(Press-News.org) CAMBRIDGE, Mass. (October 3, 2013) – Whitehead Institute researchers have redefined the function of a gene whose mutation causes Rett syndrome, a neurodevelopmental autism spectrum disorder. This new research offers an improved understanding of the defects found in the neurons of Rett syndrome patients and could lead to novel therapies for the disease.
"The action of the MECP2 protein is just the opposite of how it was held for the past 15 years," says Whitehead Founding Member Rudolf Jaenisch, who is also a professor of biology at MIT. "It was thought that this protein globally repressed the expression of methylated DNA. What this work shows is when you do the analysis in a way that takes cell size into account—cell size is very different in Rett neurons compared to wild type—then suddenly we can see that the protein acts like a global activator. We've defined the function of MECP2 in a totally different way."
Rett syndrome is an X-linked genetic disease affecting one in 10,000 newborn girls. Infants with the disease appear to develop normally for their first six to 18 months, at which point their movement and language skills begin to deteriorate. Loss of speech, reduced head size, breathing and heart rhythm irregularities, and autistic-like symptoms are common by age four. Some symptoms may be treated with prescription drugs, but no cure or disease-modifying therapy exists. Previous work by the Jaenisch lab has provided some hope for the families of Rett patients. In a mouse model lacking the MECP2 gene, which is mutated in approximately 95% of girls with Rett syndrome, mice injected with the protein IGF-1 had more regular breathing and heart rhythms than did untreated mice. In addition, the brains of treated mice had greater mass and more of the vital neuronal projections that are missing in Rett syndrome mice and human patients.
In the current research, Yun Li, a postdoctoral researcher in the Jaenisch lab, analyzed the global gene expression of MECP2-deficient neurons derived from human embryonic stem cells. Unlike earlier research, Li took into account the Rett neurons' smaller size when comparing their gene expression to neurons with intact MECP2. The Rett neurons had decreased mRNA transcription, reduced protein synthesis, and severe defects in the AKT/mTOR signaling pathway, which is activated by IGF-1. Li's work is published in the October 2nd issue of Cell Stem Cell.
"We have always found it strange that MECP2 mutant mice, which share many of the severe neurological problems as really sick kids with Rett syndrome, have very few transcriptional changes detectable on a microarray. That doesn't seem to support a global repressor role for the MECP2 protein. There had to be something wrong," says Li. "Now we have a much better understanding of the function of MECP2, and the severity of the disease on a cellular level. Knowing that human Rett neurons are impaired in both global transcription and translation is important for us to design therapeutic strategies for Rett. Growth factors such as BDNF and IGF-1 are known to activate the AKT/mTOR pathway and increase protein synthesis. Down the road, we are interested in further exploring the Akt/mTOR pathway, and investigate how activation of this pathway could reverse the disease."
###
This work is supported by the Simons Center for the Social Brain, Brain and Behavior Research Foundation, International Rett Syndrome Foundation, Croucher Foundation, Swedish Research Council (VR-B0086301), National Institutes of Health (NIH grants R01-HG002668, P30-CA14051, HD 045022, R37-CA084198), Koch Institute, Curt Marble Cancer Research Fund, Simons Foundation Autism Research Initiative, and Ethel Louise Armstrong Foundation.
Rudolf Jaenisch's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.
Full Citation:
"Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons"
Cell Stem Cell, October 3, 2013
Yun Li (1), Haoyi Wang (1), Julien Muffat (1), Albert W. Cheng (1,2), David A. Orlando (1), Jakob Lovén (1), Show-ming Kwok (3), Danielle A. Feldman (3), Helen S. Bateup (4), Qing Gao (1), Dirk Hockemeyer (1), Maisam Mitalipova (1), Caroline A. Lewis (5), Matthew G. Vander Heiden (5), Mriganka Sur (3), Richard A. Young (1,6), and Rudolf Jaenisch (1,6).
The Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Department of Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
The Picower Institute for learning and memory, Massachusetts Institute of Technology, Cambridge, Cambridge MA 02139, USA
Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
END
COLUMBUS, Ohio – A tiny but unexpected change to a segment of RNA in a single-cell organism looks a lot like a mistake, but is instead a change to the genetic information that is essential to the organism's survival.
Scientists have discovered this RNA "edit" in Trypanosoma brucei, a parasite that causes sleeping sickness in Africa and Chagas disease in Latin America. Though the organism is a model system for this work, the finding could lead to a new drug target to fight the parasite if higher species don't share this genetic behavior.
Some of the organism's genetic ...
NEW YORK (October 3, 2013) -- Using powerful genetic sequencing technology, a team of investigators, led by researchers at the Icahn School of Medicine at Mount Sinai, scanned the genome of hundreds of individuals, and discovered those diagnosed with autism spectrum disorder (ASD) were more likely to have gene deletions than were people without the disorder. That means those individuals -- seven percent of the study group -- had one copy of one or more genes when they should have had two.
The scientists further report, in the American Journal of Human Genetics, that ...
Often deadly "triple-negative" breast cancers might be effectively treated in many cases with a drug that targets a previously unknown vulnerability in the tumors, according to a UC San Francisco researcher who described her discovery in a study published online October 3, 2013 in the journal Cancer Cell.
UCSF researcher Luika Timmerman, PhD, an investigator in the UCSF Helen Diller Family Comprehensive Cancer Center, found that many cell lines obtained from triple-negative breast cancer are especially dependent on cystine, one of the 20 amino acids that are the building ...
JUPITER, FL, October 3, 2013 – Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified a new drug candidate for an inherited form of cancer with no known cure.
The new study showed the drug candidate—known as FRAX97—slowed the proliferation and progression of tumor cells in animal models of Neurofibromatosis type 2. This inherited type of cancer, caused by mutations in the anti-tumor gene NF2, leads to tumors of the auditory nerve that connects the inner ear to the brain.
The new compound, originally developed to treat neurodegenerative ...
Portland, Ore., USA (October 3, 2013) --- Lactating cats not only increase their total calorie consumption, they also significantly alter the make-up of their diet to meet the demands of feeding a litter, research from the WALTHAM® Centre for Pet Nutrition has shown. The research provides intriguing insights into cats' feeding behaviour and strong evidence that they are able to adapt their macronutrient intake, i.e. their intake of protein, fat and carbohydrate, to meet their physiological requirements.
"It's no surprise that, just like humans, cats require more energy ...
A new picture of how the nervous system interacts with the immune system to cause the itch and inflammation associated with eczema, a chronic skin disease, could lead to new therapies for the condition, according to University of California, Berkeley, scientists.
Some 10 percent of the population suffers from eczema, or atopic dermatitis, at some point in their lives, but there are no cures or even good treatments for it. Symptoms range from dry, flaky and itchy skin to flaming red rashes, and in severe cases, particularly in children, the disease often progresses to ...
When developing new drugs, monitoring cellular responses to candidate compounds is essential for assessing their efficacy and safety. Researchers from the RIKEN Center for Life Science Technologies report a new method to monitor and quantify the activity of gene promoters during the response to a drug, using the advanced gene expression analysis method CAGE followed by single-molecule sequencing. This research paves the way to a more precise analysis of cellular responses to drugs, at the level of individual promoters.
The study is published this week in the journal ...
Every day we recognize friends, family, and co-workers from afar -- even before we can distinctly see a face. New research reveals that when facial features are difficult to make out, we readily use information about someone's body to identify them -- even when we don't know we're doing so.
"Psychologists and computer scientists have concentrated almost exclusively on the role of the face in person recognition," explains lead researcher, Allyson Rice of the University of Texas at Dallas. "But our results show that the body can also provide important and useful identity ...
A study concerning the evolution of mitochondrial DNA, performed by researchers from the Universitat Autònoma de Barcelona (UAB), has allowed to determine the frequency and pattern of heteroplasmy in the complete mitochondrial genome using a representative sample of the European population. This phenomenon, which indicates the presence of different mitochondrial DNA types in a cell or an individual, can be found in more than half of the population. The data obtained indicates that many of the newly arising mutations found never reach fixation at the population level due ...
Researchers from University of Copenhagen have discovered big differences in the variability of eating habits among pigs. The newly published study showed that for some (pigs with certain genetic variants) overeating was normal behavior and for a particular group of pigs there was clear evidence they were genetically programmed to eat more food than others. The study was led by professor Haja Kadarmideen and is the first study in the world looking at pig to human comparative genetic mapping to reveal key genes on the human genome that are known to be involved in human obesity. ...
