that a protein called histone deacetylase 2 (HDAC2) accumulates in the brain early in the course of Alzheimer’s disease in mouse models and in people with the disease. HDAC2 is known to tighten up spools of DNA, effectively locking down the genes within and reducing their activity, or expression.

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ScienceDaily (Feb. 29, 2012) — In a mouse model of Alzheimer’s disease, memory problems stem from an overactive enzyme that shuts off genes related to neuron communication, a new study says.

When researchers genetically blocked the enzyme, called HDAC2, they ‘reawakened’ some of the neurons and restored the animals’ cognitive function. The results, published February 29, 2012, in the journal Nature, suggest that drugs that inhibit this particular enzyme would make good treatments for some of the most devastating effects of the incurable neurodegenerative disease.

"It’s going to be very important to develop selective chemical inhibitors against HDAC2," says Howard Hughes Medical Institute investigator Li-Huei Tsai, whose team at the Massachusetts Institute of Technology performed the experiments. "If we could delay the cognitive decline by a certain period of time, even six months or a year, that would be very significant."

In every cell, DNA wraps itself around proteins called histones. Chemical groups such as methyl and acetyl can bind to histones and affect DNA expression. HDAC2 is a histone deacetylase, an enzyme that removes acetyl groups from the histone, effectively turning off nearby genes.

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Debora A Rothmond, Cynthia S Weickert and Maree J Webster

BMC Neuroscience 2012, 13:18 doi:10.1186/1471-2202-13-18 Published: 15 February 2012           

Background

Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-O-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years).

Results

Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p<0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p<0.001) and D2L (p=0.003) isoforms, monoamine oxidase A (p<0.001) and catechol-O-methyltransferase (p=0.024) were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32kDa, p=0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p=0.002) and dopamine D1 receptor protein expression increased throughout development (p<0.001) with adults having the highest D1 protein levels (p[less than or equal to]0.01). Monoamine oxidase B mRNA and protein (p<0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r=-0.31, p=0.018) in an expression profile opposite to that of the dopamine D1 receptor.

Conclusions

We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function. 

Source: BMC Neuroscience

February 16, 2012

(Medical Xpress) — Gene therapy not only helps injured brain cells to live longer and regenerate, but also changes the shape of the cells, according to researchers The University of Western Australia. 

The study, published in the international science and medicine journal PLoS One, was led by Winthrop Professor Alan Harvey from UWA’s School of Anatomy, Physiology and Human Biology, and Associate Professor Jennifer Rodger, NHMRC Research Fellow in Experimental and Regenerative Neurosciences at UWA’s School of Animal Biology.  The research was funded primarily by the WA Neurotrauma Research Program.

Professor Harvey said gene therapy was a relatively new strategy that attempted to help injured brain cells survive and regrow.

"Our previous work has shown that when growth-promoting genes are introduced into injured brain cells for long periods of time (up to nine months), the cells’ capacity for survival and regeneration is significantly increased," he said.

"We have now shown that these same neurons have also changed shape in response to persistent over-expression of the growth factors.  Importantly, it is not just neurons containing the introduced growth-promoting gene that are affected, but neighbouring "bystander" neurons."

Professor Harvey said neural morphology was very important in determining how a cell communicated with other cells and formed the circuits that allowed the brain to function.

"Any changes in morphology are therefore likely to alter the way neurons receive and transmit information.  These changes may be beneficial but could also interfere with normal brain circuits, reducing the benefits of improved survival and regeneration."

Professor Harvey said the results were significant for those involved in designing gene therapy-based protocols to treat brain and spinal cord injury and degeneration.

"These new results suggest that we may need to be careful about the types of genes we use in neurotherapy and how long we continue the therapy.  While it may be beneficial for these genes to move around and cause changes in other cells, we need to be able to switch them off once the change has taken place."

Provided by University of Western Australia

Source: medicalxpress.com