June 8, 2012

Molecular imbalance lies at the root of many psychiatric disorders. Current EU-funded research has discovered a major RNA molecular player in neurogenesis and has characterised its action and targets in the zebrafish embryo.

Credit: Thinkstock

Neural circuits are constantly in the process of modification according to experience and changes in the environment, a phenomenon known as plasticity. Classical Hebbian plasticity is crucial for encoding information whereas homeostatic plasticity stabilises neuronal activity in the face of changes that disturb excitability.

Homeostatic plasticity plays a big role in activity-dependent development of neural circuits. Interestingly, this type of homeostasis is frequently distorted in psychiatric disorders such as schizophrenia and autism.

Unlike the molecular basis of Hebbian homeostasis, the biochemistry behind homeostatic plasticity is relatively unknown. The ‘MicroRNAs and neurogenesis control’ (Neuromir) project set about investigating neural development in the zebrafish embryo to unravel the action of one class of gene regulator in particular – microRNAs.

The microRNA machinery is potentially very powerful in cell regulation. It influences many development processes and each microRNA molecule can regulate hundreds of target genes.

Numerous microRNAs are expressed in the development of the vertebrate central nervous system (CNS). Results from the in vivo study of the zebrafish revealed that miR-9 plays an important role in balancing the production of neurons during development of the embryo.

Neuromir researchers have successfully identified the molecular targets of miR-9. Future research may exploit this knowledge base by assessing their importance in disease and using their molecular format for drug therapy design.

Provided by CORDIS

Source: medicalxpress.com

June 8, 2012

Patients vary widely in their response to concussion, but scientists haven’t understood why. Now, using a new technique for analyzing data from brain imaging studies, researchers at Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center have found that concussion victims have unique spatial patterns of brain abnormalities that change over time.

The new technique could eventually help in assessing concussion patients, predicting which head injuries are likely to have long-lasting neurological consequences, and evaluating the effectiveness of treatments, according to lead author Michael L. Lipton, M.D., Ph.D., associate director of the Gruss Magnetic Resonance Research Center at Einstein and medical director of magnetic resonance imaging (MRI) services at Montefiore. The findings are published today in the online edition of Brain Imaging and Behavior.

The Centers for Disease Control and Prevention estimates that more than one million Americans sustain a concussion (also known as mild traumatic brain injury, or mTBI) each year. Concussions in adults result mainly from motor vehicle accidents or falls. At least 300,000 adults and children are affected by sports-related concussions each year. While most people recover from concussions with no lasting ill effects, as many as 30 percent suffer permanent impairment – undergoing a personality change or being unable to plan an event. A 2003 federal study called concussions “a serious public health problem” that costs the U.S. an estimated $80 billion a year.

Previous imaging studies found differences between the brains of people who have suffered concussions and normal individuals. But those studies couldn’t assess whether concussion victims differ from one another. “In fact, most researchers have assumed that all people with concussions have abnormalities in the same brain regions,” said Dr. Lipton, who is also associate professor of radiology, of psychiatry and behavioral sciences, and in the Dominick P. Purpura Department of Neuroscience at Einstein. “But that doesn’t make sense, since it is more likely that different areas would be affected in each person because of differences in anatomy, vulnerability to injury and mechanism of injury.”

In the current study, the Einstein researchers used a recently developed MRI technique called diffusion tensor imaging (DTI) on 34 consecutive patients (19 women and 15 men aged 19 to 64) diagnosed with mTBI at Montefiore in the Bronx and on 30 healthy controls. The patients were imaged within two weeks of injury and again three and six months afterward.

The imaging data were then analyzed using a new software tool called Enhanced Z-score Microstructural Assessment Pathology (EZ-MAP), which allows researchers for the first time to examine microstructural abnormalities across the entire brain of individual patients. EZ-MAP was developed by Dr. Lipton and his colleagues at Einstein.

DTI detects subtle damage to the brain by measuring the direction of diffusion of water in white matter. The same technology was used by Dr. Lipton and his team in widely publicized research on more than 30 amateur soccer players who had all played the sport since childhood. They found that frequent headers showed brain injury similar to that seen in patients with concussion.

The uniformity of diffusion direction – an indicator of whether tissue has maintained its microstructural integrity – is measured on a zero-to-one scale called fractional anisotropy (FA). In the latest study, areas of abnormally low FA (reflecting abnormal brain regions) were observed in concussion patients but not in controls. Each concussion patient had a unique spatial pattern of low FA that evolved over the study period.

Surprisingly, each patient also had a unique, evolving pattern of abnormally high FA distinct from the areas of low FA. “We found widespread high FA at every time point, all the way out to six months and even in patients more than one year out from their injury.” said Dr. Lipton. “We suspect that high FA represents a response to the injury. In other words, the brain may be trying to compensate for the injury by developing and enhancing other neural connections. This is a new and unexpected finding.”

At present, diagnosis of concussions is based mainly on the nature of the patient’s accident and the presence of symptoms including headache, dizziness and behavioral abnormalities. DTI, combined with EZ-MAP analysis, might offer a more objective tool for diagnosing concussion injuries and for predicting which patients will have persistent and progressive symptoms.

Provided by Albert Einstein College of Medicine

Source: medicalxpress.com

ScienceDaily (June 7, 2012) — Using a new and powerful approach to understand the origins of neurodegenerative disorders such as Alzheimer’s disease, researchers at Mayo Clinic in Florida are building the case that these diseases are primarily caused by genes that are too active or not active enough, rather than by harmful gene mutations.

In the June 7 online issue of PLoS Genetics, they report that several hundred genes within almost 800 brain samples of patients with Alzheimer’s disease or other disorders had altered expression levels that did not result from neurodegeneration. Many of those variants were likely the cause.

"We now understand that disease likely develops from gene variants that have modest effects on gene expression, and which are also found in healthy people. But some of the variants — elevating expression of some genes, reducing levels of others — combine to produce a perfect storm that leads to dysfunction," says lead investigator Nilufer Ertekin-Taner, M.D., Ph.D., a Mayo Clinic neurologist and neuroscientist.

"If we can identify the genes linked to a disease that are too active or too dormant, we might be able to define new drug targets and therapies," she says. "That could be the case for both neurodegenerative disease as well as disease in general."

Dr. Ertekin-Taner says no other lab has performed the extent of brain gene expression study conducted at Mayo Clinic’s Florida campus. “The novelty, and the usefulness, of our study is the sheer number of brain samples that we looked at and the way in which we analyzed them. These results demonstrate the significant contribution of genetic factors that alter brain gene expression and increase risk of disease,” she says.

This form of data analysis measures gene expression levels by quantifying the amount of RNA produced in tissue and scans the genome of patients to identify genetic variants that associate with these levels.

Mayo researchers measured the level of 24,526 transcripts (messenger RNA) for 18,401 genes using cerebellar autopsy tissue from 197 Alzheimer’s disease patients and from 177 patients with other forms of neurodegeneration. The researchers then validated the results by examining the temporal cortex from 202 Alzheimer’s disease patients and from 197 with other pathologies. The difference between these samples is that while the temporal cortex is affected by Alzheimer’s disease, the cerebellum is relatively spared.

From these analyses, the researchers identified more than 2,000 markers of altered expression in both groups of patients that were common between the cerebellum and temporal cortex. Some of these markers also influenced risk of human diseases, suggesting their contribution to development of neurodegenerative and other diseases regardless of their location in the brain.

They identified novel expression “hits” for genetic risk markers of diseases that included progressive supranuclear palsy, Parkinson’s disease, and Paget’s disease, and confirmed other known associations for lupus, ulcerative colitis, and type 1 diabetes.

"Altered expression of brain genes can be linked to a number of diseases that affect the entire body," Dr. Ertekin-Taner says.

They then compared their eGWAS to GWAS data on Alzheimer’s disease, conducted by the federally funded Alzheimer’s Disease Genetics Consortium, to test whether some of the risk genes already identified promote disease through altered expression.

"We found that a number of genes already linked to Alzheimer’s disease do, in fact, have altered gene expression, but we also discovered that many of the variants in what we call the gray zone of the GWAS — genes whose contribution to Alzheimer’s disease was uncertain — were also influencing brain expression levels," Dr. Ertekin-Taner says. "That offers us new candidate risk genes to explore.

"This is a powerful approach to understanding disease," she says. "It can find new genes that contribute to risk, as well as new genetic pathways, and can also help us understand the function for a large number of genes and other molecular regulators in the genome that are implicated in very important diseases."

Source: Science Daily

ScienceDaily (June 7, 2012) — Degeneration of the axon and synapse, the slender projection through which neurons transmit electrical impulses to neighboring cells, is a hallmark of some of the most crippling neurodegenerative and brain diseases such as amyotrophic lateral sclerosis (ALS), Huntington’s disease and peripheral neuropathy. Scientists have worked for decades to understand axonal degeneration and its relation to these diseases. Now, researchers at the University of Massachusetts Medical School are the first to describe a gene — dSarm/Sarm1 — responsible for actively promoting axon destruction after injury. The research, published June 7 online by Science, provides evidence of an exciting new therapeutic target that could be used to delay or even stop axon decay.

"This discovery has the potential to have a profound impact on our understanding of neurodegenerative diseases, much like the discovery of apoptosis (programmed cell death) fundamentally changed our understanding of cancer," said Marc R. Freeman, PhD, associate professor of neurobiology at the University of Massachusetts Medical School and lead investigator on the study. "Identification of this gene allows us to start asking exciting new questions about the role of axon death in neurodegenerative diseases. For example, is it possible that these pathways are being inappropriately activated to cause premature axon death?"

For more than a century, scientists believed that injured axons severed from the neuron cell body passively wasted away due to a lack of nutrients. However, a mouse mutation identified in the early 1990s — called slow Wallerian degeneration (Wlds) — was able to suppress axon degeneration for weeks. This finding forced scientists to reassess Wallerian degeneration, the process through which an injured axon degenerates, as a passive process and consider the possibility that an active program of axon auto-destruction, akin to apoptotic death, was at work instead.

If Wallerian degeneration was an active process, hypothesized Dr. Freeman, a Howard Hughes Medical Institute Early Career Scientist, then it should be possible through forward genetic screens in Drosophila to identify mutants exhibiting Wlds-like axon protection. Freeman and colleagues screened more than 2,000 Drosophila mutants for ones that exhibited long-term survival of severed axons. Freeman says this was a heroic effort on the part of his colleagues. The screen took place over the next two and a half years, and involved seven students and post-docs in the Freeman lab — Jeannette M. Osterloh, A. Nicole Fox, PhD, Michelle A. Avery, PhD, Rachel Hackett, Mary A. Logan, PhD, Jennifer M. MacDonald, Jennifer S. Zeigenfuss — who performed the painstaking and labor-intensive experiments needed on each Drosophila mutant to identify flies that suppressed axonal degeneration after nerve injury.

Through these tests, they identified three mutants (out of the 2,000 screened) where severed axons survived for the lifespan of the fly. Next generation sequencing and chromosome deficiency mapping techniques were then used to isolate the single gene affected in all three — dSarm. These were loss-of-function alleles, meaning that Drosophila unable to produce the dSarm/Sarm1 molecule exhibited prolonged axon survival for as many as 30 days after injury. Freeman and colleagues went on to show that mice lacking Sarm1, the mammalian homolog of dSarm, also displayed remarkable preservation of injured axons. These findings provided the first direct evidence that Wallerian degeneration was driven by a conserved axonal death program and not a passive response to axon injury.

"For 20 years people have been looking for a gene whose normal function is to promote axon degeneration," said Osterloh, first author on the study. "Identification of the dSarm/Sarm1 gene has enormous therapeutic potential, for example as a knockdown target for patients suffering from diseases involving axonal loss."

The next step for Freeman and colleagues is to identify additional genes in the axon death pathway and investigate whether any have links with specific neurodegenerative diseases. “We’re already working with scientists at UMMS to understand the role axon death plays in ALS and Huntington’s disease,” said Freeman. “We are very excited about the possibility that these findings could have broad therapeutic potential in many neurodegenerative diseases.”

Source: Science Daily

ScienceDaily (June 7, 2012) — Scientists have discovered a new function for a protein that protects cells during injury and could eventually translate into treatment for conditions ranging from cardiovascular disease to Alzheimer’s.

Researchers report online June 7 in the journal Cell that a type of protein called thrombospondin activates a protective pathway that prevents heart cell damage in mice undergoing simulated extreme hypertension, cardiac pressure overload and heart attack.

"Our results suggest that medically this protein could be targeted as a way to help people with many different disease states where various organs are under stress,” said Jeffery Molkentin, PhD, lead investigator and a researcher at Cincinnati Children’s Hospital Medical Center and the Howard Hughes Medical Institute. "Although more study is needed to determine how our findings might be applied clinically, a possible therapeutic strategy could include a drug or gene therapy that induces overexpression of the protein in tissues or organs undergoing injury."

Thrombospondin (Thbs) proteins are produced by the body in cells where tissues are being injured, reconfigured or remodeled, such as in chronic cardiac disease. They appear in part of the cell’s internal machinery called the endoplasmic reticulum. There, Thbs triggers a stress response process to regulate production of other proteins and help correct or rid cells of proteins that misfold and lose their form and intended function. Misfolded proteins help drive tissue damage and organ dysfunction.

The researchers zeroed in on how one thrombospondin protein (Thbs4) activates cellular stress responses in mice bred to overexpress the protein in heart cells. They compared how the hearts of the Thbs4-positive mice responded to simulated stress and injury to mice not bred to overexpress cardiac-specific Thbs4.

Overexpression of Thbs4 had no effect on the animals prior to cardiac stress — although during simulated hypertension and cardiac infarction the protein reduced injury and protected them from death. Mice not bred for Thbs4 overexpression were extremely sensitive to cardiac injury, according to Molkentin, a member of the Division of Molecular Cardiovascular Biology and Cincinnati Children’s Heart Institute.

The researchers reported that overexpressed Thbs4 enhanced the ability of heart cells to secrete helpful proteins, resolve misfolded proteins and properly reconstruct extracellular matrix — connective tissues that help give the heart functional form and structural integrity.

Critical to the stress response process was Thbs4 activating and regulating a transcription factor called Aft6alpha. Transcription factors help decode genetic instructions of other genes to control their expression. In the case of Aft6alpha in the heart, it helps mediate repair processes. When Aft6alpha is activated by Thbs4, the endoplasmic reticulum in cells expands and the production of chaperone molecules and other repair proteins is enhanced.

Mice bred not to overexpress cardiac Thbs4 did not exhibit activated Aft6alpha or robust repair processes following cardiac injury, leading to their poor outcomes.

Molkentin said the research team continues to examine the Thbs-dependent stress response pathway to better understand the involved processes. This includes seeing how the pathway affects laboratory models of neurodegenerative diseases like Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis.

Source: Science Daily

June 7, 2012

The Huntington Study Group (HSG), under the leadership of Ray Dorsey, M.D. with Johns Hopkins Medical and Diana Rosas, M.D. with Massachusetts General Hospital, is conducting a clinical trial in Huntington’s disease (HD) throughout the United States and Australia, “A randomized, double-blind, placebo-controlled, study to assess the safety and tolerability, and efficacy of PBT2 in patients with early to mid-stage Huntington’s disease” comparing a 100 mg dose or 250 mg dose versus placebo. The HSG is a not-for-profit group of physicians and other clinical researchers who are experienced in the care of HD patients and dedicated to clinical research of the disease. This trial is sponsored by Prana Biotechnology Limited (Melbourne, Australia) and is being managed by the University of Rochester Medical Center.

Huntington’s disease is an inherited neurodegenerative disease which affects over 30,000 people in both the United States and Australia. HD is characterized by brain cell death that usually begins between the ages of 30 to 50, and results in motor, cognitive and behavioral signs and symptoms. While there are medications to help relieve some of the disease symptoms, there is no known treatment to address the cognitive impairment associated with HD.

Research has shown that normally occurring metals in the brain play a significant role in diseases such as Alzheimer’s disease and more recently, HD. Researchers at Prana Biotechnology are identifying drugs designed to interrupt interactions between these biological metals and target proteins in the brain, to prevent deterioration of brain cells. One of the chemical compounds, called PBT2, has shown in animal models, and as well as in a small group of patients with Alzheimer’s disease, that it may improve cognition. There is some indication in animal models of HD, that the drug may improve motor function and control, increase life span and reduce the amount of brain cell degeneration. Based on these results, Prana is investigating whether the drug will have similar effects with HD patients.

Reach2HD will evaluate how safe and well tolerated PBT2 is at a dose of 100 mg or 250 mg a day compared to a placebo over six months. The trial will also measure whether there is an effect on cognitive abilities as well as other HD symptoms including motor and overall functioning of individuals with HD.

"We are excited to work with Prana to investigate the safety and tolerability of an interesting and innovative experimental treatment for Huntington’s disease, PBT2," said Dorsey. "We have few treatment options for Huntington disease, and none for cognition. We hope this is a step to addressing this large unmet need for patients and their families."

Provided by University of Rochester Medical Center

Source: medicalxpress.com

June 7, 2012

The Allen Institute for Brain Science announced today its latest public data release, enhancing online resources available via the Allen Brain Atlas data portal and expanding its application programming interface (API).

With this release, the Allen Institute has expanded access to its data and services via the Allen Brain Atlas API and added new data and feature enhancements to four atlas resources: the Allen Human Brain Atlas, the Allen Mouse Brain Connectivity Atlas, the Allen Developing Mouse Brain Atlas, and the Allen Mouse Brain Atlas. In addition, two new video tutorials have been added to the Institute’s tutorial library.

The Allen Human Brain Atlas, a multi-modal, three-dimensional map of the human brain that integrates anatomical and gene expression data throughout the adult human brain, has been expanded to include gene expression data from brains of autistic individuals, allowing scientists to compare disease and control states. In addition, the Atlas contains new features to facilitate search, navigation, and download of data.

The Allen Mouse Brain Connectivity Atlas is a three-dimensional, high-resolution map of neural connections throughout the mouse brain. Today’s data release expands the set of available high-resolution images of axonal projections and adds multiplanar viewing capabilities, offering a first step towards three-dimensional visualization of neural connectivity throughout the mouse brain. This foundational map will help scientists understand how the brain is wired, offering new insights into how the brain works and what goes awry in brain diseases and disorders.

Additionally, the Allen Mouse Brain Atlas and the Allen Developing Mouse Brain Atlas have been updated with new search capabilities based on additional data annotation, allowing users to explore the gene expression data in new ways.

Application Programming Interface (API)

To broaden the user community and enable further innovation, the Allen Institute has expanded access to its data and services via the Allen Brain Atlas API, now offering access to data from across the suite of Allen Brain Atlas resources. The Allen Brain Atlas API provides the programming community with under-the-hood access to the Allen Institute’s vast datasets, sample applications and programming solutions for data searches and download, as well as opportunities for discovery and creation of new applications or data representations. This release coincides with the Allen Brain Atlas Hackathon, an elite programming event to be held later this month.

Available data in the Allen Brain Atlas API includes high-resolution images, 3-D expression summaries, primary microarray and RNA-sequencing results, and MRI and DTI files from across the Institute’s suite of atlas resources. Services offered by the Allen Brain Atlas API include RESTful model access to retrieve all experimental information; image download service for all gene expression, connectivity, histology and atlas data; as well as API access to various integrated search services.

Provided by Allen Institute for Brain Science

Source: medicalxpress.com

ScienceDaily (June 7, 2012) — Scientists at the Gladstone Institutes have for the first time transformed skin cells — with a single genetic factor — into cells that develop on their own into an interconnected, functional network of brain cells. The research offers new hope in the fight against many neurological conditions because scientists expect that such a transformation — or reprogramming — of cells may lead to better models for testing drugs for devastating neurodegenerative conditions such as Alzheimer’s disease.

Rendering of neural network. Scientists at the Gladstone Institutes have for the first time transformed skin cells — with a single genetic factor — into cells that develop on their own into an interconnected, functional network of brain cells. (Credit: © nobeastsofierce / Fotolia)

This research comes at a time of renewed focus on Alzheimer’s disease, which currently afflicts 5.4 million people in the United States alone — a figure expected to nearly triple by 2050. Yet there are no approved medications to prevent or reverse the progression of this debilitating disease.

In findings appearing online June 7 in Cell Stem Cell, researchers in the laboratory of Gladstone Investigator Yadong Huang, MD, PhD, describe how they transferred a single gene called Sox2 into both mouse and human skin cells. Within days the skin cells transformed into early-stage brain stem cells, also called induced neural stem cells (iNSCs). These iNSCs began to self-renew, soon maturing into neurons capable of transmitting electrical signals. Within a month, the neurons had developed into neural networks.

"Many drug candidates — especially those developed for neurodegenerative diseases — fail in clinical trials because current models don’t accurately predict the drug’s effects on the human brain," said Dr. Huang, who is also an associate professor of neurology at the University of California, San Francisco (UCSF), with which Gladstone is affiliated. "Human neurons — derived from reengineered skin cells — could help assess the efficacy and safety of these drugs, thereby reducing risks and resources associated with human trials."

Dr. Huang’s findings build on the work of other Gladstone scientists, starting with Gladstone Investigator, Shinya Yamanaka, MD, PhD. In 2007, Dr. Yamanaka used four genetic factors to turn adult human skin cells into cells that act like embryonic stem cells — called induced pluripotent stem cells.

Also known as iPS cells, these cells can become virtually any cell type in the human body — just like embryonic stem cells. Then last year, Gladstone Senior Investigator Sheng Ding, PhD, announced that he had used a combination of small molecules and genetic factors to transform skin cells directly into neural stem cells. Today, Dr. Huang takes a new tack by using one genetic factor — Sox2 — to directly reprogram one cell type into another without reverting to the pluripotent state.

Avoiding the pluripotent state as Drs. Ding and Huang have done is one approach to avoiding the potential danger that “rogue” iPS cells might develop into a tumor if used to replace or repair damaged organs or tissue.

"We wanted to see whether these newly generated neurons could result in tumor growth after transplanting them into mouse brains," said Karen Ring, UCSF Biomedical Sciences graduate student and the paper’s lead author. "Instead we saw the reprogrammed cells integrate into the mouse’s brain — and not a single tumor developed."

This research, which was performed at the Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, has also revealed the precise role of Sox2 as a master regulator that controls the identity of neural stem cells. In the future, Dr. Huang and his team hope to identify similar regulators that guide the development of specific neural progenitors and subtypes of neurons in the brain.

"If we can pinpoint which genes control the development of each neuron type, we can generate them in the petri dish from a single sample of human skin cells," said Dr. Huang. "We could then test drugs that affect different neuron types — such as those involved in Parkinson’s disease — helping us to put drug development for neurodegenerative diseases on the fast track."

Source: Science Daily

ScienceDaily (June 7, 2012) — A study led by Karolinska Institutet in Sweden reports for the first time the positive effects of an active vaccine against Alzheimer’s disease. The new vaccine, CAD106, can prove a breakthrough in the search for a cure for this seriously debilitating dementia disease. The study is published in the scientific journal Lancet Neurology.

A study led by Karolinska Institutet in Sweden reports for the first time the positive effects of an active vaccine against Alzheimer’s disease. (Credit: © Tyler Olson / Fotolia)

Alzheimer’s disease is a complex neurological dementia disease that is the cause of much human suffering and a great cost to society. According to the World Health Organisation, dementia is the fastest growing global health epidemic of our age. The prevailing hypothesis about its cause involves APP (amyloid precursor protein), a protein that resides in the outer membrane of nerve cells and that, instead of being broken down, form a harmful substance called beta-amyloid, which accumulates as plaques and kills brain cells.

There is currently no cure for Alzheimer’s disease, and the medicines in use can only mitigate the symptoms. In the hunt for a cure, scientists are following several avenues of attack, of which vaccination is currently the most popular. The first human vaccination study, which was done almost a decade ago, revealed too many adverse reactions and was discontinued. The vaccine used in that study activated certain white blood cells (T cells), which started to attack the body’s own brain tissue.

The new treatment, which is presented in Lancet Neurology, involves active immunisation, using a type of vaccine designed to trigger the body’s immune defence against beta-amyloid. In this second clinical trial on humans, the vaccine was modified to affect only the harmful beta-amyloid. The researchers found that 80 per cent of the patients involved in the trials developed their own protective antibodies against beta-amyloid without suffering any side-effects over the three years of the study. The researchers believe that this suggests that the CAD106 vaccine is a tolerable treatment for patients with mild to moderate Alzheimer’s. Larger trials must now be conducted to confirm the CAD106 vaccine’s efficacy.

Source: Science Daily

ScienceDaily (June 7, 2012) — Researchers at Columbia University Medical Center (CUMC) have identified a brain receptor that appears to play a central role in regulating appetite. The findings, published June 7 in the online edition of Cell, could lead to new drugs for preventing or treating obesity.

"We’ve identified a receptor that is intimately involved in regulating food intake," said study leader Domenico Accili, MD, professor of Medicine at CUMC. "What is especially encouraging is that this receptor is belongs to a class of receptors that turn out to be good targets for drug development, making it a highly ‘druggable’ target. In fact, several existing medications already seem to interact with this receptor. So, it’s possible that we could have new drugs for obesity sooner rather than later."

In their search for new targets for obesity therapies, scientists have focused on the hypothalamus, a tiny brain structure that regulates appetite. Numerous studies suggest that the regulatory mechanism is concentrated in neurons that express a neuropeptide, or brain modulator, called AgRP. But the specific factors that influence AgRP expression are not known.

The CUMC researchers found new clues to appetite control by tracing the actions of insulin and leptin. Both hormones are involved in maintaining the body’s energy balance, and both are known to inhibit AgRP. “Surprisingly, blocking either the insulin or leptin signaling pathway has little effect on appetite,” says Dr. Accili. “We hypothesized that both pathways have to be blocked simultaneously in order to influence feeding behavior.”

To test their hypothesis, the researchers created a strain of mice whose AgRP neurons lack a protein that is integral to both insulin and leptin signaling. As the researchers hypothesized, removing this protein — Fox01 — had a profound effect on the animals’ appetite. “Mice that lack Fox01 ate less and were leaner than normal mice,” said lead author Hongxia Ren, PhD, associate research scientist in Medicine. “In addition, the Fox01-deficient mice had better glucose balance and leptin and insulin sensitivity — all signs of a healthier metabolism.”

Since Fox01 is a poor drug target, the researchers searched for other ways to inhibit the action of this protein. Using gene-expression profiling, they found a gene that is highly expressed in mice with normal AgRP neurons but is effectively silenced in mice with Fox01-deficient neurons. That gene is Gpr17 (for G-protein coupled receptor 17), which produces a cell-surface receptor called Gpr17.

To confirm that the receptor is involved in appetite control, the researchers injected a Gpr17 activator into normal mice, and their appetite increased. Conversely, when the mice were given a Gpr17 inhibitor, their appetite decreased. Similar injections had no effect on Fox01-deficient mice.

According to Dr. Accili, there are several reasons why Gpr17, which is also found in humans, would be a good target for anti-obesity medications. Since Grp17 is part of the so-called G-protein-coupled receptor family, it is highly druggable. About a third of all existing drugs work through G-protein-coupled receptors. In addition, the receptor is abundant in AgRP neurons but not in other neurons, which should limit unwanted drug side effects.

Source: Science Daily