Tuesday, November 16, 2010

New Data Uncover Common Molecular Pathways Between Rett Syndrome, Autism and Schizophrenia

The laboratory of Huda Zoghbi, where the discovery that mutations in the gene MECP2 cause the severe childhood neurological disorder Rett Syndrome was made, has taken yet another step toward unraveling the complex epigenetic functions of this gene, implicated also in cases of autism, bipolar disease and childhood onset schizophrenia. The November 11 issue of Nature reports that removing MECP2 from a small group of neurons that typically make the inhibitory neurotransmitter, GABA, recapitulates many symptoms of Rett as well as numerous neuropsychiatric disorders.

The identification of the genetic basis of Rett allowed the development of a number of mouse models of the disorder, accurately reproducing the range of symptoms seen in humans. These are considered to be among the best existing models of neurological disease.

While removing MECP2 from every cell results in full-blown Rett symptoms, the Zoghbi lab during the past few years has been using genetic tools to knock out the gene from distinct subsets of specialized brain cells called neurons, in an attempt to correlate certain neuronal populations with specific symptoms.

GABA (gamma amino butyric acid) is the main inhibitory neurotransmitter in the brain. Neurons releasing GABA regulate the nervous system by acting like traffic lights on the brain’s information highway. Zoghbi and Hsiao-Tuan Chao, a postdoctoral fellow in the lab and lead author of the study, use this analogy to describe the action of GABA in allowing for a balanced level of neuronal activity by controlling the strength and timing of information transfer. Surprisingly, Zoghbi, Chao and colleagues found that removing MeCP2 from the small number of GABA-producing neurons reduced production of the neurotransmitter by about 30%. This reduction reproduced many symptoms of Rett including the paw-clasping that mimics the classical hand-wringing stereotypies. After a brief period of apparently normal development, the mice display brain hyperexcitability, impaired respiration, and loss of muscle control and strength and premature lethality. Learning, memory and sensory responses are also altered. Interestingly, the mice engaged in repetitive movements reminiscent of compulsive behavior seen in a number of neuropsychiatric disorders.

The study raises a number of important points. It implicates GABA as a key player in Rett and suggests that boosting the activity of GABA -producing neurons may help to alleviate the severity of some symptoms. It also begs the question: If a 30% reduction in GABA causes Rett symptoms, could a more subtle perturbation of 10% or 20% lead to certain neuropsychiatric disorders? This study suggests a possible pathway which can now be explored to answer the question fully.

“This study revealed to us the critical role of MECP2 in modulating the levels of GABA in inhibitory neurons and pinpointed all the neuropsychiatric symptoms that develop when the function of inhibitory neurons is compromised. Identifying the cellular and chemical basis of such symptoms is a first step in efforts aimed at understanding and, one day, treating such disorders,” said Zoghbi.

Dr. Zoghbi, who was first drawn into Rett research through her clinical experience at Baylor College of Medicine, is a Howard Hughes investigator and a Rett Syndrome Research Trust Scientific Advisor.

Monica Coenraads, Executive Director at the Rett Syndrome Research Trust which helped to fund this work, says “The field of Rett research has benefited incalculably from Huda Zoghbi’s dedication and perseverance. Her latest results suggest that GABAergic pathways are ripe for exploration not only as therapeutic intervention for Rett Syndrome but also for a much wider class of neurological disease.”


About Rett Syndrome
Rett Syndrome strikes little girls almost exclusively, with first symptoms usually appearing before the age of 18 months. These children lose speech, motor control and functional hand use, and many suffer from seizures, orthopedic and severe digestive problems, breathing and other autonomic impairments. Although some victims of Rett Syndrome do not survive childhood, most live to become adults who require total, round-the-clock care.

About Rett Syndrome Research Trust
The Rett Syndrome Research Trust is the premier organization devoted exclusively to promoting international research on Rett Syndrome and related MECP2 disorders. The goal is clear: to heal children and adults who will otherwise suffer from this disorder for the rest of their lives. With experience and tight focus, RSRT has an unparalleled knowledge base and extensive networking abilities in the world of high level research. RSRT is in a unique position to stimulate, evaluate, support and monitor ambitious and novel scientific projects. www.reverserett.org

About Baylor College of Medicine
Baylor College of Medicine in Houston is recognized as a premier academic health science center and is known for excellence in education, research and patient care. It is the only private medical school in the greater southwest and is ranked as one of the top 25 medical schools for research in U.S. News & World Report. BCM is listed 13th among all U.S. medical schools for National Institutes of Health funding, and No. 2 in the nation in federal funding for research and development in the biological sciences at universities and colleges by the National Science Foundation. Located in the Texas Medical Center, BCM has affiliations with eight teaching hospitals, each known for medical excellence. Currently, BCM trains more than 3,000 medical, graduate, nurse anesthesia, and physician assistant students, as well as residents and post-doctoral fellows. BCM is also home to the Baylor Clinic, an adult clinical practice that includes advanced technologies for faster, more accurate diagnosis and treatment, access to the latest clinical trials and discoveries, and groundbreaking healthcare based on proven research.

Source: Rett Syndrome Research Trust

Contact Person:
Monica Coenraads
Executive Director, RSRT
monica@rsrt.org
203.445.0041

PTC Therapeutics: Development of treatment for Genetic Disorder

PTC applies its expertise in RNA biology and drug development to pioneer novel oral treatments for patients living with serious and life-threatening conditions.

Ataluren for Genetic Disorders

Ataluren (PTC124®) is an investigational drug designed to enable the formation of a functioning protein in patients with genetic disorders due to a nonsense mutation.

A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. Ataluren is currently being investigated for use in patients with nonsense mutation cystic fibrosis (nmCF), nonsense mutation hemophilia A & B (nmHA/B) and nonsense mutation methylmalonic acidemia (nmMMA) .


Click here to read Frequently Asked Questions about ataluren.


Translation of an mRNA into protein

Mechanism of Action
In healthy individuals, ribosomes translate the informational code in the mRNA into protein until arriving at a normal stop signal in the mRNA, at which point the ribosome appropriately stops translation and a functioning protein results.

Nonsense mutations, however, create a premature stop signal in the mRNA. This premature stop signal causes the ribosome to halt translation before a functioning protein is generated, creating a shortened, nonfunctioning protein. The resulting disease is determined by which protein cannot be expressed in its entirety and is no longer functional (eg, the CFTR protein in nmCF. the Factor VIII/Factor IX protein in nmHA/B or the dystrophin protein in nmDBMD ).

Ataluren is designed to allow the ribosome to ignore the premature stop signal and continue translation of the mRNA, resulting in formation of a functioning protein. Ataluren does not cause the ribosomes to read through the normal stop signal.

Ataluren, taken orally, has the potential to address the underlying cause of the disease by overriding the premature stop signal, enabling the synthesis of a functioning protein. Ataluren does not alter the patient’s genetic code or introduce genetic materials into the body.

Nonsense Mutation Genetic Disorders
The National Institutes of Health (NIH) Office of Rare Diseases estimated that rare diseases affect 25 million people in the US and that the majority of these people have genetic disorders. In more than 2,400 genetic disorders, a nonsense mutation causes the disease in an average of 5 to 15% of the patients. Besides nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD), nonsense mutation cystic fibrosis (nmCF), nonsense mutation hemophilia A & B (nmHA/B) and nonsense mutation methylmalonic acidemia (nmMMA), these genetic disorders include a range of serious diseases across multiple therapeutic areas including, spinal muscular atrophy, lysosomal storage disorders, and some forms of cancer.


PTC124 Targets Genetic Disorders Caused by Nonsense Mutations


(Click the link above to read the article)

Genetic Testing
Ataluren has the potential to treat any genetic disorder caused by a nonsense mutation. Although current clinical trials involve only nonsense mutation CF and nonsense mutation HA/B, future trials are anticipated in other genetic disorders caused by a nonsense mutation. To determine whether a genetic disorder is caused by a nonsense mutation, patients require genetic testing. Genetic testing is done by a simple blood test that is ordered by a physician working in concert with a genetic lab.

Laboratories performing genetic testing vary by disorder and location. The NIH-funded website, www.genetest.org provides a listing of laboratories and contact information.

Ongoing Clinical Trials

* nmCF: PTC has initiated a longer-term, Phase 3 clinical study of ataluren in patients with nonsense mutation CF. The main goals of this study are to understand whether ataluren can improve how nmCF patients feel and function and whether the drug can safely be given over a long period. The trial is a multi-center, randomized, double-blind, placebo-controlled study.
* nmHA/B: PTC has initiated a Phase 2a clinical trial of ataluren in patients with nonsense mutation hemophilia type A and B (nmHA and nmHB). The trial is a multi-center, open label, dose escalation study. The main goals of the trial are to determine whether treatment with ataluren can result in an increase in Factor VIII or IX levels and whether the drug can safely be given to people with severe hemophilia due to a nonsense mutation.
* nmMMA: PTC has initiated a Phase 2 clinical trial of ataluren in patients with nonsense mutation methylmalonic acidemia (nmMMA). The trial is a non-randomized, open-label trial. Its main goals are to understand whether ataluren can be tolerated and can decrease MMacid levels.

Completed Clinical Trials

*

Phase 2b Data nonsense mutation DBMD (nmDBMD): Final analyses of Phase 2b efficacy data suggest the investigational new drug ataluren slowed the loss of walking ability in patients. The primary endpoint of the Phase 2b trial was the change in 6-minute walk distance (6MWD) from baseline to 48 weeks. The data showed a 29.7 meter (approximately 97 feet) difference in the average change in 6MWD when comparing the ataluren (10-, 10-, 20-mg/kg) and placebo arms. This result is consistent with the study hypothesis of a 30-meter difference and the average change in 6MWD observed in registration-directed trials of approved drugs for other diseases.

* Phase 2a Data nonsense mutation DBMD (nmDBMD): Data from Phase 2a clinical trials of ataluren in pediatric patients with nmDBMD show that administration of ataluren is associated with production of functional dystrophin. Ataluren treatment has also been associated with statistically significant reductions in the leakage of muscle-derived creatine kinase into the blood.
* Phase 2a Data nonsense mutation CF (nmCF): Data from Phase 2a clinical trials of ataluren in pediatric and adult patients with nmCF show that administration of ataluren results in production of functional CFTR and statistically significant improvements in CFTR chloride channel function in the airways. Ataluren treatment was associated with reductions in cough frequency and improvements in pulmonary function tests.
* Adverse Events and Safety Profile: Across all clinical studies to date, including Phase 1 healthy-volunteer studies, ataluren has been generally well tolerated. Mean compliance has been >90% in all studies.

Grants
The development of ataluren has also been supported by grants from:

* Cystic Fibrosis Foundation
* Parent Project Muscular Dystrophy
* Muscular Dystrophy Association
* FDA’s Office of Orphan Products Development
*
National Center for Research Resources
* National Heart, Lung, and Blood Institute

The FDA has granted PTC124® (ataluren) Subpart E designation for expedited development, evaluation, and marketing and has granted Orphan Drug designations for the treatment of CF and DBMD due to nonsense mutations. PTC124® (ataluren) has also been granted orphan drug status for the treatment of CF and DBMD by the European Commission.

Partnership with Genzyme
PTC Therapeutics, Inc. and Genzyme Corporation have an exclusive collaboration to develop and commercialize ataluren. PTC will commercialize ataluren in the United States and Canada and Genzyme will commercialize ataluren in all other countries.

To receive status updates on ataluren, please visit the Contact Us page of the website and join our mailing list.

Patients, families and advocacy groups may also contact Ms. Diane Goetz, Director, Patient and Professional Relations, 866-282-5873 or 908-912-9256 or patientinfo@ptcbio.com.

Source: PTC Therapeutics

Note: Click the title to read more about PTC therapeutics and its developments.

RETT SYNDROME IN A PETRI DISH: Rett Syndrome Research trust Interview series

On November 11th the high-profile journal Cell published a paper by Alysson Muotri, Ph.D. entitled A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells. The stem cell field has seen amazing progress in the last few years. Induced Pluripotent Stem Cells (iPS cells) is an especially hot area because of the clinical implications. Simply put, iPS cells allow you to study diseased cells up close and personal through their entire lifecycle. Importantly, any deficits that are identified in the cells can be used as read-outs in drug screening endeavors.

Interviewed by Monica Coenraads
(Co-Founder, Trustee, Executive Director of RSRT)

I’ve had the pleasure of knowing Dr. Muotri for a number of years, in fact since his introduction to Rett about six years ago. He became interested in the disorder while doing his post-doc in the lab of Fred (Rusty) Gage at the Salk Institute in La Jolla, CA. Thankfully his interest has continued now that he is an independent investigator at UCSD.

Below is an excerpt from a conversation Dr. Muotri and Monica Coenraads had regarding his paper.

MC Dr. Muotri, congratulations on your Cell paper which has strong implications for drug development and therefore is of interest to anyone who loves a child with Rett Syndrome. I know this is a very hectic time so thank you for taking time out to speak with me.

I’m curious, what drew you to a science career?

AM I’ve always been interested in understanding how things work. I reasoned that science was the most obvious way to achieve that. You know that I’m from Brazil. I received my PhD in genetics from the University of São Paulo. I started off in the cancer biology field but quickly switched to neuroscience in 2002 when I moved to the Salk Institute. I was there for 6 years until I got my current position here at UCSD two years ago.

MC I’m assuming it was a significant switch moving into neuroscience from cancer biology.

AM Yes, it was a bit intimidating in the beginning because there was so much to learn. But I welcomed the challenge. And as it turned out my experiences from cancer were beneficial for my transition into neuroscience. For example, when I moved to Rusty’s lab one of the first observations we made was related to a phenomenon called transposons. I knew from my previous work that retrotransposons are very active in cancer cells and I remember discussing this with my neuroscience colleagues. Most of them were not very familiar with this phenomenon and assumed it was insignificant. My feeling was that if these transpositions were really happening in the brain it would be better to look at it closely because it could be involved in a new mechanism related to brain development.

MC Since retrotransposons are actually the topic of your next Rett paper coming out in Nature soon let me take a moment to give our readers a little background information.

Retrotransposons are sequences of DNA that move around and insert themselves into new positions within the genome. Barbara McClintock received the Nobel Prize in 1983 for her discovery of this phenomenon. Historically retrotransposons have been considered “junk DNA” because they occupy around 50% of the mammalian genome and do not have a clear function in the cell. It’s probably more likely that transposons have a biological function which remains, for the moment, unknown to us. Retrotransposons have been linked to disease.

Dr. Muotri, would you like to give us a glimpse into your upcoming paper that deals with retrotransposons in Rett Syndrome?

AM So the idea is that retrotransposons , which jump around inserting themselves into the genome, result in neurons, in the same individual, which are genetically different from each other. We observed that MECP2, the gene involved in Rett Syndrome, is a major repressor of this activity. Also, we determined that these jumping events are pretty much exclusive to the brain and MECP2 seems to be one of the gate keepers controlling the amount of the activity.

MC So in a brain that is deficient in the MeCP2 protein there would be increased jumping events?

AM That is right. It remains to be seen whether these extra events contribute to the symptoms of Rett or whether the brain simply compensates and manages to work around them. We are working on this question now.

MC Fascinating. I look forward to continuing our dialogue on this subject as your research progresses. Two high profile papers in one month – very impressive.

Now, getting back to iPS. This is a field that has seen amazing advances in a short period of time. Can you highlight for our readers the excitement surrounding these cells?

AM The dream of neuroscientists is to understand the early stages of a neurological disorder. Until recently we had two options to achieve this. One is to develop a mouse model that will hopefully recapitulate the symptoms seen in humans. Of course a limitation of a mouse model is that it’s a mouse and not a human – the brain of a human is so much more complex. The other option is post-mortem brain tissue. The problem is that at that stage the damage is already done and what you see is the end stage of a disease. To really study a disease it’s beneficial to have the most primitive cell line possible and then to coax these cells into a variety of different cell populations and to study what happens at various time points.

An important breakthrough happened a few years ago that has made this type of work very feasible. The Japanese group headed by Shinya Yamanaka surprised the world when they showed that you can reprogram cells that have already differentiated back to a more naïve state resembling a human embryonic stem cell. This allows us to capture the genome of a person, including any genetic mutations, and allows us to study the neurons and other cells of interest and see how a disease progresses and what changes happen at the molecular level.

MC In general the Rett field has relied on the mouse models as their standard assay. In terms of drug screening that’s a very expensive assay. Having iPS lines with MECP2 mutations gives scientists the ability to have a cellular assay to screen for therapeutics. Thousands, and in fact, hundreds of thousands of compounds can be efficiently and quickly screened in cell lines using either low or high throughput technologies.

Can you tell us about the phenotypes that you have identified in the cells. (a phenotype is an observable characteristic or trait)

AM One of the phenotypes was related to cell soma size (cell body) of a neuron. Just looking at neurons under the microscope we saw that Rett neurons are reduced in size by 10%. That might not seem like a big deal but when you consider the 3 dimensional structure of the neuron; a 10% reduction is very significant. So size was the simplest read-out that we found.

Another phenotype is related to the morphology of neurons. (Morphology is the study of the structure and form of an organism.) The idea to look at morphology was inspired by the reports over the last decade from post-mortem brain tissue in both people and animal models. We focused on the number of spine densities in neurons and we also saw a reduction. (A dendritic spine, or simply spine, is a small membranous protrusion from a neuron’s dendrite that typically receives input from a synapse.) We looked at neuronal networks and found deficiencies in their ability to communicate.

MC You made iPS cells with different MECP2 mutations. You found that the phenotypes were consistent among mutations. Can you elaborate?

AM Yes, the four different mutations we studied led to similar phenotypes. At least the phenotypes we looked at. We were convinced that this was a strong suggestion pointing to a loss of MeCP2 function. Thus, we knocked down MeCP2 expression from control neurons and obtained the same result. We then, restored the normal MeCP2 gene in Rett neurons, suppressing the phenotypes. In combination, these experiments suggest that MeCP2 is responsible for the alterations in Rett neurons. The fact that several MeCP2 mutants revealed a similar phenotype has clinical relevancy because it may indicate that a single drug may correct them all.

MC So the goal is to use these cells as a platform for drug screening.

AM Absolutely. As a proof of principle we added a growth factor, IGF1, to the cells. As you know a paper was published in PNAS in early 2009 showing that a compound similar to IGF1 improved some of the symptoms in mice so we decided to try it in our system. We found that IGF1 corrected the phenotype, in fact it over-corrected. The over-correction is something that needs to be considered in terms of the clinical trial, a proper dose tuning in each patient is desirable. Also, something to keep in mind is that while I put IGF1 directly into the cells in the clinical trial the IGF1 has to get into the brain and we know that that doesn’t happen as much as we would like.

The other drug we tried is gentamicin , an antibiotic that has the ability to “read through” premature stop codons (nonsense mutations that end in X, such as 255X, 168X) . We found that gentamicin restored levels of the MeCP2 and phenotypically rescued the cells.

MC That is pretty interesting especially in light of the fact that read through drugs act by substituting the stop codon with a random amino acid. So in effect they swap out one mutation for another.

AM We checked that and found that the protein level was normal but there was no way for us to see what mutation was inserted. Part of the new protein that is synthesized in the presence of gentamicin, is probably correct and we believe that is exactly what is reverting the phenotypes.

MC It’s important to note that gentamicin is highly toxic and doesn’t cross the blood brain barrier very well either so this is not a drug that can be used now for the treatment of Rett Syndrome. There are however other drugs with similar modes of action that being tested in animal models.

But the take home message from your data is that iPS cell lines are an in vitro model system for Rett Syndrome and can be utilized in a drug screening platform. What are next steps to utilize the iPS lines as a platform for drug screening?

AM The next step is to scale this up and that is not easy to do. Because the experiments are very sensitive to variables and there are many steps during the conversion of the iPS cells to neurons. Thus, we need to systematically validate all the variables and make the system as robust as possible. Finally, we need to choose the appropriate read-outs (the cellular phenotypes) we would like to use. It is important to design these experiments carefully so one doesn’t lose time with false positives. My lab was recently awarded a CIRM grant (California Institute for Regenerative Medicine) exactly to optimize these steps, so I would like to start this as soon as possible. Finally, I would like to test libraries of drugs that previously failed clinical trials for other diseases. Drug repositioning, as this concept is called, is attractive because repurposed drugs can bypass much of the early cost and time needed to bring a drug to market.

MC I found your paper very encouraging for a number of reasons. Firstly, your data continues to confirm and validate the concept that Rett is reversible. Secondly, you showed that the iPS platform can be used for drug screening. Thirdly, your data suggests that while there may be many mutations in MECP2, they may share common phenotypes. That may be an important issue in terms of treatment strategies.

Dr. Muotri, I’m sure I speak for every Rett family who reads this interview … we wish you great luck and god speed in your work.

Source: Rett Syndrome Research Trust (RSRT)

Note: Click on the title the full interview and video

Monday, November 15, 2010

Women of the year 2010: Julia Roberts

Julia Roberts: The Class Act

She is a Woman of the Year because: “There are not a lot of people who can do everything she does, and be brilliant, and be gorgeous, and raise all those children. Formidable, my dear. Bravo.”
—Joanne Woodward, actress

November 1, 2010
by Susan Dominus

You have to admire that Julia Roberts arrives at an interview in the kind of standard-issue black pants that mothers rely on when they want to look presentable. Wearing the barest hint of makeup, she’s soon chatting about the challenge of running a house with three kids—six-year-old twins Hazel and Phinnaeus, and three-year-old Henry. “Trust me,” she confides, “some weeks are cleaner than other weeks.”

Not that she’s had much time lately to worry about the housecleaning. Her 2010 has been huge. She’s graced countless magazine covers and TV shows on behalf of her blockbuster Eat, Pray, Love; she produced a documentary on the power of motherhood that will air on Oprah’s OWN network in January; and she filmed her next sure-to-be hit, Larry Crowne, with pal Tom Hanks.

Despite her successes, though, Roberts says, “It’s all about the home.” Turns out one of the world’s biggest female movie stars (collective box office: more than $2 billion) is an eco-sensitive earth mother who composts and drives a tractor at her New Mexico ranch. At 43, the Oscar winner chooses roles that allow her to spend quality time with her family—proof, as she’s said, that “becoming famous doesn’t make you crazy.” Once called the Hillary of Hollywood for her trailblazing—she was the first actress to get more than $20 million for a film—Roberts has used that money and clout for good. Since 1997 she’s supported Paul Newman’s Hole in the Wall Gang camp for children with grave illnesses. She also campaigns to fund research for Rett Syndrome (a neurodevelopmental disorder that can destroy kids’ ability to walk and speak) and serves on the board of Earth Biofuels, which promotes renewable energy.

But it’s Roberts’ unique, lit-from-within quality that’s made her everyone’s favorite screen icon. In the words of Eat, Pray, Love author Elizabeth Gilbert, “The only other job she could have would be professional fairy.” Well, she did once play Tinkerbell.

Source: Glamour

Inhibitory neurons key to understanding neuropsychiatric disorders

HOUSTON -- (Nov. 11, 2010) – The brain works because 100 billion of its special nerve cells called neurons regulate trillions of connections that carry and process information. The behavior of each neuron is precisely determined by the proper function of many genes.

In 1999, Baylor College of Medicine (www.bcm.edu) researcher Dr. Huda Zoghbi (http://www.bcm.edu/genetics/index.cfm?pmid=11053), and her colleagues identified mutations in one of these genes called MECP2 as the culprit in a devastating neurological disorder called Rett syndrome (http://www.nichd.nih.gov/health/topics/rett_syndrome.cfm). In new research in mice published in the current issue of the journal Nature (www.nature.com), Zoghbi and her colleagues demonstrate that the loss of the protein MeCP2 in a special group of inhibitory nerve cells in the brain reproduces nearly all Rett syndrome features.

Children, mostly girls, born with Rett syndrome, appear normal at first, but stop or slow intellectual and motor development between three months and three years of age, losing speech, developing learning and gait problems. Some of their symptoms resemble those of autism.

These inhibitory (gamma-amino-butyric-acid [GABA]-ergic) neurons make up only 15 to 20 percent of the total number of neurons in the brain. Loss of MeCP2 causes a 30 to 40 percent reduction in the amount of GABA, the specific signaling chemical made by these neurons. This loss impairs how these neurons communicate with other neurons in the brain. These inhibitory neurons keep the brakes on the communication system, enabling proper transfer of information.

"In effect, the lack of MeCP2 impairs the GABAergic neurons that are key regulators governing the transfer of information in the brain", said Dr. Hsiao-Tuan Chao (http://www.bcm.edu/labs/zoghbi/Lab_members_info/chao.html), an M.D./Ph.D student in Zoghbi's laboratory and first author of the report.

Chao made the discovery by developing a powerful new tool or mouse model that allowed researchers to remove MeCP2 from only the GABAergic neurons.

"We did this study thinking that perhaps all we would see was a few symptoms of Rett syndrome," said Chao. "Strikingly, we saw that removing MeCP2 solely from GABAergic neurons reproduced almost all the features of Rett syndrome, including cognitive deficits, breathing difficulties, compulsive behavior, and repetitive stereotyped movements. The study tells us that MeCP2 is a key protein for the function of these neurons."

Once the authors determined that the key problem rested with the GABAergic neurons, they sought to find out how the lack of MeCP2 disturbed the function of these neurons. Chao discovered that losing MeCP2 caused the GABAergic neurons to release less of the neurotransmitter, GABA. This occurs because losing MeCP2 reduces the amount of the enzymes required for the production of GABA.

Intriguingly, prior studies showed that expression of these enzymes is also reduced in some patients with autism, schizophrenia and bipolar disorder, said Chao.

"This tells us a lot about what is going on in the brains of people with Rett syndrome, autism or even schizophrenia," said Chao. "A child is born healthy. She starts to grow and then begins to lose developmental milestones. Communication between neurons is impaired, in part due to reduced signals from GABAergic neurons."

"This study taught us that an alteration in the signal from GABAergic neurons is sufficient to produce features of autism and other neuropsychiatric disorders," said Zoghbi, a Howard Hughes Medical Institute investigator and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

###

Others who took part in this work include Hongmei Chen, Rodney C. Samaco, Mingshan Xue, Maria Chahrour, Jong Yoo, Jeffrey L. Neul, Hui-Chen Lu, Jeffrey L. Noebels and Christian Rosenmund, all of BCM, John L.R. Rubenstein of University of Calfornia in San Francisco, Marc Ekker of University of Ottawa in Ontario, and Shiaoching Gong and Nathaniel Heintz of The Rockefeller University in New York.

Funding for this work came from the Howard Hughes Medical Institute, the National Institute of Neurological Disorders and Stroke, the Simons Foundation, the Rett Syndrome Research Trust, the Intellectual and Developmental Disability Research Centers, the International Rett Syndrome Foundation, Autism Speaks, the National Institute of Mental Health, Baylor Research Advocates for Student Scientists and McNair Fellowships.

When the embargo lifts, this report will be available at www.nature.com.

For more information on basic science research at Baylor College of Medicine, please go to www.bcm.edu/news.

Source: EurekaAlert

Thursday, November 11, 2010

Website of Indian Rett Syndrome Foundation

The Website of Indian Rett syndrome Foundation was launched by Major General Ian Cardozo, Chairman of Rehabilitation Council of India and Mrs. Poonam Natrajan, Chairperson, National Trust of India in the 3rd Annual Rett Syndrome Awareness meeting, which was organized by Indian Rett Syndrome foundation and was hosted by Department of Pediatrics, AIIMS, New Delhi on 31st October, 2010.

Please click on the link or copy and paste the following link to visit the website of "Indian Rett Syndrome Foundation". You can also click on the title above to visit the site.

http://www.rettsyndrome.in/


Indian Rett Syndrome Foundation