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Researchers Scrutinize Critical Rett Mutation

Thu, 07/11/2013 - 3:17pm
Harvard Medical School

Active neuron. (Source: Harvard Medical School)

Rett syndrome is all about loss. Like autism, this disorder of neurological development steals abilities from children. It strikes around their first birthdays, just as they are learning to walk and talk.

Unlike autism, whose cause remains a mystery, Rett syndrome has been definitively traced to mutations in a single gene. An X chromosome-linked disorder, it affects girls almost exclusively, causing regression in language acquisition and motor control as well as seizures and respiratory problems.

Identifying the faulty gene is only the first step on the road toward a better understanding of what goes wrong to cause Rett syndrome and what might correct it. HMS researchers working closely with collaborators from Edinburgh and Oregon are gaining deeper understanding of the specific molecular pathways behind the cluster of genetic mutations—any one of which can derail normal development by varying degrees.

Led by Michael Greenberg, the Nathan Marsh Pusey Professor of Neurobiology and head of the HMS Department of Neurobiology, the scientists express cautious hope that their work might one day pave the way for therapies to help Rett patients regain what they have lost.

“By getting into the detailed mechanisms, one might eventually come up with ways to essentially reverse the defect,” says Greenberg, senior author of a paper appearing in Nature and co-author of another published at the same time in Nature Neuroscience. Both papers focus on MECP2, a gene whose mutated form is associated with Rett.

At a crucial point in brain development, when girls are 6 to 18 months old, MECP2  normally functions to modify synapses that young brains are creating in response to sensory experiences that send signals to make neural connections. When MECP2 is absent, so is the necessary balance between synapses that increase activity and those that dampen it, a problem some suspect may also play a role in psychiatric diseases.

“MECP2 is in the nucleus of the cells of our brains in our first year of life. It’s sitting there waiting for a signal,” Greenberg says. “If MECP2 is there and can function normally, a sensory signal comes to MECP2, changes the DNA, turns on genes and engages in this process of synaptic development and maturation. If MECP2 is mutated in such a way that the complex that’s going to receive the signal can’t get it, it’s almost as if the brain is frozen in time. It can’t process the signal.”

Mutations to the gene MECP2 do different things, depending on which amino acid change is at fault: Either the protein isn’t made at all or the mutation occurs in a critical domain of the protein that is essential for its proper function.

Daniel Ebert, a postdoctoral fellow in the Greenberg lab, focused on chemical modifications to MECP2 that affect the gene’s most basic functions. Through a technique called phosphotryptic mapping, he discovered three new sites on MECP2 where neuronal activity induces chemical changes.

One of the sites on MECP2 is where the amino acid threonine 308 (T308) sits. When T308 is mutated, the chemical change that sensory experiences are supposed to produce doesn’t happen. This loss also disrupts how MECP2 interacts with a crucial protein complex called nuclear receptor co-repressor (NCoR). Together, MECP2 and NCoR are believed to refine neurodevelopment by repressing genes and regulating the number of synapses being built.

Mice engineered to have a mutation in T308 show Rett syndrome characteristics, suggesting a crucial role for chemical modifications to MECP2 caused by sensory experiences.

Scientists Matthew Lyst and Adrian Bird at the University of Edinburgh studied the domain where MECP2 binds to NCoR, a region of MeCP2 that controls gene expression involved in synaptic function. They showed how MECP2 mutations disrupt these interactions.

“Together the two papers provide a new, basic understanding of the mechanisms of MECP2 action and what may go wrong in Rett syndrome,” Greenberg says. “Instead of having to look at the whole MECP2 molecule, we now have a particular domain to focus on. We have a new protein complex, NCoR, to study, and we now need to figure out how these proteins work together to control synapse function. These findings are exciting because they open up a lot of new research directions.”

Greenberg and Bird have been collaborating with Gail Mandel of the Oregon Health and Science University as members of the MECP2 Consortium, launched in 2011 by Monica Coenraads of the Rett Syndrome Research Trust. Mandel is pursuing potential gene therapies based on MECP2.

Bird discovered MECP2 in 1992 and 15 years later made a startling discovery in mice that raised hopes for reversing Rett’s defects. Mice whose MECP2 genes were silenced went on to develop Rett-like disease, but once those genes were turned back on, they recovered their abilities. Rather than losing function forever, the mice returned to normal.

“Understanding the different ways in which MECP2 is mutated and how the mutations affect function is really going to be important for developing therapeutics,” Greenberg says.

The work reported in Nature was supported by National Institutes of Health grants, by the Rett Syndrome Research Trust, the Dupont–Warren Fellowship in the Department of Psychiatry at Harvard Medical School, the Nancy Lurie Marks Fellowship in Autism at Harvard Medical School, and a Damon Runyon Cancer Research Foundation Grant. The Mouse Gene Manipulation Facility of the Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center was supported by grant NIHP30-HD 18655.

The work reported in Nature Neuroscience was supported by grants from the Rett Syndrome Research Trust, the Wellcome Trust and NIH grants.

 

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