Rett Syndrome Research Trust Advisor Makes Significant Discovery with Potential for Novel Therapeutic Approaches

Trumbull, CT (PRWEB) February 23, 2009

A paper published online today in Nature Neuroscience reveals the presence of methyl CpG binding protein 2 (MeCP2) in glia. MeCP2 is a protein associated with a variety of neurological disorders, including Rett Syndrome, the most physically disabling of the autism spectrum disorders. The researchers show that MeCP2-deficient astrocytes (a subset of glia) stunt the growth of neighboring neurons. Remarkably, these neurons can recover when exposed to normal glia in culture.

The discovery was made by Gail Mandel, Ph.D. of the Vollum Institute at Oregon Health and Science University and a Howard Hughes Medical Institute investigator and Nurit Ballas, Ph.D., a research associate, at the time, in the Mandel lab at the State University of New York at Stony Brook. Dr. Mandel is a scientific advisor of the Rett Syndrome Research Trust (RSRT) a recently formed nonprofit organization intensively focused on the development of treatments and cures for Rett Syndrome and related MECP2 disorders.

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. Most live into adulthood, and require total, round the clock care. Individuals with Rett and their families suffer the emotional and financial cost of the wide range of symptoms and the ongoing struggles to address them.

Glial cells, which reside throughout the nervous system, comprise the vast majority (90%) of cells in the brain. Glia support and interact with neurons in innumerable ways, from providing the structural underpinnings and guidance of axons and dendrites (the neuronal processes that carry information), to creating protective insulation for axons. These and other glial functions are essential to the health of neurons.

Since MECP2 is located on the X chromosome, girls with Rett Syndrome are mosaic: cells with a healthy copy of the gene lie side by side with cells that have the mutated version. Mandel and colleagues found that MECP2- deficient astrocytes could not sustain normal neuronal growth. In fact, their experiments suggest that MeCP2-deficient astrocytes secrete a toxic factor that impacts the entire neighborhood of neurons, including neurons with wildtype (normal) MECP2.

Conversely, they found that wildtype astrocytes could restore the stunted growth of MeCP2-deficient neurons. This finding supports the 2007 Science publication by Professor Adrian Bird showing reversal of Rett symptoms in adult mouse models of the disorder. Results from ongoing in vivo mouse studies deleting MeCP2 in glia are promising in terms of supporting the culture studies.

“This new study adds to the growing body of evidence that glial cells are critically important contributors to neurological diseases and therefore attractive targets for drug development,” said Ben Barres, Professor and Chair of the Department of Neurobiology at Stanford University and a glial cell expert.

Recent studies from multiple groups, including the lab of Dr. Tom Maniatis, a neurodegenerative disease researcher at Harvard University, have implicated glia in Lou Gehrig’s disease (Amyotrophic Lateral Sclerosis – ALS), a devastating neurodegenerative disorder that leads to the death of motor neurons and total paralysis. “In Rett Syndrome, faulty glia seem to poison neurons, inhibiting growth; in ALS glia appear to release a toxic factor that kills motor neurons.” Maniatis stated that “studies of the role of glia in a broad spectrum of neuronal diseases should lead to exciting advances in understanding disease mechanisms.”

“Dr. Mandel’s sharp insights have given the scientific community an entirely new way to think about treating Rett Syndrome. One could envision a scenario where halting the secretion of this potential toxic factor could restore health, in particular to the MECP2 positive neurons, which could bring about amelioration of symptoms. I look forward to her lab’s continued contributions as we explore the therapeutic implications of her research,” comments Monica Coenraads, Executive Director of RSRT and parent of a child with the disorder.

Other people who worked on the project include Daniel T. Lioy of the Vollum Institute and Christopher Grunseich, M.D. while at the State University of New York at Stony Brook. Nurit Ballas is now a Research Associate Professor in the Department of Biochemistry and Cell Biology at Stony Brook.

For more information on Rett Syndrome and MECP2 spectrum disorders please visit the website of the Rett Syndrome Research Trust at http://www.rsrt.org.

For an in-depth interview with Gail Mandel please visit the RSRT Blog, http://rettsyndrome.wordpress.com/.

This project was funded in part by the NIH, HHMI and IRSF.

About Rett Syndrome Research Trust

The Rett Syndrome Research Trust is a nonprofit research organization formed in the wake of the dramatic pre-clinical reversal of Rett Syndrome symptoms. The Trust is intensively focused on the development of treatments and cures for Rett Syndrome and related MECP2 disorders. Our short-term goal is to deliver clinical trials of a novel treatment strategy within five years. The strength of the Trust is based on the guidance of advisors who are largely responsible for the major advances in Rett research over the past decade. To learn more about the Trust please visit http://www.rsrt.org.

About OHSU

Oregon Health & Science University is the state’s only health and research university, and Oregon’s only academic health center. OHSU is Portland’s largest employer and the fourth largest in Oregon (excluding government), with 12,400 employees. OHSU’s size contributes to its ability to provide many services and community support activities not found anywhere else in the state. It serves patients from every corner of the state, and is a conduit for learning for more than 3,400 students and trainees. OHSU is the source of more than 200 community outreach programs that bring health and education services to every county in the state.

About Stony Brook University

Part of the State University of New York system, Stony Brook University encompasses 200 buildings on 1,600 acres. In the 50 years since its founding, the University has grown tremendously, now with nearly 24,000 students and 2,100 faculty, and is recognized as one of the nation’s important centers of learning and scholarship. It is a member of the prestigious Association of American Universities, and ranks among the top 100 national universities in America and among the top 50 public national universities in the country according to the 2008 U.S. News & World Report survey. Considered one of the “flagship” campuses in the SUNY system, Stony Brook University is a driving force of the Long Island economy, with an annual economic impact of $ 4.65 billion, generating nearly 60,000 jobs. Stony Brook accounts for nearly 4% of all economic activity in Nassau and Suffolk counties, and roughly 7.5 percent of total jobs in Suffolk County.

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Rett Syndrome Research Trust Advisor Makes Significant Discovery with Potential for Novel Therapeutic Approaches

MeCP2 Goes Global Redefining the Function of the Rett Syndrome Protein

Trumbull, CT (PRWEB) February 26, 2010

A paper published online today in Molecular Cell proposes that Methyl CpG binding protein 2 (MeCP2) impacts the entire genome in neurons, rather than acting as a regulator of specific genes. Mutations in MeCP2 cause the autism spectrum disorder Rett Syndrome as well as some cases of neuropsychiatric problems including autism, schizophrenia and learning disabilities.

The discovery of MeCP2s global reach was made in the laboratory of Adrian Bird, Ph.D. of the University of Edinburgh. Birds seminal contributions in the Rett Syndrome field include cloning the MeCP2 protein in the early 1990s and the dramatic reversal of severe symptoms in fully mature mice models of the disease published in Science in 2007. He is a Trustee and Scientific Advisor of the Rett Syndrome Research Trust, a nonprofit organization intensively focused on the development of treatments and cures for Rett Syndrome and related MECP2 disorders.

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. Most live into adulthood, and require total, round-the-clock care.

Historically, MeCP2 has been viewed as a classic transcription factor, but Birds data establishes MeCP2 as one of the most abundant neuronal nuclear proteins, with levels 100 to 1,000 times higher than typical transcription factors. In fact, there are nearly as many molecules of MeCP2 in the nucleus as there are nucleosomes, the fundamental repeating structural units of chromatin which in turn make up chromosomes. To put this in perspective, there is enough MeCP2 to cover nearly the entire genome.

Peter Skene, a post-doctoral fellow in the Bird lab and first author of the paper confirmed via chromatin immunoprecipitation and high throughput sequencing that this huge abundance of MeCP2 meticulously tracks the DNA methylation pattern of the cell. As a result, Skene observed that most regions of the genome bind to MeCP2, calling into question the previously assigned role of this protein as a target-specific transcription factor. This may explain why few clear gene targets for MeCP2 have been identified in the last decade.

The brain contains many types of neurons with different functions, but interestingly it appears that the pattern of MeCP2 binding to chromosomes is broadly similar in all of them. This raises the possibility that the neuronal defect brought about by mutations in this gene affect all neurons in a similar way. If there really is a generic defect shared by many neurons, then the causes of Rett Syndrome may be less complicated than we feared. This idea now needs to be tested by further work, said Professor Bird.

In line with its genome-wide distribution, the scientists found that MeCP2 globally impacts the packaging of the DNA in the cell. Histones are proteins which act as spools around which DNA is wound. This winding, or compaction, allows the 1.8 meters of DNA material to fit inside each of our cells. There are two classes of histones core histones and linker histones. Core histones form the spool around which DNA winds – resembling beads on a string. The linker histones, such as histone H1, seal the DNA onto the spool formed by the core histones. In this way linker histones act as a padlock to hold the DNA in this structure and stop inappropriate access to the DNA outside of genes. In the absence of MeCP2, the amount of linker histone H1 doubles, suggesting an attempt to compensate for the lack of MeCP2.

The Bird lab also found an increase in histone acetylation in MeCP2-deficient neurons, but not in glia. These chemical modifications lead to an unwinding of the chromatin spools and potentially leave the DNA open for inappropriate expression. This suggests that the role of MeCP2 is to globally suppress the genome.

Consistent with MeCP2 coating the entire genome, we observed global changes in the chromatin composition and activity. In the absence of MeCP2, we discovered an increase in the spurious transcription of the so-called junk DNA which lies between genes. This suggests to us that rather than targeting specific genes, MeCP2 functions on a genome-wide level and may act as the watchdog of the neuronal genome, said Skene.

RSRT is pursuing two parallel approaches to interventions for Rett Syndrome. One is to find assays for MeCP2 function and then screen for anything that fixes the defect. The other is to understand as much as possible about what MeCP2 does in the brain and then design rational treatments. Understanding that MeCP2 acts in a global manner rather than as a gene-specific regulator gives us a new perspective on the molecular basis of Rett Syndrome that will aid in guiding drug development and other treatment modalities, comments Monica Coenraads, Executive Director of RSRT and parent of a child with the disorder.

For an in-depth interview with Adrian Bird please visit the RSRT Blog, http://rettsyndrome.wordpress.com/

About Rett Syndrome Research Trust

The Rett Syndrome Research Trust is a nonprofit research organization formed in the wake of the dramatic pre-clinical reversal of Rett Syndrome symptoms. The Trust is intensively focused on the development of treatments and cures for Rett Syndrome and related MECP2 disorders. Our short-term goal is to deliver clinical trials of a novel treatment strategy within five years. The strength of the Trust is based on the guidance of advisors who are largely responsible for the major advances in Rett research over the past decade. To learn more about the Trust please visit http://www.reverserett.org

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MeCP2 Goes Global Redefining the Function of the Rett Syndrome Protein